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Chronic Lymphocytic Leukemia Treatment (PDQ®)–Health Professional Version

Chronic Lymphocytic Leukemia Treatment (PDQ®)–Health Professional Version

General Information About Chronic Lymphocytic Leukemia

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Incidence and Mortality

Estimated new cases and deaths from chronic lymphocytic leukemia (CLL) in the United States in 2025:[1]

  • New cases: 23,690.
  • Deaths: 4,460.

Anatomy

CLL is a disorder of morphologically mature, but immunologically less mature lymphocytes. It is manifested by progressive accumulation of these cells in the blood, bone marrow, and lymphatic tissues.[2]

EnlargeBlood cell development; drawing shows the steps a blood stem cell goes through to become a red blood cell, platelet, or white blood cell. A myeloid stem cell becomes a red blood cell, a platelet, or a myeloblast, which then becomes a granulocyte (the types of granulocytes are eosinophils, basophils, and neutrophils). A lymphoid stem cell becomes a lymphoblast and then becomes a B-lymphocyte, T-lymphocyte, or natural killer cell.
Blood cell development. A blood stem cell goes through several steps to become a red blood cell, platelet, or white blood cell.

Clinical Presentation

The clinical course of this disease progresses from an indolent lymphocytosis without other evident disease to one of generalized lymphatic enlargement with concomitant pancytopenia. Complications of pancytopenia, including hemorrhage and infection, represent a major cause of death in these patients.[3] Immunological aberrations, including Coombs-positive hemolytic anemia, immune thrombocytopenia, and depressed immunoglobulin levels, may all complicate the management of CLL.[4]

Diagnostic Evaluation and Differential Diagnosis

Tests and procedures used to diagnose CLL include the following:[5]

  • History and physical examination (including bidimensional diameters of the largest palpable lymph nodes in the cervical, axillary, and inguinal nodal sites and dimensions of the liver and spleen below their respective costal margins as assessed by palpation).
  • Complete blood count with differential and chemistry panel (including creatinine, bilirubin, transaminases, and alkaline phosphatase). Other blood tests may include lactate dehydrogenase and beta-2-microglobulin. With suspicion of autoimmune hemolytic anemia, testing for reticulocyte count, indirect bilirubin, serum haptoglobin, antiglobulin (direct Coombs), and cold agglutinin may be helpful.
  • Flow cytometry (for immunophenotyping).
  • Fluorescence in situ hybridization (FISH) (for del(11q), del(13q), del(17p), trisomy 12, and t(11;14)).
  • TP53 variant analysis.
  • IGH variant analysis.
  • Serum immunoglobulin levels.
  • Hepatitis B and C and HIV tests.
  • Computed tomography (CT) is usually not required in the absence of peripheral adenopathy; extensive adenopathy on examination should prompt investigation of retroperitoneal adenopathy.
  • Bone marrow aspiration and biopsy is usually not required.

In this disorder, lymphocyte counts in the blood are usually greater than or equal to 5,000/mm3 with a characteristic immunophenotype (CD5- and CD23-positive B cells).[6,7] As assays have become more sensitive for detecting monoclonal B-CLL–like cells in peripheral blood, researchers have detected a monoclonal B-cell lymphocytosis in 3% of adults older than 40 years and in 6% of adults older than 60 years.[8] Such early detection and diagnosis may falsely suggest improved survival for the group and may unnecessarily worry or result in therapy for some patients who would have remained undiagnosed in their lifetime, a circumstance known as overdiagnosis or pseudodisease.[9,10]

Confusion with other diseases may be avoided by determination of cell surface markers. CLL lymphocytes coexpress the B-cell antigens CD19 and CD20 along with the T-cell antigen CD5.[11] This coexpression occurs in only one other disease entity, mantle cell lymphoma. CLL B cells express relatively low levels of surface-membrane immunoglobulin (compared with normal peripheral blood B cells) and a single light chain (kappa or lambda).[12] CLL is diagnosed by an absolute increase in lymphocytosis and/or bone marrow infiltration coupled with the characteristic features of morphology and immunophenotype, which confirm the characteristic clonal population. In a database analysis, for up to 77 months before diagnosis, almost all patients with a CLL diagnosis had prediagnostic B-cell clones that were identified in peripheral blood (when available).[7,13]

About 1% of morphological CLL cases express T-cell markers (CD4 and CD7) and have clonal rearrangements of their T-cell receptor genes. These patients have a higher frequency of skin lesions, more variable lymphocyte shape, and shorter median survival (13 months) with minimal responses to chemotherapy and B-cell receptor inhibitors.[14]

The differential diagnosis must exclude the following:

  • Monoclonal B-cell lymphocytosis (MBL). MBL, the precursor to CLL, is defined as a clonal B-cell population circulating in peripheral blood with fewer than 5 × 109/L B cells and no signs of lymphadenopathy or splenomegaly.[15] Most cases have the immunophenotype of CLL. The incidence of MBL in the general population is 5% to 12% and increases with age.[16] In families with two or more cases of CLL, MBL has a prevalence of 13% to 18%. Low-count MBL (≤0.5 × 109/L B cells) rarely progresses to overt CLL, but higher levels can progress to symptomatic CLL at a rate of less than 2% per year, even for familial cases.[15,17] In two selected series of more than 900 patients monitored prospectively for a median of 5 to 7 years, overt CLL requiring chemotherapy occurred in 7% of patients.[8,18] A screening study using the Mayo Clinic Biobank identified 1,712 patients with MBL from 10,139 screened samples.[19] Low-count MBL was found in 95% of these patients. With a median follow-up of 10.0 years, only 0.58% of patients progressed to a lymphoid malignancy.[19]
  • Hairy cell leukemia. For more information, see Hairy Cell Leukemia Treatment.
  • Waldenström macroglobulinemia. Waldenström macroglobulinemia has a natural history and therapeutic options similar to CLL, with the exception of hyperviscosity syndrome associated with macroglobulinemia as a result of elevated immunoglobulin M. For more information, see Indolent B-Cell Non-Hodgkin Lymphoma Treatment.
  • Large granular lymphocyte (LGL) leukemia. LGL leukemia is characterized by lymphocytosis with a natural killer (NK) cell immunophenotype (CD2, CD16, and CD56) or a T-cell immunophenotype (CD2, CD3, and CD8).[20–22] These patients often have neutropenia and a history of rheumatoid arthritis. The natural history is indolent, often marked by anemia and splenomegaly. This condition appears to fit into the clinical spectrum of Felty syndrome.[23] A characteristic genetic finding in almost 50% of the patients with T-cell LGL involves pathogenic variants in the STAT3 gene.[24] Symptomatic patients with cytopenias typically manifest CD8-positive T cells with alpha/beta surface receptors plus a STAT3 variant, CD8-positive T cells with T gamma/delta surface receptors, or a mutated NK/T-cell phenotype.[25,26] Conversely, asymptomatic patients have wild-type STAT3 CD8-positive T cells, CD4-positive T cells, and wild-type NK cells.[25] Therapy includes low doses of oral cyclophosphamide or methotrexate, cyclosporine, and treatment of the bacterial infections acquired during severe neutropenia.[20,22,27,28]

For information on prolymphocytic leukemia, which was previously covered in this summary, see the Treatment of T-Cell Prolymphocytic Leukemia section in Peripheral T-Cell Non-Hodgkin Lymphoma Treatment.

Prognostic Factors

Prognostic markers help stratify patients in clinical trials, assess the need for therapy, and select the type of therapy.[2,29,30] Prognostic factors that may help predict clinical outcome include cytogenetic subgroup, immunoglobulin mutational status, and CD38 immunophenotype.[2,31–39]

Prognostic markers include the following:

  • IGH pathogenic variant.[32–34,39,40] The finding of significant numbers of variants in this region is associated with a median survival in excess of 20 to 25 years. The absence of variants is associated with a median survival of 8 to 10 years.
  • FISH test results. FISH chromosomal abnormalities were associated with prognosis in retrospective and prospective studies, and clonal evolution has been seen over time.[31,41–43] The following chromosomal abnormalities have been reported:
    • del(13q) is a favorable prognostic marker (median overall survival [OS], 17 years in one prospective study).[43]
    • Trisomy 12 and del(11) have a less favorable prognosis (median OS, 9–11 years in one prospective study).[43]
    • del(17p) is associated with TP53 pathogenic variants, poor response rates, and short duration of response to the standard therapeutic options.[39] del(17p) is associated with the most unfavorable prognosis (median OS, 7 years in one prospective trial).[43–45]
    • The combination of abnormal cytogenetics, such as del(11q) or del(17p) deletion (suggesting a worse prognosis), with zeta-chain-associated protein 70 kDa negativity (suggesting a better prognosis) in the same patients resulted in a poor prognosis.[38]

    These findings emphasize the need for prospective studies of combinations of these prognostic markers.[46]

Other prognostic factors include the following:

  • Anemia and thrombocytopenia. These are important adverse prognostic variables, but only if due to extensive marrow involvement by CLL. Autoimmune hemolytic anemia and immune thrombocytopenic purpura do not confer a worse prognosis.
  • Age. CLL occurs primarily in middle-aged and older adults, with worse prognosis in successive decades of life.[42]
  • Stage.[47,48] For more information, see the sections on the Rai Staging System and the Binet Classification.
  • Positron emission tomography (PET)-CT scan results. This test should only be used in the context of recurrent fever, soaking night sweats, weight loss (>10% baseline weight in 6 months), or rapidly growing lymph nodes, because these findings might herald histological transformation to a diffuse large B-cell lymphoma (DLBCL) (so-called Richter transformation). Of 432 patients retrospectively reviewed, 209 patients had a maximum standardized uptake value (SUVmax) of 5 or higher.[49] Eighty percent of these patients had histologically aggressive CLL or Richter syndrome, and both of these entities had equally worse prognoses. When the SUVmax was 10 or higher, the 5-year OS rate was only 30%.[49]
  • Lymphocyte doubling time. Doubling of the white blood cell count in less than 1 year implies a worse prognosis.[50]
  • Beta-2-microglobulin. Higher levels imply a worse prognosis.[51]
  • Richter transformation. In 2% to 10% of patients, CLL will transform into a more aggressive lymphoma, termed Richter transformation.[52] This is usually a DLBCL of the more aggressive activated B-cell subtype. The prognosis is similar to de novo presentations of DLBCL when the CLL has never required therapy or when there is no clonal connection between the CLL and DLBCL (identified if they harbor different clonal light chains or if sequencing can be accomplished at the VDJ [variable, diversity, joining] recombination sites in the immunoglobulin heavy chain variable region).[52] However, the prognosis is poor (median survival, 6–14 months) for most patients with Richter transformation to DLBCL when there has been prior therapy for CLL with chemoimmunotherapy,[53], Bruton tyrosine kinase (BTK) inhibitors, and/or venetoclax.[54] There is no standard therapeutic approach for patients with poor prognoses. Therapies under clinical evaluation include chimeric antigen receptor (CAR) T-cell therapy, T-cell engaging bispecific antibodies, and non-covalent BTK inhibitors.[52,55] Allogeneic stem cell transplant consolidation is often recommended if induction therapy achieves a response.[52] In rare cases of Richter transformation from CLL to Hodgkin lymphoma, the prognosis appears the same for age-matched patients with de novo disease.[56,57]
  • Clearance of measurable residual disease (MRD). The improvements in response rates from more intensive regimens have maximized the clearance of MRD. In one prospective trial of 493 patients, clearance of MRD was an independent predictor of OS by multivariate analysis.[58] The surrogate end point of clearance of residual disease, while prognostic,[58,59] did not show improved survival in a randomized prospective trial. The necessary study would include patients who fail to completely clear the marrow with induction therapy and randomly assign them to further alternative treatment versus the same treatment later at relapse, looking at OS as the primary end point.[29,60]
  • CD38 immunophenotype.[33,61] CD38 positivity (>30%) correlates with a worse prognosis, but there is a 30% false-positive rate and a 50% false-negative rate using IGH mutational status as the gold standard for prognosis.
  • Other malignancies. Patients with CLL are also at increased risk of developing other malignancies, even before therapy.[62] A population-based analysis of almost 2 million cancer patients in the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) Program database was performed. The findings suggested that cancer-specific survival for patients with preexisting CLL who subsequently developed colorectal and breast cancer was significantly lower (hazard ratio [HR], 1.46; P < .001 for colorectal cancer and HR, 1.41; P = .005 for breast cancer) than cancer-specific survival for patients with colorectal and breast cancer who did not have antecedent CLL, after adjusting for age, sex, race, and disease stage, and excluding CLL-related deaths.[63]

An international prognostic index for CLL (CLL-IPI) identified four prognostic subgroups based on IGH mutational status, clinical stage, age (≤65 years vs. >65 years), and TP53 status (no abnormalities vs. del(17p), TP53 variant, or both).[64] A scoring system to predict time to first treatment for early-stage CLL identified three adverse risk factors: unmutated IGH, absolute lymphocyte count higher than 15 × 109/L, and palpable lymph nodes.[65] Any new prognostic model, and even the commonly used CLL-IPI, may be outdated because of the use of highly effective frontline therapies, including BCL2 inhibitors and BTK inhibitors.[66] Revalidation of these prognostic models will be required.

Follow-Up After Treatment

CT scans have a very limited role in monitoring patients after completion of treatment. CT scan or ultrasonography results determined the decision to treat for relapse in only 2 of 176 patients in three prospective trials for the German CLL Study Group.[67]

References
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Stage Information for Chronic Lymphocytic Leukemia

Chronic lymphocytic leukemia (CLL) does not have a standard staging system. The Rai staging system (Table 1) and the Binet classification (Table 2) are presented below.[1,2] A National Cancer Institute (NCI)-sponsored working group has formulated standardized guidelines for criteria related to eligibility, response, and toxic effects to be used in future clinical trials in CLL.[3]

Rai Staging System

Table 1. Rai Staging System
Stage Stage Criteria
Stage 0 Absolute lymphocytosis (>15,000/mm3) without adenopathy, hepatosplenomegaly, anemia, or thrombocytopenia.
Stage I Absolute lymphocytosis with lymphadenopathy without hepatosplenomegaly, anemia, or thrombocytopenia.
Stage II Absolute lymphocytosis with either hepatomegaly or splenomegaly with or without lymphadenopathy.
Stage III Absolute lymphocytosis and anemia (hemoglobin <11 g/dL) with or without lymphadenopathy, hepatomegaly, or splenomegaly.
Stage IV Absolute lymphocytosis and thrombocytopenia (<100,000/mm3) with or without lymphadenopathy, hepatomegaly, splenomegaly, or anemia.

Binet Classification

Table 2. Binet Classification System
Stage Stage Criteria
aLymphoid areas include cervical, axillary, inguinal, and splenic.
Clinical stage Aa No anemia or thrombocytopenia and fewer than three areas of lymphoid involvement (Rai stages 0, I, and II).
Clinical stage Ba No anemia or thrombocytopenia with three or more areas of lymphoid involvement (Rai stages I and II).
Clinical stage C Anemia and/or thrombocytopenia regardless of the number of areas of lymphoid enlargement (Rai stages III and IV).

The Binet classification integrates the number of disease-involved nodal groups with bone marrow failure. Its major benefit derives from the recognition of a predominantly splenic form of the disease, which may have a better prognosis than was recognized in the Rai staging, and from the recognition that the presence of anemia or thrombocytopenia has a similar prognosis and does not merit a separate stage. Neither system separates immune from nonimmune causes of cytopenia. Patients with thrombocytopenia, anemia, or both, which is caused by extensive marrow infiltration and impaired production (Rai III/IV, Binet C), have a poorer prognosis than patients with immune cytopenias.[4]

The International Workshop on CLL has recommended integrating the Rai and Binet systems as follows: A(0), A(I), A(II); B(I), B(II); and C(III), C(IV).[5] The NCI-sponsored working group has published guidelines for the diagnosis and treatment of CLL in both clinical trial and general practice settings.[3] Use of these systems allows comparison of clinical results and establishment of therapeutic guidelines.

References
  1. Rai KR, Sawitsky A, Cronkite EP, et al.: Clinical staging of chronic lymphocytic leukemia. Blood 46 (2): 219-34, 1975. [PUBMED Abstract]
  2. Binet JL, Auquier A, Dighiero G, et al.: A new prognostic classification of chronic lymphocytic leukemia derived from a multivariate survival analysis. Cancer 48 (1): 198-206, 1981. [PUBMED Abstract]
  3. Hallek M, Cheson BD, Catovsky D, et al.: Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia: a report from the International Workshop on Chronic Lymphocytic Leukemia updating the National Cancer Institute-Working Group 1996 guidelines. Blood 111 (12): 5446-56, 2008. [PUBMED Abstract]
  4. Moreno C, Hodgson K, Ferrer G, et al.: Autoimmune cytopenia in chronic lymphocytic leukemia: prevalence, clinical associations, and prognostic significance. Blood 116 (23): 4771-6, 2010. [PUBMED Abstract]
  5. Chronic lymphocytic leukemia: recommendations for diagnosis, staging, and response criteria. International Workshop on Chronic Lymphocytic Leukemia. Ann Intern Med 110 (3): 236-8, 1989. [PUBMED Abstract]

Selection of Therapy for Chronic Lymphocytic Leukemia

Treatment of patients with chronic lymphocytic leukemia (CLL) must be individualized based on the clinical behavior of the disease.[1] Because this disease is generally not curable, occurs in an older population, and often progresses slowly, it is most often treated in a conservative fashion.[2]

In older trials with data collected from the 1970s through the 1990s, the median survival for all patients ranged from 8 to 12 years.[3,4] However, with the introduction of the B-cell receptor inhibitors and targeting of BCL2, the median survival for all patients has not been reached with over 10 years of follow-up.

Treatment of patients with CLL ranges from observation with treatment of infectious, hemorrhagic, or immunological complications to a variety of therapeutic options administered as single agents or combination therapy. In asymptomatic patients, treatment may be deferred until the disease progresses and symptoms occur.[3] Because the rate of progression may vary from patient to patient, with long periods of stability and sometimes spontaneous regressions, frequent and careful observation is required to monitor the clinical course.[5] Although even asymptomatic patients with del(17p) on fluorescence in situ hybridization (FISH) analysis (or those with a TP53 pathogenic variant) may be followed with watchful waiting, frequent monitoring may be required to avert rapid progression. A meta-analysis of randomized trials showed no survival benefit for immediate versus delayed therapy for patients with early-stage disease.[6][Level of evidence A1] For patients with progressing CLL, treatment will not be curative in most cases. Selected patients treated with allogeneic stem cell transplant have achieved prolonged disease-free survival (DFS), sometimes exceeding 20 years.[7–11] Prolonged DFS was also noted in young patients (<60 years) with IGH hypermutation who received the FCR regimen (fludarabine, cyclophosphamide, and rituximab).[12–14]

The following clinical factors may be helpful in predicting progression of disease:[2]

  • IGH pathogenic variant.
  • Chromosomal abnormalities found by FISH or cytogenetic analysis.
  • Beta-2-microglobulin.
  • Lymphocyte doubling time.

The International Workshop on Chronic Lymphocytic Leukemia defines symptomatic or progressive CLL as having the following signs and symptoms:[15]

  • Evidence of progressive marrow failure—the development or worsening of anemia and/or thrombocytopenia (in some patients, platelet counts <100 × 109/L may remain stable over a long period; this does not automatically require therapeutic intervention). Cutoff levels of hemoglobin less than 10 g/dL or platelet counts less than 50 × 109/L are generally regarded as an indication for treatment.
  • Massive (i.e., ≥6 cm below the left costal margin), progressive, or symptomatic splenomegaly.
  • Massive lymph nodes (i.e., ≥10 cm in longest diameter), progressive, or symptomatic lymphadenopathy.
  • Progressive lymphocytosis with an increase of 50% or more over a 2-month period, or lymphocyte-doubling time (LDT) less than 6 months. LDT can be obtained by linear regression extrapolation of absolute lymphocyte counts obtained at intervals of 2 weeks over an observation period of 2 to 3 months; patients with initial blood lymphocyte counts less than 30 × 109/L may require a longer observation period to determine the LDT. Factors contributing to lymphocytosis other than CLL (e.g., infections or steroid administration) should be excluded.
  • Autoimmune complications, including anemia or thrombocytopenia that respond poorly to corticosteroids.
  • Symptomatic or functional extranodal involvement (e.g., skin, kidney, lung, or spine). Disease-related symptoms defined as any of the following:
    • Unintentional weight loss of 10% or more within the previous 6 months.
    • Significant fatigue (i.e., Eastern Cooperative Oncology Group performance scale 2 or worse, cannot work, or unable to perform usual activities).
    • Fevers of 100.5°F or 38.0°C or higher for 2 or more weeks without evidence of infection.
    • Night sweats for at least 1 month without evidence of infection.

Considerations for the Selection of Therapy

The following general principles may provide a sequencing for available therapeutic options:

  • Despite many therapeutic options, asymptomatic or minimally affected patients with CLL are often offered observation outside the context of a clinical trial. Therapy often begins when patients develop profound cytopenias, or when symptoms, such as enlarging bulky lymphadenopathy or debilitating symptoms, substantially impact their quality of life.
  • Because nontransplant curative therapy has not been found, the initial goal of therapy is to maximize efficacy (with improvement of overall survival), while introducing the least overall short- and long-term toxicity.
  • The U.S. Food and Drug Administration approved the biological agents ibrutinib, acalabrutinib, and venetoclax for first-line use in newly diagnosed patients with CLL who require therapy.[16] In patients with poor prognostic factors (especially those with del(17p) or TP53 pathogenic variants), ibrutinib, acalabrutinib, or venetoclax should be considered.[17]
  • Standard chemotherapeutic agents, such as fludarabine, bendamustine, cyclophosphamide, and chlorambucil, induce DNA damage that can manifest as more aggressive and refractory phenotypes upon relapse and can induce secondary malignancies. Yet, prolonged DFS (over 10 years) can be seen with the use of the FCR regimen in younger patients (<60 years) with IGH hypermutation.[12–14]
    • Avoiding alkylating agents and purine analogues also prevents prolonged cytopenias and the recurrent, long-lasting, and sometimes fatal infections seen after therapy with these agents.
    • Avoiding chemotherapeutic agents up-front, when possible, is a new paradigm of sequencing therapy for CLL.
  • Older patients with comorbidities may better tolerate the newer biological agents (such as ibrutinib or venetoclax), monoclonal antibody therapy alone (such as high-dose rituximab), or dose modification of standard chemotherapeutic agents combined with rituximab. For older patients (>65 years), the combination of rituximab plus bendamustine (BR regimen) resulted in fewer adverse events and better outcomes than the FCR regimen.[18]

Adverse Sequelae of the Disease and Therapy

Infectious complications in advanced disease are in part a consequence of the hypogammaglobulinemia and the inability to mount a humoral defense against bacterial or viral agents. Herpes zoster represents a frequent viral infection in these patients, but infections with Pneumocystis carinii and Candida albicans may also occur. The early recognition of infections and the institution of appropriate therapy are critical to the long-term survival of these patients. A randomized study of intravenous immunoglobulin (400 mg/kg every 3 weeks for 1 year) in patients with CLL and hypogammaglobulinemia produced significantly fewer bacterial infections and a significant delay in onset of first infection during the study period.[19] There was, however, no effect on survival. Routine chronic administration of intravenous immunoglobulin is expensive, and the long-term benefit (>1 year) is unproven.[20,21]

Patients with CLL who required hospitalization for COVID-19 prior to the induction of vaccines fared poorly regardless of stage in two retrospective reports.[22,23] One of the studies noted a protective effect from Bruton tyrosine kinase (BTK) inhibitors (usually ibrutinib),[23] but this was not seen in the other report.[22] With enhanced testing and the advent of multiple therapeutic strategies to prevent and treat COVID-19, the case fatality rate for patients with CLL dropped from 35% in early 2020 to 11% in late 2020 and early 2021 (P < .001).[22] For patients requiring hospitalization, the case fatality rate dropped from 40% to 20% (P = .003).

Autoimmune hemolytic anemia and/or thrombocytopenia can occur in patients with any stage of CLL.[24] Initial therapy involves corticosteroids with or without alkylating agents (fludarabine can worsen the hemolytic anemia). It is often necessary to control the autoimmune destruction with corticosteroids, if possible, before administering marrow-suppressive chemotherapy because it may be difficult for a patient to successfully receive a red blood cell or platelet transfusion. Alternate therapies include high-dose immune globulin, rituximab, cyclosporine, azathioprine, splenectomy, and low-dose radiation therapy to the spleen.[3,25] Tumor lysis syndrome is an uncommon complication (presenting in 1 of 300 patients) of chemotherapy for patients with bulky disease.[26]

Second malignancies and treatment-induced acute leukemias may also occur in a small percentage of patients.[27] Transformation of CLL to diffuse large B-cell lymphoma (DLBCL, known as Richter syndrome) occurs in 2% to 10% of patients. Risk factors for transformation include unmutated IGH, TP53 or NOTCH1 pathogenic variants, CDKN2A/B loss, and a complex karyotype.[28] Up to 60% to 70% of patients develop a DLBCL clonally related to the CLL, and these patients have a significantly worse prognosis than patients with de novo DLBCL.[29–31] Patients with a clonally unrelated DLBCL have a much better prognosis, which is similar to de novo DLBCL.[29] However, there is limited availability for real-life sequencing of the immunoglobulin heavy chains in the original CLL sample to compare with the transformed sample. Characteristic molecular signatures may serve as an alternate way to assess prognosis.[32] Up to 20% to 40% of patients with clonally related Richter syndrome are disease free for more than 5 years after aggressive combination chemotherapy, typically R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) or Pola-R-CHP (polatuzumab, rituximab, cyclophosphamide, doxorubicin, and prednisone), often followed by autologous or allogeneic stem cell transplant.[33–35] For more information, see Aggressive B-Cell Non-Hodgkin Lymphoma Treatment. In two retrospective reports, CLL with transformation to Hodgkin lymphoma had the same prognosis as de novo presentations of Hodgkin lymphoma at an equivalent age.[36,37][Level of evidence C3]

The BTK inhibitors increased the risk of bleeding requiring hospitalization (3-year risk for patients who received ibrutinib, 8.8% [95% confidence interval (CI), 6.5%–11.7%]) and atrial fibrillation (3-year incidence for patients who received ibrutinib, 22.7% [95% CI, 19.0%–26.6%]).[38] A randomized trial with a median follow-up of 41 months showed less atrial fibrillation for patients with CLL who received acalabrutinib compared with ibrutinib (9.4% vs. 16%; P = .02).[39]

References
  1. Montserrat E: CLL therapy: progress at last! Blood 105 (1): 2-3, 2005.
  2. Gribben JG, O’Brien S: Update on therapy of chronic lymphocytic leukemia. J Clin Oncol 29 (5): 544-50, 2011. [PUBMED Abstract]
  3. Rozman C, Montserrat E: Chronic lymphocytic leukemia. N Engl J Med 333 (16): 1052-7, 1995. [PUBMED Abstract]
  4. Wierda WG, O’Brien S, Wang X, et al.: Prognostic nomogram and index for overall survival in previously untreated patients with chronic lymphocytic leukemia. Blood 109 (11): 4679-85, 2007. [PUBMED Abstract]
  5. Del Giudice I, Chiaretti S, Tavolaro S, et al.: Spontaneous regression of chronic lymphocytic leukemia: clinical and biologic features of 9 cases. Blood 114 (3): 638-46, 2009. [PUBMED Abstract]
  6. Chemotherapeutic options in chronic lymphocytic leukemia: a meta-analysis of the randomized trials. CLL Trialists’ Collaborative Group. J Natl Cancer Inst 91 (10): 861-8, 1999. [PUBMED Abstract]
  7. Ritgen M, Stilgenbauer S, von Neuhoff N, et al.: Graft-versus-leukemia activity may overcome therapeutic resistance of chronic lymphocytic leukemia with unmutated immunoglobulin variable heavy-chain gene status: implications of minimal residual disease measurement with quantitative PCR. Blood 104 (8): 2600-2, 2004. [PUBMED Abstract]
  8. Moreno C, Villamor N, Colomer D, et al.: Allogeneic stem-cell transplantation may overcome the adverse prognosis of unmutated VH gene in patients with chronic lymphocytic leukemia. J Clin Oncol 23 (15): 3433-8, 2005. [PUBMED Abstract]
  9. Khouri IF, Keating MJ, Saliba RM, et al.: Long-term follow-up of patients with CLL treated with allogeneic hematopoietic transplantation. Cytotherapy 4 (3): 217-21, 2002. [PUBMED Abstract]
  10. Doney KC, Chauncey T, Appelbaum FR, et al.: Allogeneic related donor hematopoietic stem cell transplantation for treatment of chronic lymphocytic leukemia. Bone Marrow Transplant 29 (10): 817-23, 2002. [PUBMED Abstract]
  11. Pavletic SZ, Khouri IF, Haagenson M, et al.: Unrelated donor marrow transplantation for B-cell chronic lymphocytic leukemia after using myeloablative conditioning: results from the Center for International Blood and Marrow Transplant research. J Clin Oncol 23 (24): 5788-94, 2005. [PUBMED Abstract]
  12. Thompson PA, Tam CS, O’Brien SM, et al.: Fludarabine, cyclophosphamide, and rituximab treatment achieves long-term disease-free survival in IGHV-mutated chronic lymphocytic leukemia. Blood 127 (3): 303-9, 2016. [PUBMED Abstract]
  13. Fischer K, Bahlo J, Fink AM, et al.: Long-term remissions after FCR chemoimmunotherapy in previously untreated patients with CLL: updated results of the CLL8 trial. Blood 127 (2): 208-15, 2016. [PUBMED Abstract]
  14. Rossi D, Terzi-di-Bergamo L, De Paoli L, et al.: Molecular prediction of durable remission after first-line fludarabine-cyclophosphamide-rituximab in chronic lymphocytic leukemia. Blood 126 (16): 1921-4, 2015. [PUBMED Abstract]
  15. Hallek M, Cheson BD, Catovsky D, et al.: iwCLL guidelines for diagnosis, indications for treatment, response assessment, and supportive management of CLL. Blood 131 (25): 2745-2760, 2018. [PUBMED Abstract]
  16. Burger JA, Tedeschi A, Barr PM, et al.: Ibrutinib as Initial Therapy for Patients with Chronic Lymphocytic Leukemia. N Engl J Med 373 (25): 2425-37, 2015. [PUBMED Abstract]
  17. Cramer P, Tausch E, von Tresckow J, et al.: Durable remissions following combined targeted therapy in patients with CLL harboring TP53 deletions and/or mutations. Blood 138 (19): 1805-1816, 2021. [PUBMED Abstract]
  18. Eichhorst B, Fink AM, Bahlo J, et al.: First-line chemoimmunotherapy with bendamustine and rituximab versus fludarabine, cyclophosphamide, and rituximab in patients with advanced chronic lymphocytic leukaemia (CLL10): an international, open-label, randomised, phase 3, non-inferiority trial. Lancet Oncol 17 (7): 928-942, 2016. [PUBMED Abstract]
  19. Intravenous immunoglobulin for the prevention of infection in chronic lymphocytic leukemia. A randomized, controlled clinical trial. Cooperative Group for the Study of Immunoglobulin in Chronic Lymphocytic Leukemia. N Engl J Med 319 (14): 902-7, 1988. [PUBMED Abstract]
  20. Griffiths H, Brennan V, Lea J, et al.: Crossover study of immunoglobulin replacement therapy in patients with low-grade B-cell tumors. Blood 73 (2): 366-8, 1989. [PUBMED Abstract]
  21. Weeks JC, Tierney MR, Weinstein MC: Cost effectiveness of prophylactic intravenous immune globulin in chronic lymphocytic leukemia. N Engl J Med 325 (2): 81-6, 1991. [PUBMED Abstract]
  22. Mato AR, Roeker LE, Lamanna N, et al.: Outcomes of COVID-19 in patients with CLL: a multicenter international experience. Blood 136 (10): 1134-1143, 2020. [PUBMED Abstract]
  23. Scarfò L, Chatzikonstantinou T, Rigolin GM, et al.: COVID-19 severity and mortality in patients with chronic lymphocytic leukemia: a joint study by ERIC, the European Research Initiative on CLL, and CLL Campus. Leukemia 34 (9): 2354-2363, 2020. [PUBMED Abstract]
  24. Mauro FR, Foa R, Cerretti R, et al.: Autoimmune hemolytic anemia in chronic lymphocytic leukemia: clinical, therapeutic, and prognostic features. Blood 95 (9): 2786-92, 2000. [PUBMED Abstract]
  25. Kaufman M, Limaye SA, Driscoll N, et al.: A combination of rituximab, cyclophosphamide and dexamethasone effectively treats immune cytopenias of chronic lymphocytic leukemia. Leuk Lymphoma 50 (6): 892-9, 2009. [PUBMED Abstract]
  26. Cheson BD, Frame JN, Vena D, et al.: Tumor lysis syndrome: an uncommon complication of fludarabine therapy of chronic lymphocytic leukemia. J Clin Oncol 16 (7): 2313-20, 1998. [PUBMED Abstract]
  27. Maddocks-Christianson K, Slager SL, Zent CS, et al.: Risk factors for development of a second lymphoid malignancy in patients with chronic lymphocytic leukaemia. Br J Haematol 139 (3): 398-404, 2007. [PUBMED Abstract]
  28. Visentin A, Bonaldi L, Rigolin GM, et al.: The complex karyotype landscape in chronic lymphocytic leukemia allows the refinement of the risk of Richter syndrome transformation. Haematologica 107 (4): 868-876, 2022. [PUBMED Abstract]
  29. Rossi D, Spina V, Deambrogi C, et al.: The genetics of Richter syndrome reveals disease heterogeneity and predicts survival after transformation. Blood 117 (12): 3391-401, 2011. [PUBMED Abstract]
  30. Chigrinova E, Rinaldi A, Kwee I, et al.: Two main genetic pathways lead to the transformation of chronic lymphocytic leukemia to Richter syndrome. Blood 122 (15): 2673-82, 2013. [PUBMED Abstract]
  31. Parry EM, Leshchiner I, Guièze R, et al.: Evolutionary history of transformation from chronic lymphocytic leukemia to Richter syndrome. Nat Med 29 (1): 158-169, 2023. [PUBMED Abstract]
  32. Parry EM, Ten Hacken E, Wu CJ: Richter syndrome: novel insights into the biology of transformation. Blood 142 (1): 11-22, 2023. [PUBMED Abstract]
  33. Robertson LE, Pugh W, O’Brien S, et al.: Richter’s syndrome: a report on 39 patients. J Clin Oncol 11 (10): 1985-9, 1993. [PUBMED Abstract]
  34. Jain N, Keating M, Thompson P, et al.: Ibrutinib and Venetoclax for First-Line Treatment of CLL. N Engl J Med 380 (22): 2095-2103, 2019. [PUBMED Abstract]
  35. Ben-Dali Y, Hleuhel MH, da Cunha-Bang C, et al.: Richter’s transformation in patients with chronic lymphocytic leukaemia: a Nationwide Epidemiological Study. Leuk Lymphoma 61 (6): 1435-1444, 2020. [PUBMED Abstract]
  36. Stephens DM, Boucher K, Kander E, et al.: Hodgkin lymphoma arising in patients with chronic lymphocytic leukemia: outcomes from a large multi-center collaboration. Haematologica 106 (11): 2845-2852, 2021. [PUBMED Abstract]
  37. Al-Sawaf O, Robrecht S, Bahlo J, et al.: Richter transformation in chronic lymphocytic leukemia (CLL)-a pooled analysis of German CLL Study Group (GCLLSG) front line treatment trials. Leukemia 35 (1): 169-176, 2021. [PUBMED Abstract]
  38. Abdel-Qadir H, Sabrie N, Leong D, et al.: Cardiovascular Risk Associated With Ibrutinib Use in Chronic Lymphocytic Leukemia: A Population-Based Cohort Study. J Clin Oncol 39 (31): 3453-3462, 2021. [PUBMED Abstract]
  39. Byrd JC, Hillmen P, Ghia P, et al.: Acalabrutinib Versus Ibrutinib in Previously Treated Chronic Lymphocytic Leukemia: Results of the First Randomized Phase III Trial. J Clin Oncol 39 (31): 3441-3452, 2021. [PUBMED Abstract]

Treatment of Asymptomatic Chronic Lymphocytic Leukemia

Treatment Options for Asymptomatic Chronic Lymphocytic Leukemia (CLL)

Observation

Because of its indolent nature, chemotherapy is not indicated for asymptomatic or minimally affected patients with CLL, and observation is the generally accepted approach.[1] Because the rate of progression may vary, with long periods of stability and sometimes spontaneous regressions, frequent and careful observation is required to monitor the clinical course. One nomogram to predict time-to-first treatment relies on the number of lymph node sites, size of cervical lymph nodes, lactate dehydrogenase level, the IGH mutational status, and the presence of del(11q) or del(17p) established by fluorescence in situ hybridization analysis.[2] Spontaneous regression, manifested by a sustained reduction of the malignant clone without therapy, occurs in less than 5% of patients. These patients almost exclusively have hypermutation of IGH.[3]

Evidence (observation):

  1. The French Cooperative Group on Chronic Lymphocytic Leukemia randomly assigned 1,535 patients with previously untreated stage A disease to receive either chlorambucil or no immediate treatment.[4]
    • The results showed no survival advantage for immediate treatment with chlorambucil.[4][Level of evidence A1]
  2. A meta-analysis evaluated six trials of patients with early-stage CLL that involved immediate versus deferred therapy with chlorambucil (including the aforementioned trial by the French Cooperative Group).[5]

Despite many therapeutic options, observation should be considered for asymptomatic or minimally affected patients, even in the context of adverse prognostic findings. Therapy begins when patients develop profound cytopenias or when symptoms adversely impact quality of life.

There are no clinical trial results that confirm that immediate treatment of asymptomatic or minimally affected patients with the B-cell receptor inhibitors or BCL2 inhibitors is superior to observation.

Clinical trials will need to establish improved outcomes using the newer biological therapies in asymptomatic patients before observation or watchful waiting is discontinued.

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

References
  1. Casper JT: Prognostic features of early chronic lymphocytic leukaemia. International Workshop on CLL. Lancet 2 (8669): 968-9, 1989.
  2. Molica S, Giannarelli D, Gentile M, et al.: External validation on a prospective basis of a nomogram for predicting the time to first treatment in patients with chronic lymphocytic leukemia. Cancer 119 (6): 1177-85, 2013. [PUBMED Abstract]
  3. Kwok M, Oldreive C, Rawstron AC, et al.: Integrative analysis of spontaneous CLL regression highlights genetic and microenvironmental interdependency in CLL. Blood 135 (6): 411-428, 2020. [PUBMED Abstract]
  4. Dighiero G, Maloum K, Desablens B, et al.: Chlorambucil in indolent chronic lymphocytic leukemia. French Cooperative Group on Chronic Lymphocytic Leukemia. N Engl J Med 338 (21): 1506-14, 1998. [PUBMED Abstract]
  5. Chemotherapeutic options in chronic lymphocytic leukemia: a meta-analysis of the randomized trials. CLL Trialists’ Collaborative Group. J Natl Cancer Inst 91 (10): 861-8, 1999. [PUBMED Abstract]

Treatment of Symptomatic or Progressive Chronic Lymphocytic Leukemia

Treatment Options for Symptomatic or Progressive Chronic Lymphocytic Leukemia (CLL)

The following regimens are considered first-line treatment approaches for patients with CLL who are experiencing symptomatic progression:

Several large prospective clinical trials have compared these approaches. A chemotherapy-free approach for first-line therapy is usually preferred for most patients, but it is mandatory for patients with del(17p) or TP53-altered disease.[1–5]

BTK inhibitors

Ibrutinib versus zanubrutinib

Evidence (ibrutinib vs. zanubrutinib):

  1. A prospective randomized trial of 652 patients with relapsed or refractory CLL compared ibrutinib and zanubrutinib.[6]
    • With a median follow-up of 29.6 months, the 2-year progression-free survival (PFS) rate was 78.4% in the zanubrutinib group and 65.9% in the ibrutinib group (hazard ratio [HR], 0.65; 95% confidence interval [CI], 0.49–0.86; P = .002).[6][Level of evidence B1]
    • Cardiac disorders leading to treatment discontinuation occurred in 1 patient (0.3%) in the zanubrutinib group and 14 patients (4.3%) in the ibrutinib group. Six deaths caused by cardiac events were all in patients who received ibrutinib.
Ibrutinib versus acalabrutinib

Evidence (ibrutinib vs. acalabrutinib):

  1. A prospective randomized trial of 533 previously untreated patients compared the BTK inhibitors acalabrutinib and ibrutinib.[7]
    • With a median follow-up of 41 months, acalabrutinib was noninferior to ibrutinib, with a median PFS of 38.4 months for patients in both arms of the trial (HR, 1.00; 95% CI, 0.79–1.27).[7][Level of evidence B1]
    • The incidence of atrial fibrillation of any grade was lower for patients who received acalabrutinib than for patients who received ibrutinib (9.4% vs. 16.0%, P = .02). In this trial, the incidence of diarrhea and headaches was significantly higher in patients who received acalabrutinib (P < .05), while musculoskeletal pain was higher in patients who received ibrutinib (P = .0229).[8]
    • Ventricular arrhythmias and sudden death events appear to be a side effect of all the BTK inhibitors. For acalabrutinib, these events occur with a relative risk of 8.2 over age-matched controls.[9]
Ibrutinib versus ibrutinib plus rituximab versus BR

Evidence (ibrutinib vs. ibrutinib plus rituximab vs. BR):

  1. A prospective trial included 547 previously untreated patients aged 65 years or older. Patients were randomly assigned to receive BR, ibrutinib alone, or ibrutinib plus rituximab.[10]
    • With a median follow-up of 38 months, the 2-year PFS rate was 74% for patients who received BR. The rates were significantly higher for patients who received ibrutinib alone (87%; HR, 0.39; 95% CI, 0.25–0.58) or ibrutinib plus rituximab (88%; HR, 0.38; 95% CI, 0.25–0.59; P < .001).[10][Level of evidence B1]
    • There was no difference in PFS between the two ibrutinib groups (HR, 1.00; 95% CI, 0.62–1.62; P = .49) and no difference in overall survival (OS) between each of the groups.
Ibrutinib versus rituximab plus ibrutinib

Evidence (ibrutinib vs. rituximab plus ibrutinib):

  1. A prospective randomized trial included 208 patients who were previously untreated or had relapsed disease. Patients received rituximab plus ibrutinib or ibrutinib alone.[11]
    • With a median follow-up of 36 months, there was no difference in PFS (86%; HR, 1.04; 95% CI, 0.49−2.20; P = .91).[11][Level of evidence B1]
Ibrutinib versus FCR

Ibrutinib is a selective irreversible inhibitor of BTK, a signaling molecule located upstream in the B-cell receptor-signaling cascade.

Evidence (ibrutinib vs. FCR):

  1. ECOG-E1912 (NCT02048813) was a prospective randomized trial that compared ibrutinib and rituximab with FCR. A total of 529 patients previously untreated for CLL were randomly assigned in a 2:1 ratio to receive either ibrutinib and rituximab followed by ibrutinib maintenance (354 patients) or six cycles of FCR (175 patients).[12,13]
    • With a median follow-up of 5.8 years, the 5-year OS rate favored the ibrutinib arm (95% vs. 89%) (HR, 0.47; 95% CI, 0.25–0.89; P = .018).[13][Level of evidence A1]
    • In 281 patients without IGH pathogenic variants, the 5-year PFS rate favored ibrutinib plus rituximab versus FCR (75% vs. 33%) (HR, 0.27; 95% CI, 0.18−0.41; P < .0001). In 114 patients with IGH pathogenic variants, the 5-year PFS rate was also significantly different, at 83% for the ibrutinib arm and 68% for the FCR arm (HR, 0.27; 95% CI, 0.11−0.62; P = .001).[12–14]
    • Although undetectable measurable residual disease (MRD) was less than 10% between 12 and 36 months follow-up, patients with detectable MRD did not have significantly worse PFS (P = .14 at 12 months, P = .90 at 24 months, and P = .53 at 36 months).[15]
Zanubrutinib versus BR

Evidence (zanubrutinib vs. BR):

  1. A prospective randomized trial included 590 previously untreated patients aged 65 years or older. Patients were randomly assigned to receive zanubrutinib or BR.[16]
    • With a median follow-up of 26.2 months, the 2-year PFS rate was 85.5% (95% CI, 80.1%–89.6%) for patients who received zanubrutinib and 69.5% (95% CI, 62.4%–75.5%) for patients who received BR (HR, 0.42; 95% CI, 0.28–0.63; P < .0001).[16][Level of evidence B1]
Acalabrutinib plus obinutuzumab versus acalabrutinib versus chlorambucil plus obinutuzumab

Acalabrutinib is a highly selective covalent irreversible BTK inhibitor, designed to minimize the gastrointestinal toxicities and risk of atrial fibrillation seen with ibrutinib.

Evidence (acalabrutinib plus obinutuzumab vs. acalabrutinib vs. chlorambucil plus obinutuzumab):

  1. The prospective ELEVATE TN trial (NCT02475681) included 535 previously untreated patients aged 65 years or older with comorbidities (e.g., creatinine clearance <70 mL/min). Patients were randomly assigned to one of three arms: acalabrutinib plus obinutuzumab, acalabrutinib alone, or chlorambucil plus obinutuzumab.[17]
    • With a median follow-up of 28 months, the 24-month PFS rates were 93% for acalabrutinib plus obinutuzumab (HR, 0.10; 95% CI, 0.06−0.17; P < .0001), 87% for acalabrutinib alone (HR, 0.20; 95% CI, 0.13−0.30; P < .0001), and 47% for chlorambucil plus obinutuzumab.[17][Level of evidence B1]
    • There was a small but significant difference in the PFS rates between the two acalabrutinib groups (93% vs. 87% at 24 months), which favored the combination (HR, 0.49; 95% CI, 0.26−0.95).[17]

Venetoclax with initial use of obinutuzumab and rituximab

Venetoclax plus obinutuzumab versus chlorambucil plus obinutuzumab

Evidence (venetoclax plus obinutuzumab vs. chlorambucil plus obinutuzumab):

  1. The prospective CLL14 trial (NCT02242942) included 432 previously untreated patients with significant medical comorbidities (6 or higher on the Cumulative Illness Rating Scale; median age, 72 years). Patients were randomly assigned to receive either venetoclax (a highly selective inhibitor of BCL2) plus obinutuzumab (the human anti-CD20 monoclonal antibody) or chlorambucil plus obinutuzumab.[18]
    • With a median follow-up of 76.4 months, the median PFS rate was 76.2 months for venetoclax plus obinutuzumab, compared with 36.4 months for chlorambucil plus obinutuzumab (HR, 0.40; 95% CI, 0.31–0.52; P < .0001).[18][Level of evidence B1]
    • The 6-year OS rate was 78.7% for venetoclax plus obinutuzumab and 69.2% for chlorambucil plus obinutuzumab (HR, 0.69; 95% CI, 0.48–1.01; P = .052).
Venetoclax plus rituximab (VenR) versus BR

Evidence (VenR vs. BR):

  1. The prospective MURANO trial (NCT02005471) included 389 patients with relapsed or refractory CLL. Patients were randomly assigned to receive either VenR (venetoclax for 2 years plus rituximab for the first 6 months) or 6 months of BR.
    • With a median follow-up of 24 months, the 2-year PFS rate was 84.9% for VenR and 36.3% for BR (HR, 0.17; 95% CI, 0.11–0.25; P < .001).[19,20] An update with a 48-month median follow-up, reported in abstract form, showed a 4-year OS rate of 85.3% for VenR and 66.8% for BR (HR, 0.41; 95% CI, 0.26−0.65; P < .0001).[21][Level of evidence A1]
    • With a median follow-up of 59.2 months, the 5-year OS rate was 82.1% (95% CI, 76.4%–87.8%) for patients who received VenR and 62.2% (95% CI, 54.8%–69.6%) for patients who received BR (P < .0001).[22][Level of evidence A1] The median time to next treatment was 57.8 months (95% CI, 55.1–not estimable) for VenR.
    • For the 43% of patients assigned to VenR who achieved undetectable MRD at the end of treatment, the median time to MRD conversion was 19.4 months. The median time from MRD conversion to overt clinical progressive disease was another 25.2 months.[22]

Bendamustine and rituximab

BR versus FCR

Evidence (BR vs. FCR):

  1. The German CLL Study Group compared BR versus FCR as first-line therapy in patients with CLL who required therapy.[23]
    • With a median follow-up of 37.1 months, the median PFS was better for patients who received FCR (55.2 months vs. 41.7 months) (HR, 1.64; 90% CI, 1.31–2.06; P = .001), but there was no difference in the OS rate at 3 years (91% vs. 92%, not significant).[23][Level of evidence B1]
    • In patients older than 65 years, there was no difference in PFS between the two arms, but more infections occurred with FCR than with BR (grade 3 to 5 infection, 47% vs. 27%).

Fludarabine, cyclophosphamide, and rituximab (FCR)

FCR

FCR is used for patients with an IGH hypermutation.

Evidence (FCR):

  1. Several trials used FCR for appropriate patients with IGH pathogenic variants who required therapy.
    • The PFS rate exceeded 60% at more than 10 years.[24–26][Level of evidence C2] Nonetheless, late relapses were seen beyond 10 years.

BTK inhibitor plus venetoclax

BTK inhibitor (ibrutinib or acalabrutinib) plus venetoclax

Evidence (BTK inhibitor [ibrutinib or acalabrutinib] plus venetoclax):

  1. A prospective randomized trial included 523 patients with previously untreated CLL. Patients received either ibrutinib plus venetoclax for up to 6 years or FCR for six cycles.[27] This comparison was embedded in a larger three-arm randomization that also included ibrutinib alone for up to 6 years; the statistics were thought too preliminary to analyze the ibrutinib-alone group versus the other arms.
    • With a median follow-up of 43.7 months, the 3-year OS rate was 98.0% (95% CI, 95.2%–99.2%) in the ibrutinib-plus-venetoclax group and 93.0% (95% CI, 88.9%–95.6%) in the FCR group (HR, 0.31; 95% CI, 0.15–0.67).[27][Level of evidence A1]
    • The 3-year OS benefit favored ibrutinib plus venetoclax (HR, 0.23; 95% CI, 0.06–0.81) for patients without IGH pathogenic variants, but not for those with IGH pathogenic variants (HR, 0.61; 95% CI, 0.20–1.82).
    • The 3-year PFS rate was 97.2% (95% CI, 94.1%–98.6%) in the ibrutinib-plus-venetoclax group and 76.8% (95% CI, 70.8%–81.7%) in the FCR group (HR, 0.13; 95% CI, 0.07–0.24; P < .001).
    • MRD negativity was a requirement for stopping therapy with venetoclax and ibrutinib after 2 years. This trial did not randomly assign patients to either continued therapy or cessation of therapy based on MRD status. The utility and value of MRD could not be determined from this trial due to its design.
  2. A prospective randomized trial (GLOW [NCT03462719]) included 211 patients with previously untreated CLL. Patients were aged 65 and older or aged 18 to 64 with comorbidities and an Eastern Cooperative Oncology Group performance status of 0 to 2. Patients were randomly assigned to receive either fixed-duration ibrutinib and venetoclax (15 months total) or chlorambucil and obinutuzumab (6 months total).[28]
    • With a median follow-up of 46 months, the 42-month PFS rate was 74.6% in the ibrutinib-plus-venetoclax group and 24.8% in the chlorambucil-plus-obinutuzumab group (HR, 0.214; 95% CI, 0.138–0.334; P < .0001).[28][Level of evidence B1]
    • Ibrutinib was given for 3 months prior to the combination of venetoclax with ibrutinib to avoid tumor lysis syndrome.
    • At 3 months after the end of therapy, 40.6% of patients who received ibrutinib and venetoclax achieved undetectable MRD (<10-5 by next-generation sequencing) in the bone marrow, and 43.4% of patients achieved undetectable MRD in the peripheral blood.[28] However, the PFS rate exceeded 90% at 12 months after the end of therapy regardless of if the MRD was detectable or not.
  3. A prospective trial included 867 patients with previously untreated CLL. Patients were randomly assigned to one of three treatment regimens: (1) AV (acalabrutinib and venetoclax), (2) AVO (acalabrutinib, venetoclax, and obinutuzumab), or (3) either BR or FCR (at the discretion of the investigator).[29]
    • With a median follow-up of 41 months, the 3-year OS rate was 94.1% for patients who received AV and 85.9% for patients who received BR or FCR (HR, 0.33; 95% CI, 0.18–0.56; P < .0001). However, the 3-year OS rate was 87.7% for patients who received AVO compared with 85.9% for patients who received BR or FCR (HR, 0.76; 95% CI, 0.49–1.18; P = nonsignificant).[29][Level of evidence A1]
    • The 3-year PFS rate was 76.5% for patients who received AV, 83.1% for patients who received AVO, and 66.5% for patients who received BR or FCR. The PFS for patients who received AV versus those who received BR or FCR had an HR of 0.65 (95% CI, 0.49–0.87; P = .004). The PFS for patients who received AVO versus those who received BR or FCR had an HR of 0.42 (95% CI, 0.30–0.59; P < .001).
    • Although treatment with AVO resulted in a better PFS than AV, there were increased infectious deaths with AVO, especially from COVID-19 (SARS-CoV-2). These deaths accounted for a nonsignificant difference in OS rates between patients who received AVO (87.7%) and patients who received BR or FCR (85.9%).
  4. A phase II trial included 80 previously untreated patients who were aged 65 or older or had high-risk disease. Patients were treated with ibrutinib for 3 months followed by combined ibrutinib plus venetoclax for a total of 24 months.[30]
    • With a median follow-up of 38.5 months, the 2-year response rate was 82%, the 3-year PFS rate was 93% (95% CI, 88%–99%), and the 3-year OS rate was 96%.[30][Level of evidence C1]
    • The toxicity of the combination is similar to either agent alone and avoids the tumor lysis syndrome seen when starting with venetoclax.
    • High rates of undetectable MRD (<10-4 by 8-color flow cytometry) in the peripheral blood (75%) and bone marrow (72%) is unprecedented. The clinical significance of this finding awaits prospective randomized trials to establish clinical outcomes versus either drug alone. This combination has also been tested in the relapsed/refractory setting.[31]
  5. A phase II trial included 159 previously untreated patients aged 70 years or older. Patients received 3 cycles of ibrutinib alone followed by 12 cycles of ibrutinib plus venetoclax.[32]
    • With a median follow-up of 27.9 months, the complete response rate was 55% (95% CI, 48%–63%), the undetectable MRD rate was 77% (95% CI, 70%–83%) for blood and 60% (95% CI, 52%–67%) for bone marrow, the 2-year PFS rate was 95% (95% CI, 90%–97%), and the 2-year OS rate was 98% (95% CI, 94%–99%).[32][Level of evidence C1]
    • The toxicity of the ibrutinib-venetoclax combination was similar to either agent alone, and the ibrutinib-alone lead-in avoided tumor lysis syndrome.
  6. A phase II trial included 41 previously untreated patients who received ibrutinib plus venetoclax and obinutuzumab. Patients with undetectable MRD at cycle 16 could opt to discontinue treatment if they had a complete response.[33]
    • With a median follow-up of 38.4 months, the 3-year PFS rate was 79.9% and the 3-year OS rate was 92.6%.[33][Level of evidence C1]

In summary, these trials establish the use of venetoclax with obinutuzumab or rituximab, or the use of ibrutinib, acalabrutinib, or zanubrutinib as first-line therapy in patients with previously untreated CLL. A lower rate of atrial fibrillation occurs with acalabrutinib or zanubrutinib than with ibrutinib.[6,7,34,35] Unlike ibrutinib or acalabrutinib, which are given continuously until relapse, venetoclax may be stopped after 12 months, with durable maintenance of remission. Venetoclax, ibrutinib, acalabrutinib, or zanubrutinib can be readministered with success, if needed.[35,36] These targeting drugs are also effective for patients with TP53 pathogenic variants.[37] Different regimens of these drugs, as standalone agents or in combinations, with or without obinutuzumab, need to be evaluated in prospective randomized trials. Several provocative phase II and III trials with these combinations have resulted in unprecedented rates of MRD-negative disease which appear more durable;[30,38–41] whether this results in any clinical advantage to a more sequential approach requires prospective randomized trials. The National Comprehensive Cancer Network has listed the combination of venetoclax and ibrutinib as a first-line treatment option for patients with previously untreated CLL.[42] The considerable financial toxicity of these combinations mandates verification of superior efficacy. These trials further establish the rationale for a chemotherapy-free approach for first-line therapy for CLL instead of the previous standard of BR and FCR (which proved more efficacious than chlorambucil regimens). Patients at the highest risk of relapse have multiple poor prognostic factors, including TP53 pathogenic variants, elevated lactate dehydrogenase, elevated beta-2 microglobulin, and prior treatment.[43] These highest risk patients should consider clinical trials.

MRD Testing Outside the Context of a Clinical Trial

Undetectable MRD (≤1 × 10-4 CLL cells in peripheral blood or bone marrow aspirates) can be confirmed by flow cytometry or next-generation sequencing. The attainment of undetectable MRD represents an even more stringent complete remission that was prognostic for improved PFS and OS in multiple studies.[22,44–46]The use of time-limited therapy with venetoclax, or the investigational combination of venetoclax and a BTK inhibitor, has produced complete responses, and even undetectable MRD, in most patients.[22,44,47]

Testing for undetectable MRD has become a standard parameter for defining responses in all modern clinical trials for CLL. Undetectable MRD has prognostic value but its status as a predictive marker is uncertain. The potential value of MRD testing in routine clinical practice depends on whether it can be used for clinical decision making such as stopping, changing, or continuing treatment. High-level evidence for this intervention would require a prospective randomized clinical trial in which MRD was used as a predictive biomarker for a group attaining an OS advantage compared with a control group disregarding MRD status. Such evidence has not been attained. Similar to outcomes in follicular lymphoma and other indolent lymphoid neoplasms, improved PFS in patients with CLL does not directly predict OS.

A phase II trial used a combination of venetoclax and ibrutinib in patients with undetectable MRD after 1 year of therapy. Patients were randomly assigned to receive either ibrutinib maintenance therapy or treatment cessation.[47] All MRD-positive patients continued to receive ibrutinib. With a median follow-up of 34.4 months, the 1-year PFS rates were 98% for patients with undetectable MRD who ceased therapy, 96% for patients with undetectable MRD who received continued ibrutinib, and 97% for MRD-positive patients who received continued ibrutinib. All patients did well at 12 months. Knowledge of MRD status to guide discontinuation of therapy did not affect the outcome.[47]

Another phase II trial included 70 previously untreated patients who received 1 year of venetoclax plus obinutuzumab. Patients were randomly assigned to receive another year of venetoclax irrespective of MRD status, or another year of venetoclax only if they were MRD-positive. With a median follow-up of 35.2 months, the MRD rates were identical for both randomized groups, suggesting no improved efficacy with this approach, although increased adverse events were reported with an extra year of venetoclax.[48]

Before MRD is used outside the context of a clinical trial, conclusive evidence is required to establish that MRD is a predictive biomarker that can guide clinical decisions.

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

References
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  22. Seymour JF, Kipps TJ, Eichhorst BF, et al.: Enduring undetectable MRD and updated outcomes in relapsed/refractory CLL after fixed-duration venetoclax-rituximab. Blood 140 (8): 839-850, 2022. [PUBMED Abstract]
  23. Eichhorst B, Fink AM, Bahlo J, et al.: First-line chemoimmunotherapy with bendamustine and rituximab versus fludarabine, cyclophosphamide, and rituximab in patients with advanced chronic lymphocytic leukaemia (CLL10): an international, open-label, randomised, phase 3, non-inferiority trial. Lancet Oncol 17 (7): 928-942, 2016. [PUBMED Abstract]
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  25. Fischer K, Bahlo J, Fink AM, et al.: Long-term remissions after FCR chemoimmunotherapy in previously untreated patients with CLL: updated results of the CLL8 trial. Blood 127 (2): 208-15, 2016. [PUBMED Abstract]
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  29. Brown JR, Seymour JF, Jurczak W, et al.: Fixed-Duration Acalabrutinib Combinations in Untreated Chronic Lymphocytic Leukemia. N Engl J Med 392 (8): 748-762, 2025. [PUBMED Abstract]
  30. Wierda WG, Allan JN, Siddiqi T, et al.: Ibrutinib Plus Venetoclax for First-Line Treatment of Chronic Lymphocytic Leukemia: Primary Analysis Results From the Minimal Residual Disease Cohort of the Randomized Phase II CAPTIVATE Study. J Clin Oncol 39 (34): 3853-3865, 2021. [PUBMED Abstract]
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Treatment of Recurrent or Refractory Chronic Lymphocytic Leukemia

Treatment Options for Recurrent or Refractory Chronic Lymphocytic Leukemia (CLL)

The same regimens considered for first-line therapy for patients with CLL can be readministered in a sequential fashion. These regimens are described in more detail under first-line therapy. For more information, see the Treatment of Symptomatic or Progressive CLL section.

  • Bruton tyrosine kinase (BTK) inhibitors (acalabrutinib, zanubrutinib, or ibrutinib).
  • Venetoclax with initial use of obinutuzumab or rituximab.
  • Bendamustine and rituximab (BR).
  • Fludarabine, cyclophosphamide, and rituximab (FCR).
  • BTK inhibitor (ibrutinib or acalabrutinib) plus venetoclax.
  • R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) (only if Richter syndrome with histological progression is suspected clinically).

In the relapsed setting, venetoclax showed similar efficacy and safety even after previous therapy with ibrutinib or idelalisib (the phosphatidylinositol 3-kinase [PI3K] delta inhibitor).[1,2]

Similarly, in a trial reported in abstract form, ibrutinib and acalabrutinib showed similar efficacy and safety after previous therapy with venetoclax.[3] Sequencing these novel agents showed efficacy in the relapsed/refractory setting.[4,5]

Noncovalent BTK inhibitors

Unlike other BTK inhibitors (ibrutinib, acalabrutinib, and zanubrutinib), pirtobrutinib binds to BTK in a noncovalent manner.[6]

  1. In a prospective phase I/II study, 317 patients with CLL/small lymphocytic leukemia received pirtobrutinib. A total of 247 of these patients had been treated previously with a covalent-binding BTK inhibitor.[7]
    • With a median follow-up of 19.4 months, the median progression-free survival (PFS) was 19.6 months (95% confidence interval [CI], 16.9–22.1) for all patients and 16.8 months (95% CI, 13.2–18.7) for the subgroup of patients with BTK inhibitor resistance, intolerance, or BTK C481 variants (a resistance variant for the covalent agents).[7][Level of evidence C3]
    • In this trial, 82 patients had a diagnosis of Richter transformation. Among those patients, the overall response rate was 50.0% (95% CI, 38.7%–61.3%), and the complete response rate was 13%.[8][Level of evidence C3]

Chimeric antigen receptor (CAR) T-cell therapy

Autologous T cells can be modified by viral vectors to incorporate antigen receptor specificity for the B-cell antigen CD19 and then infused into previously treated patients.[9] A dramatic response lasting 6 months has prompted larger trials of this concept. Ongoing clinical trials are testing the concept of T cells directed at CD19 with engineered CAR T cells.[10–12]

PI3K inhibitors

Idelalisib is an oral inhibitor of the delta isoform of PI3K, which is in the B-cell receptor-signaling cascade. This drug has been withdrawn from its U.S. Food and Drug Administration (FDA) indication due to toxicity and is no longer available. Duvelisib is an oral dual inhibitor of the delta and gamma isoforms of PI3K.[13]

  1. In a prospective trial, 319 patients with relapsed and refractory CLL/small lymphocytic lymphoma were randomly assigned to receive duvelisib versus ofatumumab.[14]
    • With a median follow-up of 22.4 months, the median PFS was significantly higher for patients who received duvelisib, at 13.3 months, than for patients who received ofatumumab, at 9.9 months (hazard ratio [HR], 0.52; P < .0001).[14][Level of evidence B1]
    • Serious side effects include infections, pneumonitis, diarrhea or colitis, dermatitis, neutropenia, rash, fatigue, pyrexia, nausea, anemia, and transaminitis.
    • The FDA has approved duvelisib for third-line (or greater) use. However, follow-up data submitted to the FDA showed, with a median follow-up of 63 months, a median OS of 52.3 months (95% CI, 41.8–68.0) in the duvelisib group and 63.3 months (95% CI, 41.2–not estimable) in the ofatumumab group.[15]

Lenalidomide (with or without rituximab)

Lenalidomide is an oral immunomodulatory agent with response rates of more than 50%, with or without rituximab, for patients with previously treated and untreated disease.[16–22][Level of evidence C3] Prolonged, lower-dose approaches and attention to prevention of tumor lysis syndrome are suggested with this agent.[16,23] Combination therapy and long-term toxicities from using lenalidomide (such as increased myelodysplasia, as seen in myeloma patients) remain undefined for patients with CLL.

Bone marrow or peripheral blood stem cell transplant

In a prospective randomized trial, 241 previously untreated patients younger than 66 years with advanced-stage disease received induction therapy with a CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone)-based regimen followed by fludarabine.[24] Complete responders (105 patients) were randomly assigned to undergo autologous stem cell transplant (SCT) or observation, while the other 136 patients were randomly assigned to receive dexamethasone, high-dose cytarabine, and cisplatin reinduction followed by either autologous SCT or fludarabine plus cyclophosphamide (FC). Although the 3-year event-free survival (EFS) favored autologous SCT in complete responders, there was no difference in OS in any of the randomized comparisons.[24][Level of evidence B1] Autologous bone marrow/stem cell transplant is rarely employed for patients with relapsed CLL.

Patients with adverse prognostic factors are very likely to die from CLL. These patients are candidates for clinical trials that employ high-dose chemotherapy and immunotherapy with myeloablative or nonmyeloablative allogeneic peripheral blood SCT.[25–30] Although most patients who attain complete remission after autologous SCT eventually relapse, a survival plateau for allogeneic SCT suggests an additional graft-versus-leukemia effect.[30] A series (NCT00281983) of 90 patients with relapsed or refractory CLL who underwent allogeneic SCT reported a 6-year OS rate of 58% and a 6-year EFS rate of 38%, which included patients with the worst prognostic factors (such as a TP53 pathogenic variant).[31][Level of evidence C2]

Ofatumumab

Ofatumumab is a humanized anti-CD20 monoclonal antibody.

Evidence (ofatumumab alone and in combination with chlorambucil):

  1. A prospective trial included 474 previously treated patients who attained partial or complete remission to second- or third-line chemotherapy. Patients were randomly assigned to 2 years of maintenance therapy with ofatumumab versus observation.[32]
    • With a median follow-up of 19 months, median PFS favored the ofatumumab maintenance arm, at 29.4 months versus 15.2 months (HR, 0.50; 95% CI, 0.38–0.66; P < .0001). There was no difference in OS.[32][Level of evidence B1]
  2. A prospective randomized trial of 447 patients who were previously untreated compared ofatumumab plus chlorambucil with chlorambucil alone.[33]
    • With a median follow-up of 2 years, median PFS favored the ofatumumab plus chlorambucil arm, at 22.4 months versus 13.1 months (HR, 0.57; 95% CI, 0.45–0.72; P = .0001). There was no difference in OS.[33][Level of evidence B1]

Involved-field radiation therapy

Relatively low doses of radiation therapy can be administered for lymphadenopathy that causes problems due to size or encroachment on adjacent organs. Sometimes radiation therapy to one nodal area or the spleen will result in an abscopal effect (i.e., the shrinkage of lymph nodes in untreated sites).

Alemtuzumab

Alemtuzumab is no longer available commercially in the United States for neoplastic indications but can be obtained from the pharmaceutical company on a compassionate-use basis (Lemtrada REMS [Risk Evaluation and Mitigation Strategy] Program).

Alemtuzumab, the monoclonal antibody directed at CD52, shows activity in the setting of chemotherapy-resistant disease or high-risk untreated patients with del(17p) or TP53 pathogenic variants.[34–36] As a single agent, the subcutaneous route of delivery is preferred to the intravenous route in patients because of the similar efficacy and decreased adverse effects, including less acute allergic reactions that were shown in some nonrandomized reports.[36–40]

In a combination regimen, subcutaneous alemtuzumab plus fludarabine (with or without cyclophosphamide) or intravenous alemtuzumab plus alkylating agents have resulted in excess infectious toxicities and death, with no compensatory improvement in efficacy in three phase II trials and one randomized trial.[41–43][Level of evidence C3]; [44][Level of evidence B1]

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

References
  1. Jones JA, Mato AR, Wierda WG, et al.: Venetoclax for chronic lymphocytic leukaemia progressing after ibrutinib: an interim analysis of a multicentre, open-label, phase 2 trial. Lancet Oncol 19 (1): 65-75, 2018. [PUBMED Abstract]
  2. Coutre S, Choi M, Furman RR, et al.: Venetoclax for patients with chronic lymphocytic leukemia who progressed during or after idelalisib therapy. Blood 131 (15): 1704-1711, 2018. [PUBMED Abstract]
  3. Kater AP, Wu JQ, Kipps T, et al.: Venetoclax Plus Rituximab in Relapsed Chronic Lymphocytic Leukemia: 4-Year Results and Evaluation of Impact of Genomic Complexity and Gene Mutations From the MURANO Phase III Study. J Clin Oncol 38 (34): 4042-4054, 2020. [PUBMED Abstract]
  4. Mato AR, Hill BT, Lamanna N, et al.: Optimal sequencing of ibrutinib, idelalisib, and venetoclax in chronic lymphocytic leukemia: results from a multicenter study of 683 patients. Ann Oncol 28 (5): 1050-1056, 2017. [PUBMED Abstract]
  5. Kater AP, Arslan Ö, Demirkan F, et al.: Activity of venetoclax in patients with relapsed or refractory chronic lymphocytic leukaemia: analysis of the VENICE-1 multicentre, open-label, single-arm, phase 3b trial. Lancet Oncol 25 (4): 463-473, 2024. [PUBMED Abstract]
  6. Thompson PA, Tam CS: Pirtobrutinib: a new hope for patients with BTK inhibitor-refractory lymphoproliferative disorders. Blood 141 (26): 3137-3142, 2023. [PUBMED Abstract]
  7. Mato AR, Woyach JA, Brown JR, et al.: Pirtobrutinib after a Covalent BTK Inhibitor in Chronic Lymphocytic Leukemia. N Engl J Med 389 (1): 33-44, 2023. [PUBMED Abstract]
  8. Wierda WG, Shah NN, Cheah CY, et al.: Pirtobrutinib, a highly selective, non-covalent (reversible) BTK inhibitor in patients with B-cell malignancies: analysis of the Richter transformation subgroup from the multicentre, open-label, phase 1/2 BRUIN study. Lancet Haematol 11 (9): e682-e692, 2024. [PUBMED Abstract]
  9. Porter DL, Levine BL, Kalos M, et al.: Chimeric antigen receptor-modified T cells in chronic lymphoid leukemia. N Engl J Med 365 (8): 725-33, 2011. [PUBMED Abstract]
  10. Turtle CJ, Hay KA, Hanafi LA, et al.: Durable Molecular Remissions in Chronic Lymphocytic Leukemia Treated With CD19-Specific Chimeric Antigen Receptor-Modified T Cells After Failure of Ibrutinib. J Clin Oncol 35 (26): 3010-3020, 2017. [PUBMED Abstract]
  11. Siddiqi T, Soumerai JD, Dorritie KA: Rapid undetectable MRD (uMRD) responses in patients with relapsed/refractory (R/R) chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) treated with lisocabtagene maraleucel (liso-cel), a CD19-directed CAR T cell product: updated results from Transcend CLL 004, a phase 1/2 study including patients with high-risk disease previously treated with ibrutinib. [Abstract] Blood 134 (Suppl 1): 503, 2019.
  12. Frey NV, Gill S, Hexner EO, et al.: Long-Term Outcomes From a Randomized Dose Optimization Study of Chimeric Antigen Receptor Modified T Cells in Relapsed Chronic Lymphocytic Leukemia. J Clin Oncol 38 (25): 2862-2871, 2020. [PUBMED Abstract]
  13. Patel K, Danilov AV, Pagel JM: Duvelisib for CLL/SLL and follicular non-Hodgkin lymphoma. Blood 134 (19): 1573-1577, 2019. [PUBMED Abstract]
  14. Flinn IW, Hillmen P, Montillo M, et al.: The phase 3 DUO trial: duvelisib vs ofatumumab in relapsed and refractory CLL/SLL. Blood 132 (23): 2446-2455, 2018. [PUBMED Abstract]
  15. U.S. Food and Drug Administration: FDA warns about possible increased risk of death and serious side effects with cancer drug Copiktra (duvelisib). Silver Spring, Md: U.S. Food and Drug Administration, 2022. Available online. Last accessed April 3, 2025.
  16. Chen CI, Bergsagel PL, Paul H, et al.: Single-agent lenalidomide in the treatment of previously untreated chronic lymphocytic leukemia. J Clin Oncol 29 (9): 1175-81, 2011. [PUBMED Abstract]
  17. Chanan-Khan A, Miller KC, Musial L, et al.: Clinical efficacy of lenalidomide in patients with relapsed or refractory chronic lymphocytic leukemia: results of a phase II study. J Clin Oncol 24 (34): 5343-9, 2006. [PUBMED Abstract]
  18. Ferrajoli A, Lee BN, Schlette EJ, et al.: Lenalidomide induces complete and partial remissions in patients with relapsed and refractory chronic lymphocytic leukemia. Blood 111 (11): 5291-7, 2008. [PUBMED Abstract]
  19. Strati P, Keating MJ, Wierda WG, et al.: Lenalidomide induces long-lasting responses in elderly patients with chronic lymphocytic leukemia. Blood 122 (5): 734-7, 2013. [PUBMED Abstract]
  20. Wendtner CM, Hillmen P, Mahadevan D, et al.: Final results of a multicenter phase 1 study of lenalidomide in patients with relapsed or refractory chronic lymphocytic leukemia. Leuk Lymphoma 53 (3): 417-23, 2012. [PUBMED Abstract]
  21. Badoux XC, Keating MJ, Wen S, et al.: Phase II study of lenalidomide and rituximab as salvage therapy for patients with relapsed or refractory chronic lymphocytic leukemia. J Clin Oncol 31 (5): 584-91, 2013. [PUBMED Abstract]
  22. Takahashi K, Hu B, Wang F, et al.: Clinical implications of cancer gene mutations in patients with chronic lymphocytic leukemia treated with lenalidomide. Blood 131 (16): 1820-1832, 2018. [PUBMED Abstract]
  23. Moutouh-de Parseval LA, Weiss L, DeLap RJ, et al.: Tumor lysis syndrome/tumor flare reaction in lenalidomide-treated chronic lymphocytic leukemia. J Clin Oncol 25 (31): 5047, 2007. [PUBMED Abstract]
  24. Sutton L, Chevret S, Tournilhac O, et al.: Autologous stem cell transplantation as a first-line treatment strategy for chronic lymphocytic leukemia: a multicenter, randomized, controlled trial from the SFGM-TC and GFLLC. Blood 117 (23): 6109-19, 2011. [PUBMED Abstract]
  25. Toze CL, Dalal CB, Nevill TJ, et al.: Allogeneic haematopoietic stem cell transplantation for chronic lymphocytic leukaemia: outcome in a 20-year cohort. Br J Haematol 158 (2): 174-85, 2012. [PUBMED Abstract]
  26. Khouri IF, Saliba RM, Admirand J, et al.: Graft-versus-leukaemia effect after non-myeloablative haematopoietic transplantation can overcome the unfavourable expression of ZAP-70 in refractory chronic lymphocytic leukaemia. Br J Haematol 137 (4): 355-63, 2007. [PUBMED Abstract]
  27. Sorror ML, Storer BE, Sandmaier BM, et al.: Five-year follow-up of patients with advanced chronic lymphocytic leukemia treated with allogeneic hematopoietic cell transplantation after nonmyeloablative conditioning. J Clin Oncol 26 (30): 4912-20, 2008. [PUBMED Abstract]
  28. Schetelig J, van Biezen A, Brand R, et al.: Allogeneic hematopoietic stem-cell transplantation for chronic lymphocytic leukemia with 17p deletion: a retrospective European Group for Blood and Marrow Transplantation analysis. J Clin Oncol 26 (31): 5094-100, 2008. [PUBMED Abstract]
  29. Malhotra P, Hogan WJ, Litzow MR, et al.: Long-term outcome of allogeneic stem cell transplantation in chronic lymphocytic leukemia: analysis after a minimum follow-up of 5 years. Leuk Lymphoma 49 (9): 1724-30, 2008. [PUBMED Abstract]
  30. Dreger P, Döhner H, Ritgen M, et al.: Allogeneic stem cell transplantation provides durable disease control in poor-risk chronic lymphocytic leukemia: long-term clinical and MRD results of the German CLL Study Group CLL3X trial. Blood 116 (14): 2438-47, 2010. [PUBMED Abstract]
  31. Dreger P, Schnaiter A, Zenz T, et al.: TP53, SF3B1, and NOTCH1 mutations and outcome of allotransplantation for chronic lymphocytic leukemia: six-year follow-up of the GCLLSG CLL3X trial. Blood 121 (16): 3284-8, 2013. [PUBMED Abstract]
  32. van Oers MH, Kuliczkowski K, Smolej L, et al.: Ofatumumab maintenance versus observation in relapsed chronic lymphocytic leukaemia (PROLONG): an open-label, multicentre, randomised phase 3 study. Lancet Oncol 16 (13): 1370-9, 2015. [PUBMED Abstract]
  33. Hillmen P, Robak T, Janssens A, et al.: Chlorambucil plus ofatumumab versus chlorambucil alone in previously untreated patients with chronic lymphocytic leukaemia (COMPLEMENT 1): a randomised, multicentre, open-label phase 3 trial. Lancet 385 (9980): 1873-83, 2015. [PUBMED Abstract]
  34. Moreton P, Kennedy B, Lucas G, et al.: Eradication of minimal residual disease in B-cell chronic lymphocytic leukemia after alemtuzumab therapy is associated with prolonged survival. J Clin Oncol 23 (13): 2971-9, 2005. [PUBMED Abstract]
  35. Parikh SA, Keating MJ, O’Brien S, et al.: Frontline chemoimmunotherapy with fludarabine, cyclophosphamide, alemtuzumab, and rituximab for high-risk chronic lymphocytic leukemia. Blood 118 (8): 2062-8, 2011. [PUBMED Abstract]
  36. Pettitt AR, Jackson R, Carruthers S, et al.: Alemtuzumab in combination with methylprednisolone is a highly effective induction regimen for patients with chronic lymphocytic leukemia and deletion of TP53: final results of the national cancer research institute CLL206 trial. J Clin Oncol 30 (14): 1647-55, 2012. [PUBMED Abstract]
  37. Stilgenbauer S, Zenz T, Winkler D, et al.: Subcutaneous alemtuzumab in fludarabine-refractory chronic lymphocytic leukemia: clinical results and prognostic marker analyses from the CLL2H study of the German Chronic Lymphocytic Leukemia Study Group. J Clin Oncol 27 (24): 3994-4001, 2009. [PUBMED Abstract]
  38. Cortelezzi A, Pasquini MC, Gardellini A, et al.: Low-dose subcutaneous alemtuzumab in refractory chronic lymphocytic leukaemia (CLL): results of a prospective, single-arm multicentre study. Leukemia 23 (11): 2027-33, 2009. [PUBMED Abstract]
  39. Osterborg A, Foà R, Bezares RF, et al.: Management guidelines for the use of alemtuzumab in chronic lymphocytic leukemia. Leukemia 23 (11): 1980-8, 2009. [PUBMED Abstract]
  40. Gritti G, Reda G, Maura F, et al.: Low dose alemtuzumab in patients with fludarabine-refractory chronic lymphocytic leukemia. Leuk Lymphoma 53 (3): 424-9, 2012. [PUBMED Abstract]
  41. Lin TS, Donohue KA, Byrd JC, et al.: Consolidation therapy with subcutaneous alemtuzumab after fludarabine and rituximab induction therapy for previously untreated chronic lymphocytic leukemia: final analysis of CALGB 10101. J Clin Oncol 28 (29): 4500-6, 2010. [PUBMED Abstract]
  42. Badoux XC, Keating MJ, Wang X, et al.: Cyclophosphamide, fludarabine, alemtuzumab, and rituximab as salvage therapy for heavily pretreated patients with chronic lymphocytic leukemia. Blood 118 (8): 2085-93, 2011. [PUBMED Abstract]
  43. Lepretre S, Aurran T, Mahé B, et al.: Excess mortality after treatment with fludarabine and cyclophosphamide in combination with alemtuzumab in previously untreated patients with chronic lymphocytic leukemia in a randomized phase 3 trial. Blood 119 (22): 5104-10, 2012. [PUBMED Abstract]
  44. Geisler CH, van T’ Veer MB, Jurlander J, et al.: Frontline low-dose alemtuzumab with fludarabine and cyclophosphamide prolongs progression-free survival in high-risk CLL. Blood 123 (21): 3255-62, 2014. [PUBMED Abstract]

Key References for Chronic Lymphocytic Leukemia Treatment

These references have been identified by members of the PDQ Adult Treatment Editorial Board as significant in the field of chronic lymphocytic leukemia (CLL) treatment. This list is provided to inform users of important studies that have helped shape the current understanding of and treatment options for CLL. Listed after each reference are the sections within this summary where the reference is cited.

Latest Updates to This Summary (04/25/2025)

The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.

Treatment of Symptomatic or Progressive Chronic Lymphocytic Leukemia (CLL)

Revised text about the results of a prospective trial that included 432 previously untreated patients with significant medical comorbidities. Patients were randomly assigned to receive either venetoclax plus obinutuzumab or chlorambucil plus obinutuzumab (cited Al-Sawaf et al. as reference 18).

Added text about a prospective trial that included 867 patients with previously untreated CLL. Patients were randomly assigned to one of three treatment regimens: (1) acalabrutinib and venetoclax, (2) acalabrutinib, venetoclax, and obinutuzumab, or (3) either bendamustine and rituximab or fludarabine, cyclophosphamide, and rituximab (at the discretion of the investigator) (cited Brown et al. as reference 29 and level of evidence A1).

Added text to state that the National Comprehensive Cancer Network has listed the combination of venetoclax and ibrutinib as a first-line treatment option for patients with previously untreated CLL (cited Wierda et al. as reference 42).

Treatment of Recurrent or Refractory CLL

Revised text about the results of a prospective phase I/II study of pirtobrutinib in 317 patients with CLL/small lymphocytic leukemia (cited Wierda et al. as reference 8 and level of evidence C3).

This summary is written and maintained by the PDQ Adult Treatment Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ® Cancer Information for Health Professionals pages.

About This PDQ Summary

Purpose of This Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of chronic lymphocytic leukemia. It is intended as a resource to inform and assist clinicians in the care of their patients. It does not provide formal guidelines or recommendations for making health care decisions.

Reviewers and Updates

This summary is reviewed regularly and updated as necessary by the PDQ Adult Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).

Board members review recently published articles each month to determine whether an article should:

  • be discussed at a meeting,
  • be cited with text, or
  • replace or update an existing article that is already cited.

Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.

The lead reviewer for Chronic Lymphocytic Leukemia Treatment is:

  • Eric J. Seifter, MD (Johns Hopkins University)

Any comments or questions about the summary content should be submitted to Cancer.gov through the NCI website’s Email Us. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.

Levels of Evidence

Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Adult Treatment Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.

Permission to Use This Summary

PDQ is a registered trademark. Although the content of PDQ documents can be used freely as text, it cannot be identified as an NCI PDQ cancer information summary unless it is presented in its entirety and is regularly updated. However, an author would be permitted to write a sentence such as “NCI’s PDQ cancer information summary about breast cancer prevention states the risks succinctly: [include excerpt from the summary].”

The preferred citation for this PDQ summary is:

PDQ® Adult Treatment Editorial Board. PDQ Chronic Lymphocytic Leukemia Treatment. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: /types/leukemia/hp/cll-treatment-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389470]

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Aggressive B-Cell Non-Hodgkin Lymphoma Treatment (PDQ®)–Health Professional Version

Aggressive B-Cell Non-Hodgkin Lymphoma Treatment (PDQ®)–Health Professional Version

General Information About B-Cell Non-Hodgkin Lymphoma

The non-Hodgkin lymphomas (NHL) are a heterogeneous group of lymphoproliferative malignancies with differing patterns of behavior and responses to treatment.[1] This summary focuses primarily on aggressive B-cell NHL. For information about B-cell and T-cell lymphomas, see Indolent B-Cell Non-Hodgkin Lymphoma Treatment, Peripheral T-Cell Non-Hodgkin Lymphoma Treatment, Mycosis Fungoides and Other Cutaneous T-Cell Lymphomas Treatment, and Mantle Cell Lymphoma Treatment.

Like Hodgkin lymphoma, NHL usually originates in lymphoid tissues and can spread to other organs. However, NHL is much less predictable than Hodgkin lymphoma and has a far greater tendency to spread to extranodal sites. The prognosis depends on the histological type, disease stage, and treatment.

Incidence and Mortality

Estimated new cases and deaths from all types of NHL in the United States in 2025:[2]

  • New cases: 80,350.
  • Deaths: 19,390.

B-cell lymphomas make up about 85% of NHL cases.[3]

Anatomy

NHL usually originates in lymphoid tissues.

EnlargeLymphatic system; drawing shows the lymph vessels and lymph organs, including the lymph nodes, tonsils, thymus, spleen, and bone marrow. Also shown is the small intestine (one site of mucosal-associated lymphoid tissue). There are also two pullouts: one showing a close up of the inside structure of a lymph node and the attached artery, vein, and lymph vessels with arrows showing how the lymph (clear, watery fluid) moves into and out of the lymph node, and another showing a close up of bone marrow with blood cells.
The lymph system is part of the body’s immune system and is made up of tissues and organs that help protect the body from infection and disease. These include the tonsils, adenoids (not shown), thymus, spleen, bone marrow, lymph vessels, and lymph nodes. Lymph tissue is also found in many other parts of the body, including the small intestine.

Prognosis and Survival

NHL can be divided into two prognostic groups: indolent lymphomas and aggressive lymphomas.

Indolent NHL has a relatively good prognosis, with a median survival as long as 20 years, but it is usually not curable in advanced clinical stages.[4]

Aggressive NHL has a worse prognosis in the short term, but a significant number of these patients can be cured with intensive combination chemotherapy regimens. Patients who present with, or convert to, aggressive forms of NHL may have sustained complete remissions with combination chemotherapy regimens or aggressive consolidation with marrow or stem cell support.[5,6]

In general, with modern treatment of patients with NHL, the 5-year overall survival rate is over 60%. More than 70% of patients with aggressive NHL can be cured. Most relapses occur in the first 2 years after therapy. The risk of late relapse is higher in patients who manifest both indolent and aggressive histologies.[7]

Late Effects of Treatment of NHL

Late effects of treatment of non-Hodgkin lymphoma (NHL) have been observed. Impaired fertility may occur after exposure to alkylating agents.[8] For as many as three decades after diagnosis, patients are at a significantly elevated risk of developing second primary cancers, especially the following:[9–12]

  • Lung cancer.
  • Brain cancer.
  • Kidney cancer.
  • Bladder cancer.
  • Melanoma.
  • Hodgkin lymphoma.
  • Acute nonlymphocytic leukemia.

Left ventricular dysfunction was a significant late effect in long-term survivors of high-grade NHL who received more than 200 mg/m² of doxorubicin.[8,13]

Myelodysplastic syndrome and acute myelogenous leukemia are late complications of myeloablative therapy with autologous bone marrow or peripheral blood stem cell support, as well as conventional chemotherapy-containing alkylating agents.[10,14–21] Most of these patients show clonal hematopoiesis even before the transplant, suggesting that the hematologic injury usually occurs during induction or reinduction chemotherapy.[16,22,23] A series of 605 patients who received autologous bone marrow transplant (BMT) with cyclophosphamide and total-body radiation therapy (as conditioning) were followed for a median of 10 years. The incidence of a second malignancy was 21%, and 10% of those malignancies were solid tumors.[24]

A study of young women who received autologous BMT reported successful pregnancies with children born free of congenital abnormalities.[25] Late-occurring venous thromboembolism can occur after allogeneic or autologous BMT.[26]

Some patients have osteopenia or osteoporosis at the start of therapy; bone density may worsen after therapy for lymphoma.[27]

Long-term impaired immune health was evaluated in a retrospective cohort study of 21,690 survivors of diffuse large B-cell lymphoma from the California Cancer Registry. Elevated incidence rate ratios were found up to 10 years later for pneumonia (10.8-fold), meningitis (5.3-fold), immunoglobulin deficiency (17.6-fold), and autoimmune cytopenias (12-fold).[28] Similarly, there are impaired humoral responses to COVID-19 virus vaccination in patients with lymphoma who receive B-cell–directed therapies.[29,30]

References
  1. Shankland KR, Armitage JO, Hancock BW: Non-Hodgkin lymphoma. Lancet 380 (9844): 848-57, 2012. [PUBMED Abstract]
  2. American Cancer Society: Cancer Facts and Figures 2025. American Cancer Society, 2025. Available online. Last accessed January 16, 2025.
  3. American Cancer Society: Types of B-cell Lymphoma. American Cancer Society, 2019. Available online. Last accessed February 7, 2025.
  4. Tan D, Horning SJ, Hoppe RT, et al.: Improvements in observed and relative survival in follicular grade 1-2 lymphoma during 4 decades: the Stanford University experience. Blood 122 (6): 981-7, 2013. [PUBMED Abstract]
  5. Bastion Y, Sebban C, Berger F, et al.: Incidence, predictive factors, and outcome of lymphoma transformation in follicular lymphoma patients. J Clin Oncol 15 (4): 1587-94, 1997. [PUBMED Abstract]
  6. Yuen AR, Kamel OW, Halpern J, et al.: Long-term survival after histologic transformation of low-grade follicular lymphoma. J Clin Oncol 13 (7): 1726-33, 1995. [PUBMED Abstract]
  7. Cabanillas F, Velasquez WS, Hagemeister FB, et al.: Clinical, biologic, and histologic features of late relapses in diffuse large cell lymphoma. Blood 79 (4): 1024-8, 1992. [PUBMED Abstract]
  8. Haddy TB, Adde MA, McCalla J, et al.: Late effects in long-term survivors of high-grade non-Hodgkin’s lymphomas. J Clin Oncol 16 (6): 2070-9, 1998. [PUBMED Abstract]
  9. Travis LB, Curtis RE, Glimelius B, et al.: Second cancers among long-term survivors of non-Hodgkin’s lymphoma. J Natl Cancer Inst 85 (23): 1932-7, 1993. [PUBMED Abstract]
  10. Mudie NY, Swerdlow AJ, Higgins CD, et al.: Risk of second malignancy after non-Hodgkin’s lymphoma: a British Cohort Study. J Clin Oncol 24 (10): 1568-74, 2006. [PUBMED Abstract]
  11. Hemminki K, Lenner P, Sundquist J, et al.: Risk of subsequent solid tumors after non-Hodgkin’s lymphoma: effect of diagnostic age and time since diagnosis. J Clin Oncol 26 (11): 1850-7, 2008. [PUBMED Abstract]
  12. Major A, Smith DE, Ghosh D, et al.: Risk and subtypes of secondary primary malignancies in diffuse large B-cell lymphoma survivors change over time based on stage at diagnosis. Cancer 126 (1): 189-201, 2020. [PUBMED Abstract]
  13. Moser EC, Noordijk EM, van Leeuwen FE, et al.: Long-term risk of cardiovascular disease after treatment for aggressive non-Hodgkin lymphoma. Blood 107 (7): 2912-9, 2006. [PUBMED Abstract]
  14. Darrington DL, Vose JM, Anderson JR, et al.: Incidence and characterization of secondary myelodysplastic syndrome and acute myelogenous leukemia following high-dose chemoradiotherapy and autologous stem-cell transplantation for lymphoid malignancies. J Clin Oncol 12 (12): 2527-34, 1994. [PUBMED Abstract]
  15. Stone RM, Neuberg D, Soiffer R, et al.: Myelodysplastic syndrome as a late complication following autologous bone marrow transplantation for non-Hodgkin’s lymphoma. J Clin Oncol 12 (12): 2535-42, 1994. [PUBMED Abstract]
  16. Armitage JO, Carbone PP, Connors JM, et al.: Treatment-related myelodysplasia and acute leukemia in non-Hodgkin’s lymphoma patients. J Clin Oncol 21 (5): 897-906, 2003. [PUBMED Abstract]
  17. André M, Mounier N, Leleu X, et al.: Second cancers and late toxicities after treatment of aggressive non-Hodgkin lymphoma with the ACVBP regimen: a GELA cohort study on 2837 patients. Blood 103 (4): 1222-8, 2004. [PUBMED Abstract]
  18. Oddou S, Vey N, Viens P, et al.: Second neoplasms following high-dose chemotherapy and autologous stem cell transplantation for malignant lymphomas: a report of six cases in a cohort of 171 patients from a single institution. Leuk Lymphoma 31 (1-2): 187-94, 1998. [PUBMED Abstract]
  19. Lenz G, Dreyling M, Schiegnitz E, et al.: Moderate increase of secondary hematologic malignancies after myeloablative radiochemotherapy and autologous stem-cell transplantation in patients with indolent lymphoma: results of a prospective randomized trial of the German Low Grade Lymphoma Study Group. J Clin Oncol 22 (24): 4926-33, 2004. [PUBMED Abstract]
  20. McLaughlin P, Estey E, Glassman A, et al.: Myelodysplasia and acute myeloid leukemia following therapy for indolent lymphoma with fludarabine, mitoxantrone, and dexamethasone (FND) plus rituximab and interferon alpha. Blood 105 (12): 4573-5, 2005. [PUBMED Abstract]
  21. Morton LM, Curtis RE, Linet MS, et al.: Second malignancy risks after non-Hodgkin’s lymphoma and chronic lymphocytic leukemia: differences by lymphoma subtype. J Clin Oncol 28 (33): 4935-44, 2010. [PUBMED Abstract]
  22. Mach-Pascual S, Legare RD, Lu D, et al.: Predictive value of clonality assays in patients with non-Hodgkin’s lymphoma undergoing autologous bone marrow transplant: a single institution study. Blood 91 (12): 4496-503, 1998. [PUBMED Abstract]
  23. Lillington DM, Micallef IN, Carpenter E, et al.: Detection of chromosome abnormalities pre-high-dose treatment in patients developing therapy-related myelodysplasia and secondary acute myelogenous leukemia after treatment for non-Hodgkin’s lymphoma. J Clin Oncol 19 (9): 2472-81, 2001. [PUBMED Abstract]
  24. Brown JR, Yeckes H, Friedberg JW, et al.: Increasing incidence of late second malignancies after conditioning with cyclophosphamide and total-body irradiation and autologous bone marrow transplantation for non-Hodgkin’s lymphoma. J Clin Oncol 23 (10): 2208-14, 2005. [PUBMED Abstract]
  25. Jackson GH, Wood A, Taylor PR, et al.: Early high dose chemotherapy intensification with autologous bone marrow transplantation in lymphoma associated with retention of fertility and normal pregnancies in females. Scotland and Newcastle Lymphoma Group, UK. Leuk Lymphoma 28 (1-2): 127-32, 1997. [PUBMED Abstract]
  26. Gangaraju R, Chen Y, Hageman L, et al.: Risk of venous thromboembolism in patients with non-Hodgkin lymphoma surviving blood or marrow transplantation. Cancer 125 (24): 4498-4508, 2019. [PUBMED Abstract]
  27. Westin JR, Thompson MA, Cataldo VD, et al.: Zoledronic acid for prevention of bone loss in patients receiving primary therapy for lymphomas: a prospective, randomized controlled phase III trial. Clin Lymphoma Myeloma Leuk 13 (2): 99-105, 2013. [PUBMED Abstract]
  28. Shree T, Li Q, Glaser SL, et al.: Impaired Immune Health in Survivors of Diffuse Large B-Cell Lymphoma. J Clin Oncol 38 (15): 1664-1675, 2020. [PUBMED Abstract]
  29. Ghione P, Gu JJ, Attwood K, et al.: Impaired humoral responses to COVID-19 vaccination in patients with lymphoma receiving B-cell-directed therapies. Blood 138 (9): 811-814, 2021. [PUBMED Abstract]
  30. Terpos E, Trougakos IP, Gavriatopoulou M, et al.: Low neutralizing antibody responses against SARS-CoV-2 in older patients with myeloma after the first BNT162b2 vaccine dose. Blood 137 (26): 3674-3676, 2021. [PUBMED Abstract]

Cellular Classification of B-Cell Non-Hodgkin Lymphoma

A pathologist should be consulted before a biopsy because some studies require special preparation of tissue (e.g., frozen tissue). Knowledge of cell surface markers and immunoglobulin and T-cell receptor gene rearrangements may help with diagnostic and therapeutic decisions. The clonal excess of light-chain immunoglobulin may differentiate malignant cells from reactive cells. Because the prognosis and the approach to treatment are influenced by histopathology, outside biopsy specimens should be carefully reviewed by a hematopathologist who is experienced in diagnosing lymphomas. Although lymph node biopsies are recommended whenever possible, sometimes immunophenotypic data are sufficient for diagnosis of lymphoma when fine-needle aspiration cytology or core needle biopsy is preferred.[1,2]

Historical Classification Systems

Historically, uniform treatment of patients with non-Hodgkin lymphoma (NHL) has been hampered by the lack of a uniform classification system. In 1982, results of a consensus study were published as the Working Formulation.[3] The Working Formulation combined results from six major classification systems into one classification. This allowed comparison of studies from different institutions and countries. The Rappaport classification, which also follows, is no longer in common use.

Table 1. Historical Classification Systems for Non-Hodgkin Lymphoma (NHL)
Working Formulation [3] Rappaport Classification
Low grade  
A. Small lymphocytic, consistent with chronic lymphocytic leukemia Diffuse lymphocytic, well-differentiated
B. Follicular, predominantly small-cleaved cell Nodular lymphocytic, poorly differentiated
C. Follicular, mixed small-cleaved, and large cell Nodular mixed, lymphocytic, and histiocytic
Intermediate grade  
D. Follicular, predominantly large cell Nodular histiocytic
E. Diffuse small-cleaved cell Diffuse lymphocytic, poorly differentiated
F. Diffuse mixed, small and large cell Diffuse mixed, lymphocytic, and histiocytic
G. Diffuse, large cell, cleaved, or noncleaved cell Diffuse histiocytic
High grade  
H. Immunoblastic, large cell Diffuse histiocytic
I. Lymphoblastic, convoluted, or nonconvoluted cell Diffuse lymphoblastic
J. Small noncleaved-cell, Burkitt, or non-Burkitt Diffuse undifferentiated Burkitt or non-Burkitt

Current Classification Systems

As the histopathological diagnosis of NHL has become more sophisticated with the use of immunologic and genetic techniques, a number of new pathological entities have been described.[4] In addition, the understanding and treatment of many of the previously described pathological subtypes have changed. As a result, the Working Formulation has become outdated and less useful to clinicians and pathologists. European and American pathologists have proposed a new classification, the Revised European American Lymphoma (REAL) classification.[5–8] Since 1995, members of the European and American Hematopathology societies have been collaborating on a new World Health Organization (WHO) classification, which represents an updated version of the REAL system.[9,10]

Updated REAL/WHO classification

The World Health Organization (WHO) modification of the Revised European American Lymphoma (REAL) classification recognizes three major categories of lymphoid malignancies based on morphology and cell lineage: B-cell neoplasms, T-cell/natural killer (NK)-cell neoplasms, and Hodgkin lymphoma (HL). Both lymphomas and lymphoid leukemias are included in this classification because both solid and circulating phases are present in many lymphoid neoplasms and distinction between them is artificial. For example, B-cell chronic lymphocytic leukemia (CLL) and B-cell small lymphocytic lymphoma are simply different manifestations of the same neoplasm, as are lymphoblastic lymphomas and acute lymphocytic leukemias. Within the B-cell and T-cell categories, two subdivisions are recognized: precursor neoplasms, which correspond to the earliest stages of differentiation, and more mature differentiated neoplasms.[9,10]

B-cell neoplasms

  1. Precursor B-cell neoplasm: precursor B-acute lymphoblastic leukemia/lymphoblastic lymphoma (LBL).
  2. Peripheral B-cell neoplasms.
    1. B-cell CLL/small lymphocytic lymphoma.
    2. B-cell prolymphocytic leukemia.
    3. Lymphoplasmacytic lymphoma/immunocytoma.
    4. Mantle cell lymphoma.
    5. Follicular lymphoma.
    6. Extranodal marginal zone B-cell lymphoma of mucosa-associated lymphatic tissue (MALT) type.
    7. Nodal marginal zone B-cell lymphoma (± monocytoid B cells).
    8. Splenic marginal zone lymphoma (± villous lymphocytes).
    9. Hairy cell leukemia.
    10. Plasmacytoma/plasma cell myeloma.
    11. Diffuse large B-cell lymphoma.
    12. Burkitt lymphoma.

T-cell and putative NK-cell neoplasms

  1. Precursor T-cell neoplasm: precursor T-acute lymphoblastic leukemia/LBL. For more information, see Acute Lymphoblastic Leukemia Treatment.
  2. Peripheral T-cell and NK-cell neoplasms.
    1. T-cell CLL/prolymphocytic leukemia.
    2. T-cell granular lymphocytic leukemia.
    3. Mycosis fungoides (including Sézary syndrome).
    4. Peripheral T-cell lymphoma, not otherwise specified.
    5. Hepatosplenic gamma/delta T-cell lymphoma.
    6. Subcutaneous panniculitis-like T-cell lymphoma.
    7. Extranodal T-/NK-cell lymphoma, nasal type.
    8. Nodal lymphomas of T follicular helper cell origin (including angioimmunoblastic T-cell lymphoma, follicular peripheral T-cell lymphoma, and nodal peripheral T-cell lymphoma with T follicular helper phenotype).
    9. Enteropathy-associated intestinal T-cell lymphoma.
    10. Monomorphic epitheliotropic intestinal T-cell lymphoma.
    11. Adult T-cell lymphoma/leukemia (human T-lymphotrophic virus [HTLV] 1+).
    12. Anaplastic large cell lymphoma, primary systemic type.
    13. Anaplastic large cell lymphoma, primary cutaneous type.
    14. Aggressive NK-cell leukemia.

HL

  1. Nodular lymphocyte-predominant HL.
  2. Classical HL.
    1. Nodular sclerosis HL.
    2. Lymphocyte-rich classical HL.
    3. Mixed-cellularity HL.
    4. Lymphocyte-depleted HL.

The REAL classification encompasses all lymphoproliferative neoplasms. For more information, see the following PDQ summaries:

References
  1. Zeppa P, Marino G, Troncone G, et al.: Fine-needle cytology and flow cytometry immunophenotyping and subclassification of non-Hodgkin lymphoma: a critical review of 307 cases with technical suggestions. Cancer 102 (1): 55-65, 2004. [PUBMED Abstract]
  2. Young NA, Al-Saleem T: Diagnosis of lymphoma by fine-needle aspiration cytology using the revised European-American classification of lymphoid neoplasms. Cancer 87 (6): 325-45, 1999. [PUBMED Abstract]
  3. National Cancer Institute sponsored study of classifications of non-Hodgkin’s lymphomas: summary and description of a working formulation for clinical usage. The Non-Hodgkin’s Lymphoma Pathologic Classification Project. Cancer 49 (10): 2112-35, 1982. [PUBMED Abstract]
  4. Pugh WC: Is the working formulation adequate for the classification of the low grade lymphomas? Leuk Lymphoma 10 (Suppl 1): 1-8, 1993.
  5. Harris NL, Jaffe ES, Stein H, et al.: A revised European-American classification of lymphoid neoplasms: a proposal from the International Lymphoma Study Group. Blood 84 (5): 1361-92, 1994. [PUBMED Abstract]
  6. Pittaluga S, Bijnens L, Teodorovic I, et al.: Clinical analysis of 670 cases in two trials of the European Organization for the Research and Treatment of Cancer Lymphoma Cooperative Group subtyped according to the Revised European-American Classification of Lymphoid Neoplasms: a comparison with the Working Formulation. Blood 87 (10): 4358-67, 1996. [PUBMED Abstract]
  7. Armitage JO, Weisenburger DD: New approach to classifying non-Hodgkin’s lymphomas: clinical features of the major histologic subtypes. Non-Hodgkin’s Lymphoma Classification Project. J Clin Oncol 16 (8): 2780-95, 1998. [PUBMED Abstract]
  8. A clinical evaluation of the International Lymphoma Study Group classification of non-Hodgkin’s lymphoma. The Non-Hodgkin’s Lymphoma Classification Project. Blood 89 (11): 3909-18, 1997. [PUBMED Abstract]
  9. Pileri SA, Milani M, Fraternali-Orcioni G, et al.: From the R.E.A.L. Classification to the upcoming WHO scheme: a step toward universal categorization of lymphoma entities? Ann Oncol 9 (6): 607-12, 1998. [PUBMED Abstract]
  10. Society for Hematopathology Program: Society for Hematopathology Program. Am J Surg Pathol 21 (1): 114-121, 1997.

Stage Information for Aggressive B-Cell Non-Hodgkin Lymphoma

Stage is important in selecting a treatment for patients with non-Hodgkin lymphoma (NHL). Chest and abdominal computed tomography (CT) scans are usually part of the staging evaluation for all patients with lymphoma. The staging system for NHL is similar to the staging system used for Hodgkin lymphoma (HL).

It is common for patients with NHL to have involvement of the following sites:

  • Noncontiguous lymph nodes.
  • Waldeyer ring.
  • Epitrochlear nodes.
  • Gastrointestinal tract.
  • Extranodal presentations. (A single extranodal site is occasionally the only site of involvement in patients with diffuse lymphoma.)
  • Bone marrow.
  • Liver (especially common in patients with low-grade lymphomas).

Cytological examination of cerebrospinal fluid may be positive in patients with aggressive NHL. Involvement of hilar and mediastinal lymph nodes is less common than in HL. Mediastinal adenopathy, however, is a prominent feature of lymphoblastic lymphoma and primary mediastinal B-cell lymphoma, entities primarily found in young adults.

Most patients with NHL present with advanced (stage III or stage IV) disease often identified by CT scans or biopsies of the bone marrow and other accessible sites of involvement. In a retrospective review of over 32,000 cases of lymphoma in France, up to 40% of diagnoses were made by core needle biopsy, and 60% were made by excisional biopsy.[1] After expert review, core needle biopsy provided a definite diagnosis in 92.3% of cases; excisional biopsy provided a definite diagnosis in 98.1% of cases (P < .0001). Laparoscopic biopsy or laparotomy is not required for staging but rarely may be necessary to establish a diagnosis or histological type.[2]

Positron emission tomography (PET) with fluorine F 18-fludeoxyglucose can be used for initial staging. It can also be used for follow-up after therapy as a supplement to CT scanning.[3] Multiple studies have demonstrated that interim PET scans after two to four cycles of therapy do not provide reliable prognostic information. A large cooperative group trial (ECOG-E344 [NCT00274924]) reported problems with interobserver reproducibility. Two prospective trials and one meta-analysis showed no differences in outcomes between PET-negative and PET-positive/biopsy-negative patients.[4–7]

In a retrospective study of 130 patients with diffuse large B-cell lymphoma, PET scanning identified all clinically important marrow involvement from lymphoma, and bone marrow biopsy did not upstage any patient’s lymphoma.[8] A retrospective study of 580 patients with follicular lymphoma from seven National Cancer Institute–sponsored trials showed no improvement in assessing response to therapy when bone marrow biopsy was added to radiological imaging.[9] The workup of NHL should include bone marrow biopsy when management would change (e.g., determining limited stage vs. advanced stage) or when evaluating cytopenias.

For patients with follicular lymphoma, a positive PET result after therapy has a worse prognosis; however, it is unclear whether a positive PET result is predictive when further or different therapy is implemented.[10]

Staging Subclassification System

Lugano classification

The American Joint Committee on Cancer (AJCC) has adopted the Lugano classification to evaluate and stage lymphoma.[11] The Lugano classification system replaces the Ann Arbor classification system, which was adopted in 1971 at the Ann Arbor Conference,[12] with some modifications 18 years later from the Cotswolds meeting.[13,14]

Table 2. Lugano Classification for Hodgkin and Non-Hodgkin Lymphomaa
Stage Stage Description Illustration
CSF = cerebrospinal fluid; CT = computed tomography; DLBCL = diffuse large B-cell lymphoma; NHL = non-Hodgkin lymphoma.
aHodgkin and Non-Hodgkin Lymphomas. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp. 937–58.
bStage II bulky may be considered either early or advanced stage based on lymphoma histology and prognostic factors.
cThe definition of disease bulk varies according to lymphoma histology. In the Lugano classification, bulk ln Hodgkin lymphoma is defined as a mass greater than one-third of the thoracic diameter on CT of the chest or a mass >10 cm. For NHL, the recommended definitions of bulk vary by lymphoma histology. In follicular lymphoma, 6 cm has been suggested based on the Follicular Lymphoma International Prognostic Index-2 and its validation. In DLBCL, cutoffs ranging from 5 cm to 10 cm have been used, although 10 cm is recommended.
Limited stage
I Involvement of a single lymphatic site (i.e., nodal region, Waldeyer’s ring, thymus, or spleen).
EnlargeStage I adult lymphoma; drawing shows cancer in one lymph node group and in the spleen. Also shown are the Waldeyer’s ring and the thymus. An inset shows a lymph node with a lymph vessel, an artery, and a vein. Cancer cells are shown in the lymph node.
IE Single extralymphatic site in the absence of nodal involvement (rare in Hodgkin lymphoma).  
II Involvement of two or more lymph node regions on the same side of the diaphragm.
EnlargeStage II adult lymphoma; drawing shows cancer in two lymph node groups above the diaphragm and below the diaphragm. An inset shows a lymph node with a lymph vessel, an artery, and a vein. Cancer cells are shown in the lymph node.
IIE Contiguous extralymphatic extension from a nodal site with or without involvement of other lymph node regions on the same side of the diaphragm.
EnlargeStage IIE adult lymphoma; drawing shows cancer that has spread from a group of lymph nodes to a nearby area. Also shown is a lung and the diaphragm. An inset shows a lymph node with a lymph vessel, an artery, and a vein. Cancer cells are shown in the lymph node.
II bulkyb Stage II with disease bulk.c  
Advanced stage
III Involvement of lymph node regions on both sides of the diaphragm; nodes above the diaphragm with spleen involvement.
EnlargeStage III adult lymphoma; drawing shows the right and left sides of the body. The right side of the body shows cancer in a group of lymph nodes above the diaphragm and below the diaphragm. The left side of the body shows cancer in a group of lymph nodes above the diaphragm and cancer in the spleen.
IV Diffuse or disseminated involvement of one or more extralymphatic organs, with or without associated lymph node involvement; or noncontiguous extralymphatic organ involvement in conjunction with nodal stage II disease; or any extralymphatic organ involvement in nodal stage III disease. Stage IV includes any involvement of the CSF, bone marrow, liver, or multiple lung lesions (other than by direct extension in stage IIE disease).
EnlargeStage IV adult lymphoma; drawing shows four panels: (a) the top left panel shows cancer in the liver; (b) the top right panel shows cancer in the left lung and in two groups of lymph nodes below the diaphragm; (c) the bottom left panel shows cancer in the left lung and in a group of lymph nodes above the diaphragm and below the diaphragm; and (d) the bottom right panel shows cancer in both lungs, the liver, and the bone marrow (pullout). Also shown is primary cancer in the lymph nodes and a pullout of the brain with cerebrospinal fluid (in blue).
Note: Hodgkin lymphoma uses A or B designation with stage group. A/B is no longer used in NHL.

Occasionally, specialized staging systems are used. The physician should be aware of the system used in a specific report.

The E designation is used when extranodal lymphoid malignancies arise in tissues separate from, but near, the major lymphatic aggregates. Stage IV refers to disease that is diffusely spread throughout an extranodal site, such as the liver. If pathological proof of involvement of one or more extralymphatic sites has been documented, the symbol for the site of involvement, followed by a plus sign (+), is listed.

Table 3. Notation to Identify Specific Sites
N = nodes H = liver L = lung M = bone marrow
S = spleen P = pleura O = bone D = skin

Current practice assigns a clinical stage based on the findings of the clinical evaluation and a pathological stage based on the findings from invasive procedures beyond the initial biopsy.

For example, on percutaneous biopsy, a patient with inguinal adenopathy and a positive lymphangiogram without systemic symptoms might have involvement of the liver and bone marrow. The precise stage of such a patient would be clinical stage IIA, pathological stage IVA(H+)(M+).

Several other factors that are not included in the above staging system are important for the staging and prognosis of patients with NHL. These factors include the following:

  • Age.
  • Performance status (PS).
  • Tumor size.
  • Lactate dehydrogenase (LDH) values.
  • The number of extranodal sites.

The National Comprehensive Cancer Network International Prognostic Index (IPI) for aggressive NHL (diffuse large cell lymphoma) identifies the following five significant risk factors prognostic of overall survival (OS) and their associated risk scores:[15]

  • Age.
    • <40 years: 0.
    • 41–60 years: 1.
    • 61–75 years: 2.
    • >75 years: 3.
  • Stage III/IV: 1.
  • Performance status (PS) 2/3/4: 1.
  • Serum lactate dehydrogenase (LDH).
    • Normalized: 0.
    • >1x–3x: 1.
    • >3x: 2.
  • Number of extranodal sites ≥2: 1.

Risk scores:

  • Low (0 or 1): 5-year OS rate, 96%; progression-free survival (PFS) rate, 91%.
  • Low intermediate (2 or 3): 5-year OS rate, 82%; PFS rate, 74%.
  • High intermediate (4 or 5): 5-year OS rate, 64%; PFS rate, 51%.
  • High (>6): 5-year OS rate, 33%; PFS rate, 30%.

Age-adjusted and stage-adjusted modifications of this IPI are used for younger patients with localized disease.[16] Shorter intervals of time between diagnosis and treatment appear to be a surrogate for poor prognostic biological factors.[17]

The BCL2 gene and rearrangement of the MYC gene or dual overexpression of the MYC gene, or both, confer a particularly poor prognosis.[18,19] Patients at high risk of relapse may benefit from consolidation therapy or other approaches under clinical evaluation.[20] Molecular profiles of gene expression using DNA microarrays may help to stratify patients in the future for therapies directed at specific targets and to better predict survival after standard chemotherapy.[21]

References
  1. Syrykh C, Chaouat C, Poullot E, et al.: Lymph node excisions provide more precise lymphoma diagnoses than core biopsies: a French Lymphopath network survey. Blood 140 (24): 2573-2583, 2022. [PUBMED Abstract]
  2. Mann GB, Conlon KC, LaQuaglia M, et al.: Emerging role of laparoscopy in the diagnosis of lymphoma. J Clin Oncol 16 (5): 1909-15, 1998. [PUBMED Abstract]
  3. Barrington SF, Mikhaeel NG, Kostakoglu L, et al.: Role of imaging in the staging and response assessment of lymphoma: consensus of the International Conference on Malignant Lymphomas Imaging Working Group. J Clin Oncol 32 (27): 3048-58, 2014. [PUBMED Abstract]
  4. Horning SJ, Juweid ME, Schöder H, et al.: Interim positron emission tomography scans in diffuse large B-cell lymphoma: an independent expert nuclear medicine evaluation of the Eastern Cooperative Oncology Group E3404 study. Blood 115 (4): 775-7; quiz 918, 2010. [PUBMED Abstract]
  5. Moskowitz CH, Schöder H, Teruya-Feldstein J, et al.: Risk-adapted dose-dense immunochemotherapy determined by interim FDG-PET in Advanced-stage diffuse large B-Cell lymphoma. J Clin Oncol 28 (11): 1896-903, 2010. [PUBMED Abstract]
  6. Pregno P, Chiappella A, Bellò M, et al.: Interim 18-FDG-PET/CT failed to predict the outcome in diffuse large B-cell lymphoma patients treated at the diagnosis with rituximab-CHOP. Blood 119 (9): 2066-73, 2012. [PUBMED Abstract]
  7. Sun N, Zhao J, Qiao W, et al.: Predictive value of interim PET/CT in DLBCL treated with R-CHOP: meta-analysis. Biomed Res Int 2015: 648572, 2015. [PUBMED Abstract]
  8. Khan AB, Barrington SF, Mikhaeel NG, et al.: PET-CT staging of DLBCL accurately identifies and provides new insight into the clinical significance of bone marrow involvement. Blood 122 (1): 61-7, 2013. [PUBMED Abstract]
  9. Rutherford SC, Yin J, Pederson L, et al.: Relevance of Bone Marrow Biopsies for Response Assessment in US National Cancer Institute National Clinical Trials Network Follicular Lymphoma Clinical Trials. J Clin Oncol 41 (2): 336-342, 2023. [PUBMED Abstract]
  10. Pyo J, Won Kim K, Jacene HA, et al.: End-therapy positron emission tomography for treatment response assessment in follicular lymphoma: a systematic review and meta-analysis. Clin Cancer Res 19 (23): 6566-77, 2013. [PUBMED Abstract]
  11. Hodgkin and non-Hodgkin lymphoma. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. Springer; 2017, pp. 937–58.
  12. Carbone PP, Kaplan HS, Musshoff K, et al.: Report of the Committee on Hodgkin’s Disease Staging Classification. Cancer Res 31 (11): 1860-1, 1971. [PUBMED Abstract]
  13. Lister TA, Crowther D, Sutcliffe SB, et al.: Report of a committee convened to discuss the evaluation and staging of patients with Hodgkin’s disease: Cotswolds meeting. J Clin Oncol 7 (11): 1630-6, 1989. [PUBMED Abstract]
  14. National Cancer Institute sponsored study of classifications of non-Hodgkin’s lymphomas: summary and description of a working formulation for clinical usage. The Non-Hodgkin’s Lymphoma Pathologic Classification Project. Cancer 49 (10): 2112-35, 1982. [PUBMED Abstract]
  15. Zhou Z, Sehn LH, Rademaker AW, et al.: An enhanced International Prognostic Index (NCCN-IPI) for patients with diffuse large B-cell lymphoma treated in the rituximab era. Blood 123 (6): 837-42, 2014. [PUBMED Abstract]
  16. Møller MB, Christensen BE, Pedersen NT: Prognosis of localized diffuse large B-cell lymphoma in younger patients. Cancer 98 (3): 516-21, 2003. [PUBMED Abstract]
  17. Maurer MJ, Ghesquières H, Link BK, et al.: Diagnosis-to-Treatment Interval Is an Important Clinical Factor in Newly Diagnosed Diffuse Large B-Cell Lymphoma and Has Implication for Bias in Clinical Trials. J Clin Oncol 36 (16): 1603-1610, 2018. [PUBMED Abstract]
  18. Scott DW, King RL, Staiger AM, et al.: High-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements with diffuse large B-cell lymphoma morphology. Blood 131 (18): 2060-2064, 2018. [PUBMED Abstract]
  19. Horn H, Ziepert M, Becher C, et al.: MYC status in concert with BCL2 and BCL6 expression predicts outcome in diffuse large B-cell lymphoma. Blood 121 (12): 2253-63, 2013. [PUBMED Abstract]
  20. A predictive model for aggressive non-Hodgkin’s lymphoma. The International Non-Hodgkin’s Lymphoma Prognostic Factors Project. N Engl J Med 329 (14): 987-94, 1993. [PUBMED Abstract]
  21. Sha C, Barrans S, Cucco F, et al.: Molecular High-Grade B-Cell Lymphoma: Defining a Poor-Risk Group That Requires Different Approaches to Therapy. J Clin Oncol 37 (3): 202-212, 2019. [PUBMED Abstract]

Aggressive B-Cell Non-Hodgkin Lymphoma

Aggressive B-cell non-Hodgkin lymphoma (NHL) includes the following subtypes:

  • Diffuse large B-cell lymphoma.
  • Primary mediastinal large B-cell lymphoma.
  • Intravascular large B-cell lymphoma (intravascular lymphomatosis).
  • Follicular lymphoma (grade 3b).
  • Mantle cell lymphoma. (For more information, see Mantle Cell Lymphoma Treatment.)
  • Burkitt lymphoma/diffuse small noncleaved-cell lymphoma.
  • B-cell lymphoblastic lymphoma.
  • Primary effusion lymphoma.
  • Plasmablastic lymphoma.
  • Polymorphic posttransplant lymphoproliferative disorder.
  • Lymphomatoid granulomatosis.

Diffuse Large B-Cell Lymphoma

Diffuse large B-cell lymphoma (DLBCL) is the most common type of NHL and makes up 30% of newly diagnosed cases.[1] Most patients present with rapidly enlarging masses, often with both local and systemic symptoms (designated B symptoms with fever, recurrent night sweats, or weight loss). For more information about weight loss, see Nutrition in Cancer Care.

Some cases of large B-cell lymphoma have a prominent background of reactive T cells and histiocytes, and is so-called T-cell/histiocyte-rich large B-cell lymphoma. This subtype of large cell lymphoma has frequent liver, spleen, and bone marrow involvement; however, the outcome is equivalent to that of similarly staged patients with DLBCL.[2–4] At diagnosis, some patients with DLBCL have a concomitant indolent small B-cell component. While overall survival (OS) appears similar to de novo DLBCL after multidrug chemotherapy, there is a higher risk of indolent relapse.[5]

Prognosis

For most patients, localized disease can be cured with combined-modality therapy or combination chemotherapy alone, typically R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone).[6] Among patients with advanced-stage disease, 50% are cured with doxorubicin-based combination chemotherapy and rituximab, typically Pola-R-CHP (polatuzumab, rituximab, cyclophosphamide, doxorubicin, and prednisone) or R-CHOP.[7–10]

The National Comprehensive Cancer Network has identified risk factors and associated risk scores.

The BCL2 gene and rearrangement of the MYC gene or dual overexpression of the MYC gene, or both, confer a particularly poor prognosis.[11–13] Dose-intensive therapies, infusional therapies, and stem cell transplant (SCT) consolidation are being explored in this high-risk group.[14–17]

In a retrospective review of 117 patients with relapsed or refractory DLBCL who underwent autologous SCT, the 4-year OS rate was 25% for patients with double-hit lymphomas (rearrangement of BCL2 and MYC), 61% for patients with double-expressor lymphomas (no rearrangement, but increased expression of BCL2 and MYC), and 70% for patients without these features.[18]

Molecular profiles of gene expression using DNA microarrays may help to stratify patients in the future for therapies directed at specific targets and to better predict survival after standard chemotherapy.[19] For example, true ALK-positive large B-cell lymphomas are extremely rare, and they do not respond well to conventional R-CHOP therapy. Anecdotal responses to ALK inhibitors like lorlatinib or alectinib have been reported.[20][Level of evidence C3] Coexpression of CD20 and CD30 may define a subgroup of patients with DLBCL with a unique molecular signature and a more favorable prognosis. Patients in this subgroup may be treated with an anti-CD30–specific therapy, such as brentuximab vedotin.[21] Patients with DLBCL who are event-free after 2 years have a subsequent OS equivalent to that of the age- and sex-matched general population.[22]

Patients at high risk for central nervous system (CNS) relapse may be candidates for prophylaxis. For more information, see the CNS Prophylaxis section in the Treatment of Aggressive, Noncontiguous Stage II/III/IV B-Cell Non-Hodgkin Lymphoma section.

Primary Mediastinal Large B-Cell Lymphoma

Primary mediastinal (thymic) large B-cell lymphoma (PMBCL) is a subset of DLBCL with molecular characteristics that are most similar to nodular-sclerosing Hodgkin lymphoma (HL).[23] Mediastinal lymphomas with features intermediate between primary mediastinal B-cell lymphoma and nodular-sclerosing HL are called mediastinal gray-zone lymphomas.[24,25] Patients are usually female and young (median age, 30–40 years). Patients present with a locally invasive anterior mediastinal mass that may cause respiratory symptoms or superior vena cava syndrome.

Prognosis and therapy are the same as for other comparably staged patients with DLBCL. Uncontrolled phase II studies using dose-adjusted R-EPOCH (etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin plus rituximab) or R-CHOP showed high cure rates while avoiding any mediastinal radiation.[25–31][Level of evidence C1] These results suggest that patients who receive R-CHOP–based regimens may avoid the serious long-term complications of radiation therapy when given with chemotherapy. Posttreatment fluorine F 18-fludeoxyglucose (18F-FDG) positron emission tomography–computed tomography (PET-CT) scans are controversial. It remains unclear if PET scans can reliably identify patients who can undergo or omit radiation therapy consolidation.[26,32–34]

A retrospective review of 109 patients with PMBCL showed that 63% had a negative end-of-treatment PET-CT (EOT-PET-CT) (Deauville score 1–3).[35] No radiation therapy was offered and the 5-year time-to-progression rate (similar to disease-free survival, but restricted to lymphoma relapse) was 90% (95% confidence interval [CI], 74%–95%), and the 5-year OS rate was 97% (95% CI, 88%–99%).[35][Level of evidence C3] Patients with a positive EOT-PET-CT received radiation therapy consolidation. It is unclear from this study whether those patients might have done just as well without radiation therapy. Clinicians may monitor patients with Deauville 4 scores on EOT-PET-CT scans for improvement over time, as an alternative to giving radiation therapy. However, this approach has not been studied in a clinical trial.

Because PMBCL is characterized by high expression of programmed death-ligand 1 and variable expression of CD30, a phase II study evaluated nivolumab plus brentuximab vedotin in 30 patients with relapsed disease. With a median follow-up of 11.1 months, the objective response rate was 73% (95% CI, 54%−88%).[36][Level of evidence C3] Similarly, a phase II trial of pembrolizumab in 53 patients with relapsed or refractory disease showed an objective response rate of 41.5%. With a median follow-up of 48.7 months, the 4-year progression-free survival (PFS) rate was 33.0% and the 4-year OS rate was 45.3%.[37][Level of evidence C3] Among the 11 patients who achieved a complete response, all remained in complete response at the time of the final analysis.

Among those who had received two prior lines of therapy, more than one-half of patients who received chimeric antigen receptor (CAR) T-cell therapy with lisocabtagene maraleucel had a disease response.[38][Level of evidence C3]

Intravascular Large B-Cell Lymphoma (Intravascular Lymphomatosis)

Intravascular lymphomatosis is characterized by large cell lymphoma confined to the intravascular lumen. The brain, kidneys, lungs, and skin are the organs most likely to be affected by intravascular lymphomatosis.

With the use of aggressive R-CHOP–based combination chemotherapy, as is used in DLBCL, the prognosis is similar to that of conventional stage IV DLBCL.[39–41]

Follicular Lymphoma (Grade 3b)

Prognosis

The natural history of follicular large cell lymphoma remains controversial.[42] While there is agreement about the significant number of long-term disease-free survivors with early-stage disease, the potential for cure in patients with advanced disease (stage III or stage IV) remains uncertain. Some groups report a continuous relapse rate similar to the other follicular lymphomas (a pattern of indolent lymphoma).[43] Other investigators report a plateau in freedom from progression at levels expected for an aggressive lymphoma (40% at 10 years).[44,45] This discrepancy may be caused by variations in histological classification between institutions and the rarity of patients with follicular large cell lymphoma. A retrospective review of 252 patients, all treated with anthracycline-containing combination chemotherapy, showed that patients with more than 50% diffuse components on biopsy had a worse OS than other patients with follicular large cell lymphoma.[46]

Therapeutic approaches

Treatment of follicular large cell lymphoma is more similar to the treatment of aggressive NHL than it is to the treatment of indolent NHL. In support of this approach, treatment with high-dose chemotherapy and autologous hematopoietic peripheral SCT shows the same curative potential in patients with follicular large cell lymphoma who relapse as it does in patients with diffuse large cell lymphoma who relapse.[47][Level of evidence C1]

Among patients who had received two prior lines of therapy, more than one-half who received CAR T-cell therapy with lisocabtagene maraleucel had a disease response.[38][Level of evidence C3]

Burkitt Lymphoma/Diffuse Small Noncleaved-Cell Lymphoma

Burkitt lymphoma/diffuse small noncleaved-cell lymphoma typically involves younger patients and represents the most common type of pediatric NHL.[48] These types of aggressive extranodal B-cell lymphomas are characterized by translocation and deregulation of the MYC gene on chromosome 8.[49] A subgroup of patients with dual translocation of MYC and BCL2 appear to have an extremely poor outcome despite aggressive therapy (median OS, 5 months).[50][Level of evidence C1]

In some patients with larger B cells, there is morphological overlap with DLBCL. These Burkitt-like large cell lymphomas show MYC deregulation, extremely high proliferation rates, and a gene-expression profile as expected for classic Burkitt lymphoma.[51–53] Endemic cases, usually from Africa, involve the facial bones or jaws of children, mostly containing Epstein-Barr virus (EBV) genomes. Sporadic cases usually involve the gastrointestinal system, ovaries, or kidneys. Patients present with rapidly growing masses and a very high lactate dehydrogenase (LDH) level but are potentially curable with intensive doxorubicin-based combination chemotherapy.

Therapeutic approaches

Treatment of Burkitt lymphoma/diffuse small noncleaved-cell lymphoma involves aggressive multidrug regimens in combination with rituximab, similar to those used for the advanced-stage aggressive lymphomas (DLBCL).[54–57] Aggressive combination chemotherapy, which is modeled after that used in childhood Burkitt lymphoma, has been successful for adult patients with more than 60% of advanced-stage patients free of disease at 5 years.[58–61] Adverse prognostic factors include bulky abdominal disease and a high serum LDH level. Patients with Burkitt lymphoma have a 20% to 30% lifetime risk of CNS involvement. Prophylaxis with intrathecal chemotherapy is required as part of induction therapy.[62] Patients with HIV-associated Burkitt lymphoma also benefit from less-toxic modification of the aggressive multidrug regimens in combination with rituximab.[63][Level of evidence C3] For more information, see Primary Central Nervous System Lymphoma Treatment and AIDS-Related Lymphoma Treatment.

B-Cell Lymphoblastic Lymphoma

B-cell lymphoblastic lymphoma (precursor T-cell) is a very aggressive form of NHL. Treatment is usually modeled after that for acute lymphoblastic leukemia. Intensive combination chemotherapy with or without bone marrow transplant is the standard treatment for this aggressive histological type of NHL.[64–66] Radiation therapy is sometimes given to areas of bulky tumor masses. Because these forms of NHL tend to progress quickly, combination chemotherapy is instituted rapidly once the diagnosis is confirmed. Careful review of the pathological specimens, bone marrow aspirate, biopsy specimen, cerebrospinal fluid cytology, and lymphocyte marker constitute the most important aspects of the pretreatment staging workup. For more information, see Acute Lymphoblastic Leukemia Treatment.

Primary Effusion Lymphoma

Primary effusion lymphoma presents exclusively or mainly in the pleural, pericardial, or abdominal cavities in the absence of an identifiable tumor mass.[67] Patients are usually HIV seropositive, and the tumor usually contains Kaposi sarcoma–associated herpes virus/human herpes virus 8.[68]

Prognosis

The prognosis of primary effusion lymphoma is extremely poor.

Therapeutic approaches

Therapy is usually modeled after the treatment of comparably staged diffuse large cell lymphomas.

Plasmablastic Lymphoma

Plasmablastic lymphoma is most often seen in patients with HIV infection and is characterized by CD20-negative large B cells with plasmacytic features. This type of lymphoma has a very aggressive clinical course, including poor responses and short remissions with standard chemotherapy.[69] Anecdotal reports suggest using aggressive chemotherapy for Burkitt or lymphoblastic lymphoma, followed by SCT consolidation in responding patients, when feasible.[69–71]

Polymorphic Posttransplant Lymphoproliferative Disorder

Patients who undergo a transplant of the heart, lung, liver, kidney, or pancreas usually require lifelong immunosuppression. This may result in posttransplant lymphoproliferative disorder (PTLD) in 1% to 3% of recipients, which appears as an aggressive lymphoma.[72] Pathologists can distinguish a polyclonal B-cell hyperplasia from a monoclonal B-cell lymphoma; both are almost always associated with EBV.[73]

Prognosis

Poor performance status, grafted organ involvement, high International Prognostic Index, elevated LDH, and multiple sites of disease are poor prognostic factors for PTLD.[74,75]

Therapeutic options

In some cases, withdrawal of immunosuppression results in eradication of the lymphoma.[76,77] When this is unsuccessful or not feasible, a course of rituximab may be considered because it has shown durable remissions in approximately 60% of patients and a favorable toxicity profile.[76,78,79] If these measures fail, doxorubicin-based combination chemotherapy (R-CHOP) is recommended, although some patients can avoid cytotoxic therapy.[79,80] Localized presentations can be controlled with surgery or radiation therapy alone. These localized mass lesions, which may grow over a period of months, are often phenotypically polyclonal and tend to occur within weeks or a few months after transplant.[73] Multifocal, rapidly progressive disease occurs late after transplant (>1 year) and is usually phenotypically monoclonal and associated with EBV.[81] These patients may have durable remissions using standard chemotherapy regimens for aggressive lymphoma.[81–83] Instances of EBV-negative PTLD occur even later (median, 5 years posttransplant) and have a worse prognosis; R-CHOP can be given directly in this circumstance.[84] A sustained clinical response in patients with chemotherapy-refractory disease was attained using an immunotoxin (anti-CD22 B-cell surface antigen antibody linked with ricin, a plant toxin).[85] An anti-interleukin-6 monoclonal antibody is also under clinical evaluation.[86]

Lymphomatoid Granulomatosis

Lymphomatoid granulomatosis is an EBV-positive large B-cell lymphoma with a predominant T-cell background.[87,88] The histology shows association with angioinvasion and vasculitis, usually manifesting as pulmonary lesions or paranasal sinus involvement.

Patients are managed like others with diffuse large cell lymphoma and require doxorubicin-based combination chemotherapy.

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  77. Dierickx D, Tousseyn T, Gheysens O: How I treat posttransplant lymphoproliferative disorders. Blood 126 (20): 2274-83, 2015. [PUBMED Abstract]
  78. Kuehnle I, Huls MH, Liu Z, et al.: CD20 monoclonal antibody (rituximab) for therapy of Epstein-Barr virus lymphoma after hemopoietic stem-cell transplantation. Blood 95 (4): 1502-5, 2000. [PUBMED Abstract]
  79. Trappe RU, Dierickx D, Zimmermann H, et al.: Response to Rituximab Induction Is a Predictive Marker in B-Cell Post-Transplant Lymphoproliferative Disorder and Allows Successful Stratification Into Rituximab or R-CHOP Consolidation in an International, Prospective, Multicenter Phase II Trial. J Clin Oncol 35 (5): 536-543, 2017. [PUBMED Abstract]
  80. Leblond V, Sutton L, Dorent R, et al.: Lymphoproliferative disorders after organ transplantation: a report of 24 cases observed in a single center. J Clin Oncol 13 (4): 961-8, 1995. [PUBMED Abstract]
  81. Mamzer-Bruneel MF, Lomé C, Morelon E, et al.: Durable remission after aggressive chemotherapy for very late post-kidney transplant lymphoproliferation: A report of 16 cases observed in a single center. J Clin Oncol 18 (21): 3622-32, 2000. [PUBMED Abstract]
  82. Swinnen LJ: Durable remission after aggressive chemotherapy for post-cardiac transplant lymphoproliferation. Leuk Lymphoma 28 (1-2): 89-101, 1997. [PUBMED Abstract]
  83. McCarthy M, Ramage J, McNair A, et al.: The clinical diversity and role of chemotherapy in lymphoproliferative disorder in liver transplant recipients. J Hepatol 27 (6): 1015-21, 1997. [PUBMED Abstract]
  84. Leblond V, Davi F, Charlotte F, et al.: Posttransplant lymphoproliferative disorders not associated with Epstein-Barr virus: a distinct entity? J Clin Oncol 16 (6): 2052-9, 1998. [PUBMED Abstract]
  85. Senderowicz AM, Vitetta E, Headlee D, et al.: Complete sustained response of a refractory, post-transplantation, large B-cell lymphoma to an anti-CD22 immunotoxin. Ann Intern Med 126 (11): 882-5, 1997. [PUBMED Abstract]
  86. Haddad E, Paczesny S, Leblond V, et al.: Treatment of B-lymphoproliferative disorder with a monoclonal anti-interleukin-6 antibody in 12 patients: a multicenter phase 1-2 clinical trial. Blood 97 (6): 1590-7, 2001. [PUBMED Abstract]
  87. Guinee D, Jaffe E, Kingma D, et al.: Pulmonary lymphomatoid granulomatosis. Evidence for a proliferation of Epstein-Barr virus infected B-lymphocytes with a prominent T-cell component and vasculitis. Am J Surg Pathol 18 (8): 753-64, 1994. [PUBMED Abstract]
  88. Myers JL, Kurtin PJ, Katzenstein AL, et al.: Lymphomatoid granulomatosis. Evidence of immunophenotypic diversity and relationship to Epstein-Barr virus infection. Am J Surg Pathol 19 (11): 1300-12, 1995. [PUBMED Abstract]

Other Lymphoproliferative and Related Disorders

Castleman Disease

A biopsy of localized or multifocal collections of lymph nodes may lead to a diagnosis of Castleman disease (CD). Strictly speaking, this uncommon diagnosis is not a lymphoma or even a malignancy. Yet, many patients with CD may be seen and treated by hematologists or oncologists.

Localized or unicentric CD is usually asymptomatic and occurs in the mediastinum, which is the most common presentation for CD.[1] Watchful waiting, surgery, or radiation therapy can be used to treat this indolent form. Multicentric CD (30% of CD patients) presents with lymphadenopathy in multiple sites; symptoms such as fever, night sweats, weight loss, and fatigue; and laboratory abnormalities such as anemia, low albumin level, elevated C-reactive protein level, and high fibrinogen level.[1] Multicentric CD (MCD) is subdivided into human herpes virus-8–associated MCD (usually with HIV or severe immunocompromise) or idiopathic MCD. Cytopenias and cytokine storm are attributed to interleukin-6 (IL-6) overproduction. MCD is a feature seen in POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin abnormalities) syndrome [2] and TAFRO (thrombocytopenia, anasarca, fever, reticulin fibrosis, and organomegaly) syndrome.[3,4] Therapy with siltuximab (an anti–IL-6 monoclonal antibody), rituximab (an anti-CD20 monoclonal antibody), or chemotherapeutic agents has been presented in anecdotal nonrandomized series.[5–8]

True Histiocytic Lymphoma

True histiocytic lymphomas are very rare tumors that show histiocytic differentiation and express histiocytic markers in the absence of B-cell or T-cell lineage-specific immunologic markers.[9,10] Care must be taken with immunophenotypic tests to exclude anaplastic large cell lymphoma or hemophagocytic syndromes caused by viral infections, especially Epstein-Barr virus.

Therapeutic options

Therapy is modeled after the treatment of comparably staged diffuse large cell lymphomas, but the optimal approach remains to be defined.

References
  1. van Rhee F, Voorhees P, Dispenzieri A, et al.: International, evidence-based consensus treatment guidelines for idiopathic multicentric Castleman disease. Blood 132 (20): 2115-2124, 2018. [PUBMED Abstract]
  2. Dispenzieri A: POEMS Syndrome: 2019 Update on diagnosis, risk-stratification, and management. Am J Hematol 94 (7): 812-827, 2019. [PUBMED Abstract]
  3. Zhang Y, Suo SS, Yang HJ, et al.: Clinical features and treatment of 7 Chinese TAFRO syndromes from 96 de novo Castleman diseases: a 10-year retrospective study. J Cancer Res Clin Oncol 146 (2): 357-365, 2020. [PUBMED Abstract]
  4. Fujimoto S, Sakai T, Kawabata H, et al.: Is TAFRO syndrome a subtype of idiopathic multicentric Castleman disease? Am J Hematol 94 (9): 975-983, 2019. [PUBMED Abstract]
  5. Tonialini L, Bonfichi M, Ferrero S, et al.: Siltuximab in relapsed/refractory multicentric Castleman disease: Experience of the Italian NPP program. Hematol Oncol 36 (4): 689-692, 2018. [PUBMED Abstract]
  6. Dong Y, Zhang L, Nong L, et al.: Effectiveness of rituximab-containing treatment regimens in idiopathic multicentric Castleman disease. Ann Hematol 97 (9): 1641-1647, 2018. [PUBMED Abstract]
  7. Zhang L, Zhao AL, Duan MH, et al.: Phase 2 study using oral thalidomide-cyclophosphamide-prednisone for idiopathic multicentric Castleman disease. Blood 133 (16): 1720-1728, 2019. [PUBMED Abstract]
  8. van Rhee F, Wong RS, Munshi N, et al.: Siltuximab for multicentric Castleman’s disease: a randomised, double-blind, placebo-controlled trial. Lancet Oncol 15 (9): 966-74, 2014. [PUBMED Abstract]
  9. Soslow RA, Davis RE, Warnke RA, et al.: True histiocytic lymphoma following therapy for lymphoblastic neoplasms. Blood 87 (12): 5207-12, 1996. [PUBMED Abstract]
  10. Kamel OW, Gocke CD, Kell DL, et al.: True histiocytic lymphoma: a study of 12 cases based on current definition. Leuk Lymphoma 18 (1-2): 81-6, 1995. [PUBMED Abstract]

Treatment Option Overview for Aggressive B-Cell Non-Hodgkin Lymphoma

Treatment of aggressive non-Hodgkin lymphoma (NHL) depends on the histological type and stage. Many of the improvements in survival have been made because of clinical trials that have attempted to improve conventional or standard therapy.

In asymptomatic patients with indolent forms of advanced NHL, treatment may be deferred until the patient becomes symptomatic as the disease progresses. When treatment is deferred, the clinical course of patients with indolent NHL varies; frequent and careful observation is required so that effective treatment can be initiated when the clinical course of the disease accelerates. Some patients have a prolonged indolent course, but others have disease that rapidly evolves into more aggressive types of NHL that require immediate treatment.

Radiation techniques differ somewhat from those used in the treatment of Hodgkin lymphoma. The dose of radiation therapy usually varies from 25 Gy to 50 Gy and is dependent on factors that include the histological type of lymphoma, the patient’s stage and overall condition, the goal of treatment (curative or palliative), the proximity of sensitive surrounding organs, and whether the patient is being treated with radiation therapy alone or in combination with chemotherapy. Given the patterns of disease presentations and relapse, treatment may need to include unusual sites such as Waldeyer ring, epitrochlear nodes, or mesenteric nodes. The associated morbidity of the treatment must be considered carefully. Most patients who receive radiation are treated on only one side of the diaphragm. Localized presentations of extranodal NHL may be treated with involved-field techniques with significant (>50%) success.

In situations where mediastinal radiation therapy would encompass the left side of the heart or would increase breast cancer risk in young female patients, proton therapy may be considered to reduce radiation dose to organs at risk.[1] For more information, see the Superior Vena Cava Syndrome section in Cardiopulmonary Syndromes.

Table 4. Treatment Options for Aggressive B-Cell Non-Hodgkin Lymphoma (NHL)
Stage Treatment Options
BMT = bone marrow transplant; CAR = chimeric antigen receptor; CNS = central nervous system; IF-XRT = involved-field radiation therapy; Pola-R-CHP = polatuzumab vedotin, rituximab, cyclophosphamide, doxorubicin, and prednisone; R-ACVBP = rituximab, doxorubicin, cyclophosphamide, vindesine, bleomycin, prednisone; R-CHOP = rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone; SCT = stem cell transplant.
Aggressive Stage I and Aggressive, Contiguous Stage II B-cell NHL R-CHOP with or without IF-XRT
R-ACVBP
Aggressive, Noncontiguous Stage II/III/IV B-cell NHL Pola-R-CHP (for IPI 2 to 5)
R-CHOP
Radiation therapy consolidation to sites of bulky disease (under clinical evaluation)
Aggressive, Recurrent B-cell NHL CAR T-cell therapy for primary refractory disease or relapse within 1 year (or for relapse after autologous SCT)
BMT or SCT consolidation
Tafasitamab plus lenalidomide
Bispecific T-cell engagers
Polatuzumab vedotin plus rituximab and bendamustine
Loncastuximab tesirine
Rituximab plus lenalidomide
Palliative radiation therapy
B-cell Lymphoblastic Lymphoma/Acute Lymphoblastic Leukemia See Acute Lymphoblastic Leukemia Treatment
Diffuse Small Noncleaved-Cell/Burkitt Lymphoma Aggressive multidrug regimens
CNS prophylaxis

Even though existing treatments cure a significant fraction of patients with lymphoma, numerous clinical trials that explore treatment improvements are in progress. If possible, patients can participate in these studies. Standardized guidelines for response assessment have been suggested for use in clinical trials.[2]

Several retrospective reviews suggest that routine surveillance scans offer little to no value in patients with diffuse-large B-cell lymphoma (DLBCL) who have attained a clinical complete remission after induction therapy. Prognostic value is also difficult to identify for an interim positron emission tomography-computed tomography scan during induction therapy for DLBCL.[3–6]

Aggressive lymphomas are increasingly seen in patients with HIV. Treatment of these patients requires special consideration. For more information, see AIDS-Related Lymphoma Treatment

In addition to screening for HIV among patients with aggressive lymphomas, active hepatitis B or hepatitis C can be assessed before treatment with rituximab and/or chemotherapy.[7,8] Patients with detectable hepatitis B virus (HBV) benefit from prophylaxis with entecavir in the context of rituximab therapy.[9,10] Patients with a resolved HBV infection (defined as hepatitis B surface antigen-negative but hepatitis B core antibody-positive) are at risk of reactivation of HBV and require monitoring of HBV DNA. In a retrospective study of 326 patients, prophylactic nucleoside analogue therapy lowered HBV reactivation from 10.8% to 2.1%.[11] Similarly, prophylaxis for herpes zoster with acyclovir or valacyclovir and prophylaxis for Pneumocystis with trimethoprim/sulfamethoxazole or dapsone are usually given to patients receiving rituximab with or without combination chemotherapy. Long-term impaired immune health was evaluated in a retrospective cohort study of 21,690 survivors of DLBCL from the California Cancer Registry. Elevated incidence rate ratios were found up to 10 years later for pneumonia (10.8-fold), meningitis (5.3-fold), immunoglobulin deficiency (17.6-fold), and autoimmune cytopenias (12-fold).[12]

Among 2,508 patients in a Danish registry, the incidence of doxorubicin-induced congestive heart failure increased for 115 NHL survivors with a history of cardiac disease (hazard ratio [HR], 2.71; 95% confidence interval [CI], 1.15−6.36) and/or multiple cardiovascular risk factors (HR, 2.86; 95% CI, 1.56−5.23).[13]

For more information, see Primary Central Nervous System Lymphoma Treatment.

References
  1. Dabaja BS, Hoppe BS, Plastaras JP, et al.: Proton therapy for adults with mediastinal lymphomas: the International Lymphoma Radiation Oncology Group guidelines. Blood 132 (16): 1635-1646, 2018. [PUBMED Abstract]
  2. Cheson BD, Horning SJ, Coiffier B, et al.: Report of an international workshop to standardize response criteria for non-Hodgkin’s lymphomas. NCI Sponsored International Working Group. J Clin Oncol 17 (4): 1244, 1999. [PUBMED Abstract]
  3. Mamot C, Klingbiel D, Hitz F, et al.: Final Results of a Prospective Evaluation of the Predictive Value of Interim Positron Emission Tomography in Patients With Diffuse Large B-Cell Lymphoma Treated With R-CHOP-14 (SAKK 38/07). J Clin Oncol 33 (23): 2523-9, 2015. [PUBMED Abstract]
  4. Thompson CA, Ghesquieres H, Maurer MJ, et al.: Utility of routine post-therapy surveillance imaging in diffuse large B-cell lymphoma. J Clin Oncol 32 (31): 3506-12, 2014. [PUBMED Abstract]
  5. El-Galaly TC, Jakobsen LH, Hutchings M, et al.: Routine Imaging for Diffuse Large B-Cell Lymphoma in First Complete Remission Does Not Improve Post-Treatment Survival: A Danish-Swedish Population-Based Study. J Clin Oncol 33 (34): 3993-8, 2015. [PUBMED Abstract]
  6. Huntington SF, Svoboda J, Doshi JA: Cost-effectiveness analysis of routine surveillance imaging of patients with diffuse large B-cell lymphoma in first remission. J Clin Oncol 33 (13): 1467-74, 2015. [PUBMED Abstract]
  7. Niitsu N, Hagiwara Y, Tanae K, et al.: Prospective analysis of hepatitis B virus reactivation in patients with diffuse large B-cell lymphoma after rituximab combination chemotherapy. J Clin Oncol 28 (34): 5097-100, 2010. [PUBMED Abstract]
  8. Dong HJ, Ni LN, Sheng GF, et al.: Risk of hepatitis B virus (HBV) reactivation in non-Hodgkin lymphoma patients receiving rituximab-chemotherapy: a meta-analysis. J Clin Virol 57 (3): 209-14, 2013. [PUBMED Abstract]
  9. Huang YH, Hsiao LT, Hong YC, et al.: Randomized controlled trial of entecavir prophylaxis for rituximab-associated hepatitis B virus reactivation in patients with lymphoma and resolved hepatitis B. J Clin Oncol 31 (22): 2765-72, 2013. [PUBMED Abstract]
  10. Li H, Zhang HM, Chen LF, et al.: Prophylactic lamivudine to improve the outcome of HBsAg-positive lymphoma patients during chemotherapy: a systematic review and meta-analysis. Clin Res Hepatol Gastroenterol 39 (1): 80-92, 2015. [PUBMED Abstract]
  11. Kusumoto S, Arcaini L, Hong X, et al.: Risk of HBV reactivation in patients with B-cell lymphomas receiving obinutuzumab or rituximab immunochemotherapy. Blood 133 (2): 137-146, 2019. [PUBMED Abstract]
  12. Shree T, Li Q, Glaser SL, et al.: Impaired Immune Health in Survivors of Diffuse Large B-Cell Lymphoma. J Clin Oncol 38 (15): 1664-1675, 2020. [PUBMED Abstract]
  13. Salz T, Zabor EC, de Nully Brown P, et al.: Preexisting Cardiovascular Risk and Subsequent Heart Failure Among Non-Hodgkin Lymphoma Survivors. J Clin Oncol 35 (34): 3837-3843, 2017. [PUBMED Abstract]

Treatment of Aggressive Stage I and Aggressive, Contiguous Stage II B-Cell Non-Hodgkin Lymphoma

Patients with aggressive stage I or aggressive, contiguous stage II diffuse large B-cell lymphoma (DLBCL) are candidates for combination chemotherapy with or without involved-field radiation therapy (IF-XRT).

Patients with a resolved hepatitis B virus (HBV) infection (defined as hepatitis B surface antigen-negative but hepatitis B core antibody-positive) are at risk of reactivation of HBV and require monitoring of HBV DNA. In a retrospective study of 326 patients, prophylactic nucleoside analogue therapy lowered HBV reactivation from 10.8% to 2.1%.[1]

Stage IE or IIE Gastric DLBCL

Four case series involving more than 100 patients with stage IE or IIE disease (with or without mucosa-associated lymphatic tissue) and with positive Helicobacter pylori infection. The series reported that more than 50% of patients attained a durable complete remission after appropriate antibiotic therapy to eradicate H. pylori.[2–5][Level of evidence C3]

Treatment Options for Aggressive Stage I and Aggressive, Contiguous Stage II B-Cell Non-Hodgkin Lymphoma

Treatment options for aggressive stage I and aggressive, contiguous stage II B-cell non-Hodgkin lymphoma include:

  1. R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) with or without IF-XRT.
  2. R-ACVBP (rituximab, doxorubicin, cyclophosphamide, vindesine, bleomycin, prednisone).[6,7]

R-CHOP with or without IF-XRT

Rituximab has efficacy in advanced-stage disease. However, its use is only supported by retrospective comparisons in studies of R-CHOP with or without radiation therapy.[8][Level of evidence C2]

  • R-CHOP (four to six cycles).
  • R-CHOP (three to six cycles) + IF-XRT.

Evidence (R-CHOP with or without IF-XRT):

  1. In a randomized prospective trial of 334 patients with nonbulky (≤7 cm) stage I or stage II DLBCL, after receiving four to six cycles of R-CHOP-14 (R-CHOP delivered every 2 weeks), patients were randomly assigned to undergo 40 Gy of radiation therapy or no radiation therapy.[9]
    • After a median follow-up of 64 months, the 5-year event-free survival rate (89%–92%; P = .18) and 5-year overall survival (OS) rate (92%–96%; P = .32) were the same.[9][Level of evidence A1]

      Similar to the results of randomized studies of radiation therapy in the era before rituximab, radiation therapy can be deferred in patients with nonbulky early-stage disease. For patients unable to tolerate prolonged-course chemotherapy, three cycles of R-CHOP plus radiation therapy has produced equivalent results based on single-arm retrospective trials.[8]

  2. In a randomized prospective trial (NCT00278421) of 592 patients younger than 60 years with nonbulky (<7.5 cm) stage I or stage II DLBCL, patients were randomly assigned to receive either four or six cycles of R-CHOP (with an extra two cycles of rituximab after four cycles).[10]
    • With a median follow-up of 66 months, the 3-year progression-free survival (PFS) rate was 96% (95% confidence interval [CI], 94%−99%) for patients who received four cycles of R-CHOP, which was 3% better (lower limit of one-sided 95% CI was zero) than the PFS rate for patients who received six cycles, establishing noninferiority for the four-cycle regimen.[10][Level of evidence B1]
  3. A retrospective analysis at Memorial Sloan Kettering Cancer Center between 2001 and 2015 included 341 patients with stage I disease. The analysis found that 66% of patients had an extranodal presentation. After R-CHOP (or a similar regimen), with or without radiation therapy, the 5-year disease-free survival rate was 77%, and the 5-year OS rate was 94%.[11][Level of evidence C3] A multivariate analysis suggested that radiation therapy may improve outcomes for patients with extranodal disease that is positron emission tomography (PET)–positive at the end of therapy. This hypothesis needs confirmation in a prospective randomized trial.[11]

In summary, for patients with favorable prognosis, nonbulky (<7 cm), stage I or stage II DLBCL, four cycles of R-CHOP are sufficient. For patients with an unfavorable prognosis, six cycles of R-CHOP or three cycles of R-CHOP and 40 Gy of radiation therapy can be used. Early-stage patients with bulky disease (>7.5 cm) have not been studied in randomized trials; combined-modality therapy with R-CHOP for four to six cycles plus radiation therapy is usually chosen. Although a retrospective study suggested that patients with stage I extranodal disease and a positive PET scan at the end of therapy may benefit from radiation therapy, this hypothesis must be confirmed in a prospective randomized trial.

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

References
  1. Kusumoto S, Arcaini L, Hong X, et al.: Risk of HBV reactivation in patients with B-cell lymphomas receiving obinutuzumab or rituximab immunochemotherapy. Blood 133 (2): 137-146, 2019. [PUBMED Abstract]
  2. Morgner A, Miehlke S, Fischbach W, et al.: Complete remission of primary high-grade B-cell gastric lymphoma after cure of Helicobacter pylori infection. J Clin Oncol 19 (7): 2041-8, 2001. [PUBMED Abstract]
  3. Chen LT, Lin JT, Shyu RY, et al.: Prospective study of Helicobacter pylori eradication therapy in stage I(E) high-grade mucosa-associated lymphoid tissue lymphoma of the stomach. J Clin Oncol 19 (22): 4245-51, 2001. [PUBMED Abstract]
  4. Chen LT, Lin JT, Tai JJ, et al.: Long-term results of anti-Helicobacter pylori therapy in early-stage gastric high-grade transformed MALT lymphoma. J Natl Cancer Inst 97 (18): 1345-53, 2005. [PUBMED Abstract]
  5. Kuo SH, Yeh KH, Wu MS, et al.: Helicobacter pylori eradication therapy is effective in the treatment of early-stage H pylori-positive gastric diffuse large B-cell lymphomas. Blood 119 (21): 4838-44; quiz 5057, 2012. [PUBMED Abstract]
  6. Reyes F, Lepage E, Ganem G, et al.: ACVBP versus CHOP plus radiotherapy for localized aggressive lymphoma. N Engl J Med 352 (12): 1197-205, 2005. [PUBMED Abstract]
  7. Ketterer N, Coiffier B, Thieblemont C, et al.: Phase III study of ACVBP versus ACVBP plus rituximab for patients with localized low-risk diffuse large B-cell lymphoma (LNH03-1B). Ann Oncol 24 (4): 1032-7, 2013. [PUBMED Abstract]
  8. Persky DO, Unger JM, Spier CM, et al.: Phase II study of rituximab plus three cycles of CHOP and involved-field radiotherapy for patients with limited-stage aggressive B-cell lymphoma: Southwest Oncology Group study 0014. J Clin Oncol 26 (14): 2258-63, 2008. [PUBMED Abstract]
  9. Lamy T, Damaj G, Soubeyran P, et al.: R-CHOP 14 with or without radiotherapy in nonbulky limited-stage diffuse large B-cell lymphoma. Blood 131 (2): 174-181, 2018. [PUBMED Abstract]
  10. Poeschel V, Held G, Ziepert M, et al.: Four versus six cycles of CHOP chemotherapy in combination with six applications of rituximab in patients with aggressive B-cell lymphoma with favourable prognosis (FLYER): a randomised, phase 3, non-inferiority trial. Lancet 394 (10216): 2271-2281, 2019. [PUBMED Abstract]
  11. Bobillo S, Joffe E, Lavery JA, et al.: Clinical characteristics and outcomes of extranodal stage I diffuse large B-cell lymphoma in the rituximab era. Blood 137 (1): 39-48, 2021. [PUBMED Abstract]

Treatment of Aggressive, Noncontiguous Stage II/III/IV B-Cell Non-Hodgkin Lymphoma

The treatment of choice for patients with advanced stages of aggressive non-Hodgkin lymphoma (NHL) is combination chemotherapy, either alone or supplemented by local-field radiation therapy.[1]

The following drug combinations are referred to in this section:

  • Pola-R-CHP: polatuzumab vedotin + rituximab + cyclophosphamide + doxorubicin + prednisone.
  • R-CHOP: rituximab + cyclophosphamide + doxorubicin + vincristine + prednisone.
  • R-ACVBP: rituximab, an anti–CD20 monoclonal antibody + doxorubicin + cyclophosphamide + vindesine + bleomycin + prednisone.

Treatment Options for Aggressive, Noncontiguous Stage II/III/IV B-Cell NHL

Treatment options for aggressive, noncontiguous stage II/III/IV B-cell NHL include:

  1. Pola-R-CHP (for National Comprehensive Cancer Network International Prognostic Index [IPI] score of 2 to 5).
  2. R-CHOP.
  3. Radiation therapy consolidation to sites of bulky disease (under clinical evaluation).

Pola-R-CHP

R-CHOP has been compared with Pola-R-CHP. Polatuzumab is an antibody-drug conjugate composed of an anti-CD79B monoclonal antibody attached to vedotin (monomethyl auristatin E), a microtubule inhibitor.

Evidence (Pola-R-CHP):

  1. A prospective, randomized study (POLARIX [NCT03274492]) of 879 patients with previously untreated diffuse large B-cell lymphoma (DLBCL) and an IPI score of 2 or higher compared R-CHOP with Pola-R-CHP.[2] Polatuzumab vedotin was substituted for vincristine to mitigate neurological toxicity.
    • At a median follow-up of 28.2 months, the 2-year progression-free survival (PFS) rate was significantly higher in the Pola-R-CHP group than in the R-CHOP group: 76.7% (95% confidence interval [CI], 72.7%–80.0%) versus 70.2% (95% CI, 65.8%–74.6%) (hazard ratio [HR], 0.73; 95% CI, 0.57–0.95; P = .02).[2][Level of evidence B1]
    • The 2-year overall survival (OS) rate was 88.7% (95% CI, 85.7%–91.6%) for patients who received Pola-R-CHP and 88.6% (95% CI, 85.6%–91.6%) for patients who received R-CHOP (HR, 0.94; 95% CI, 0.65–1.37; P = .75).
    • A similar 7.7% improvement in 2-year PFS for Pola-R-CHP versus R-CHOP has been seen in an Asian subpopulation analysis from this trial.[3][Level of evidence C2]

The follow-up interval was too short to establish whether the 6% improvement in the PFS rate will plateau or improve after 2 years, and there is no evidence of OS advantage. Nonetheless, updated outcomes with a median follow-up over 3 years showed continued improvement of PFS, prompting the U.S. Food and Drug Administration (FDA) to approve Pola-R-CHP. Pola-R-CHP is the first regimen in over 20 years to be approved by the FDA as a therapy for patients with noncontiguous stage II, stage III, and stage IV disease. The new regimen is more than twice the cost of R-CHOP using acquisition prices in 2022, and polatuzumab may not be available worldwide.

The Pola-R-CHP regimen demonstrated substantial efficacy for patients with DLBCL non–germinal center B-cell (GCB)-origin tumors, predominantly those with the ABC (activated B-cell) subtype.[4] In the POLARIX trial, the HRPFS for Pola-R-CHP versus R-CHOP in patients with ABC-subtype tumors was 0.34 (95% CI, 0.13–0.85), and the HROS for those patients was 0.27 (95% CI, 0.06–1.26). In contrast, no such benefit was observed for patients with GCB-subtype tumors in this trial. For Pola-R-CHP, the HRPFS was 1.18 (95% CI, 0.75–1.84), and the HROS was 1.64 (95% CI, 0.87–3.07). This differential efficacy in favor of the non-GCB or ABC subtype was seen in five prospective phase I and II trials of the Pola-R-CHP regimen in patients with relapsed or refractory disease, with a combined analysis of data showing a level of significance P < .001.[4] Combining the data for a randomized phase II trial studying Pola-R-CHP in patients with relapsed or refractory disease with data from the POLARIX trial in patients with previously untreated disease, the HRdisease relapse/progression/death was 0.25 for patients with ABC-subtype tumors and 0.98 for patients with GCB-subtype tumors (P < .001).[4] The only exception to this observation is the clear benefit of Pola-R-CHP in GCB patients with double-hit variants (MYC gene and BCL2 gene). Given the increased rates of febrile neutropenia in patients who receive Pola-R-CHP and the significant financial toxicity, it is reasonable to consider R-CHOP as a standard regimen for patients with GCB-subtype DLBCL without a double-hit variant. However, assessing the GCB subtype using commercially available immunophenotyping is less accurate than using the molecular genetic signatures used in the POLARIX study. Some patients may miss the PFS benefit of polatuzumab. Some clinicians err on the side of using Pola-R-CHP for GCB subtype when patients have other high-risk features (e.g., CD5 positivity or involvement in two or more extranodal sites).

R-CHOP

The following studies established R-CHOP as a standard regimen for patients with newly diagnosed DLBCL and noncontiguous stage II, stage III, and stage IV disease for over 20 years.[5] Dose intensification of R-CHOP by a 14-day versus a 21-day cycle did not result in improved outcomes.[6] R-CHOP is the preferred regimen when polatuzumab is not available or affordable, or when contraindicated due to adverse side effects.

Evidence (R-CHOP):

  1. R-CHOP showed improved event-free survival (EFS) and OS compared with CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) alone in 399 patients older than 60 years with advanced-stage DLBCL (EFS rate, 57% vs. 38%; P = .002, and OS rate, 70% vs. 57%; P = .007 at 2 years).[7][Level of evidence A1] At a median follow-up of 10 years, the OS rate of patients who received R-CHOP was 44% compared with 28% for patients who received CHOP (P < .0001).[8]
  2. Similarly, for 326 evaluable patients younger than 61 years, R-CHOP showed improved EFS and OS compared with CHOP alone (EFS rate, 79% vs. 59%, P = .001, and OS rate, 93% vs. 84%, P = .001 at 3 years).[9][Level of evidence A1]
  3. A randomized study (DSHNHL-1999-1A [NCT00052936]) of 1,222 patients older than 60 years compared R-CHOP given every 2 weeks for six or eight cycles with CHOP given every 2 weeks for six or eight cycles.[10] With a median follow-up of 72 months, the EFS favored R-CHOP given every 2 weeks for six or eight cycles (6-year EFS rate, 74% vs. 56%; P < .0001). The OS favored R-CHOP for only six cycles because of increased toxicity in the eight-cycle arm (6-year OS rate, 90% vs. 80%; P = .0004).[10][Level of evidence A1] There was no comparison with standard R-CHOP or CHOP given every 3 weeks.
  4. A trial (NCT00140595) of 380 patients younger than 60 years with DLBCL and an age-adjusted IPI score of 1 randomly assigned patients to receive ACVBP and R-ACVBP plus consolidation with methotrexate, ifosfamide, etoposide, and cytarabine versus CHOP and rituximab.[11] With a median follow-up of 44 months, 3-year OS rates favored R-ACVBP (92% vs. 84%; HR, 0.44; 95% CI, 0.28–0.81, P = .007).[11][Level of evidence A1] The significantly worse toxicities with R-ACVBP, the narrow target population (<60 years with either elevated lactate dehydrogenase [LDH] or stage III-stage IV disease, but not both), and the lack of a confirmatory trial may inhibit adoption of R-ACVBP as a new standard of care.[12]

There is no validated trial for interim positron emission tomography–based treatment intensification.[13] R-CHOP has curative potential, even in patients older than 80 years who are frail and require reduced dosage of R-CHOP components. In a retrospective review of 239 patients, the 5-year cause-specific survival rate was 48% (95% CI, 41%−55%).[14][Level of evidence C3]

Less than 10% of patients with DLBCL present with a concurrent indolent lymphoma at diagnosis, and these are predominantly of GCB phenotype. A retrospective review of 1,324 patients showed similar EFS (HR, 1.19) and OS (HR, 1.09).[15][Level of evidence C3] For 847 patients who were treated with R-CHOP and free of disease 24 months after therapy, the rate of indolent lymphoma relapse by 5 years was higher with a concurrent diagnosis of follicular lymphoma (7.4% vs. 2.1%, P < .01) and with a GCB phenotype (3.9% vs. 0.0% at 5 years, P = .02).[16]

Modifications to R-CHOP to achieve improved efficacy continue to be explored in clinical trials.

Radiation therapy consolidation to sites of bulky disease

After R-CHOP induction chemotherapy (or similar regimens), the addition of involved-field radiation therapy to sites of initial bulky disease (≥5–10 cm) or to extralymphatic sites remains controversial.[17–19] Increased risks, such as long-term toxicities (e.g., second malignancies), must be considered.

Bone marrow transplant (BMT) or stem cell transplant (SCT)

Several randomized prospective trials evaluated the role of autologous BMT or SCT consolidation versus chemotherapy alone in patients with diffuse large cell lymphoma in first remission.[20–27]; [28–30][Level of evidence A1] Although some of these trials demonstrated significant increases in EFS (by 10% to 20%) among patients who received high-dose therapy, significant differences in OS could not be demonstrated prospectively in any of the series.

Retrospective analyses of high-intermediate (two risk factors) or high-risk (more than three risk factors) patients as defined by IPI suggest improved survival with BMT in two of the trials.[21,27] These studies do not establish that high-dose consolidation is of value to patients with aggressive lymphoma who are truly at high risk of relapse, and they also demonstrate that EFS may be a poor surrogate for OS for these patients.[31]

Prognostic factors

The National Comprehensive Cancer Network International Prognostic Index (IPI) for aggressive NHL (diffuse large cell lymphoma) identifies the following five significant risk factors prognostic of overall survival (OS) and their associated risk scores:[32]

  • Age.
    • <40 years: 0.
    • 41–60 years: 1.
    • 61–75 years: 2.
    • >75 years: 3.
  • Stage III/IV: 1.
  • Performance status (PS) 2/3/4: 1.
  • Serum lactate dehydrogenase (LDH).
    • Normalized: 0.
    • >1x–3x: 1.
    • >3x: 2.
  • Number of extranodal sites ≥2: 1.

Risk scores:

  • Low (0 or 1): 5-year OS rate, 96%; progression-free survival (PFS) rate, 91%.
  • Low intermediate (2 or 3): 5-year OS rate, 82%; PFS rate, 74%.
  • High intermediate (4 or 5): 5-year OS rate, 64%; PFS rate, 51%.
  • High (>6): 5-year OS rate, 33%; PFS rate, 30%.

Age-adjusted and stage-adjusted modifications of this IPI are used for younger patients with localized disease.[33] Shorter intervals of time between diagnosis and treatment appear to be a surrogate for poor prognostic biological factors.[34]

The BCL2 gene and rearrangement of the MYC gene or dual overexpression of the MYC gene, or both, confer a particularly poor prognosis.[35–38] Patients at high risk of relapse may be considered for clinical trials.[39] Molecular profiles of gene expression using DNA microarrays may help to stratify patients in the future for therapies directed at specific targets and to better predict survival after standard chemotherapy.[40]

Treatment of Tumor Lysis Syndrome

Patients with bulky and extensive lymphadenopathy and elevations of serum uric acid and LDH are at increased risk of tumor lysis syndrome, resulting in metabolic derangements such as hyperuricemia, hyperkalemia, hyperphosphatemia, hypocalcemia, and subsequent acute renal failure.[41] Treatment options include alkaline hydration, allopurinol, and rasburicase (a recombinant urate oxidase).[42]

Central Nervous System (CNS) Prophylaxis

The CNS-IPI tool predicts which patients have a CNS relapse risk exceeding 10%.[43,44] It was developed by the German Lymphoma Study Group and validated by the British Columbia Cancer Agency database. The presence of four to six of the CNS-IPI risk factors (age >60 years, performance status ≥2, elevated LDH, stage III or IV disease, >1 extranodal site, or involvement of the kidneys or adrenal glands) was used to define a high-risk group for CNS recurrence (a 12% risk of CNS involvement by 2 years).[44]

CNS prophylaxis (usually with four to six doses of intrathecal methotrexate) is often recommended for patients with testicular involvement.[45–47][Level of evidence C3] A retrospective analysis of the German RICOVER studies compared intrathecal methotrexate with no prophylaxis in patients with DLBCL. This study was completed during the R-CHOP treatment era. With the possible exception of patients with testicular involvement, the analysis showed that intrathecal methotrexate did not reduce the risk of CNS disease.[48][Level of evidence C3]

Some clinicians use high-dose intravenous (IV) methotrexate (usually four doses) as an alternative to intrathecal therapy because drug delivery is improved and patient morbidity is decreased.[43,49] Five retrospective studies and one network meta-analysis evaluating high-dose methotrexate alone in patients with high-risk DLBCL also showed no improvement in CNS relapse rate.[50–55][Level of evidence C3] Patients deemed at high risk for CNS relapse (e.g., patients with testicular, renal, or adrenal disease and three or more extranodal sites) may receive intrathecal methotrexate or high-dose IV methotrexate, but the lack of confirmatory randomized studies calls this standard into question and shows an urgent need for better therapeutics verified in clinical trials.[43,43] While there is insufficient evidence to support a significant benefit for CNS prophylaxis in most high-risk patients, the perceived risk of not treating for CNS relapse has often outweighed the lack of evidence for its efficacy.[43] Although patients with testicular involvement or kidney/adrenal involvement are considered an exception, there is only anecdotal benefit from intrathecal or high-dose IV methotrexate in reducing CNS recurrence.[45–47][Level of evidence C3]

In retrospective analyses, the addition of rituximab to CHOP-based regimens has significantly reduced the risk of CNS relapse.[48,56][Level of evidence C3] Patients with CNS dissemination at diagnosis or at relapse usually receive rituximab and high doses of methotrexate and/or cytarabine followed by autologous SCT, but this approach has not been assessed in randomized trials.[57,58][Level of evidence C3]

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

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Treatment of Aggressive, Recurrent B-Cell Non-Hodgkin Lymphoma

Treatment Options for Aggressive, Recurrent B-Cell Non-Hodgkin Lymphoma

In a retrospective review of multiple international trials, 636 patients were identified as having refractory diffuse large B-cell lymphoma (DLBCL), which was defined as progression or stable disease during or just at completion of full-course chemotherapy or relapse within 1 year after autologous stem cell transplant (SCT).[1] With subsequent therapy, the objective response rate was 26%, complete response rate was 7%, median overall survival (OS) was 6.3 months, and only 20% of patients were alive at 2 years. Even with reinduction chemotherapy with planned autologous SCT, outcomes remain poor.[2]

Treatment options for aggressive, recurrent B-cell non-Hodgkin lymphoma include the following:

  1. Chimeric antigen receptor (CAR) T-cell therapy for primary refractory disease or relapse within 1 year (or for relapse after autologous SCT).
    • Axicabtagene ciloleucel (axi-cel).
    • Lisocabtagene maraleucel (liso-cel).
  2. Bone marrow transplant (BMT)/SCT consolidation.
  3. Tafasitamab plus lenalidomide.
  4. Bispecific T-cell engagers.
  5. Polatuzumab vedotin plus rituximab and bendamustine.
  6. Loncastuximab tesirine.
  7. Rituximab plus lenalidomide.
  8. Palliative radiation therapy.

CAR T-cell therapy for primary refractory disease or relapse within 1 year (or relapse after autologous SCT)

Patients with DLBCL who relapse during or within 2 months of receiving R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) chemotherapy have primary refractory disease. Any patient with disease relapse within 1 year of R-CHOP chemotherapy or with primary refractory disease has a poor prognosis, even with reinduction using chemoimmunotherapy followed by autologous SCT.[1,2] Patients who received CAR T-cell therapy had a 40% to 50% 3-year progression-free survival (PFS) rate with a 40-month follow-up, a result equivalent retrospectively to autologous SCT in bone marrow registries.[3–6]

Three randomized trials compared chemoimmunotherapy followed by autologous SCT with CAR T-cell therapy with or without bridging chemoimmunotherapy for patients with high-risk relapsed disease, defined as primary refractory disease or relapse within 12 months of initial R-CHOP therapy.

Evidence (CAR T-cell therapy):

  1. A prospective randomized trial included 359 patients with primary refractory disease or relapse within 12 months of initial R-CHOP chemotherapy. Patients received the CAR T-cell therapy axicabtagene ciloleucel (axi-cel) with only bridging steroids or second-line chemoimmunotherapy (usually R-ICE [rituximab, ifosfamide, etoposide, and carboplatin] or R-DHAP [rituximab, dexamethasone, high-dose cytarabine, and cisplatin]) followed by autologous SCT.[7,8]
    • With a median follow-up of 47.2 months, the median OS was not reached in the axi-cel cohort and was 31.1 months in the chemoimmunotherapy cohort. The estimated 4-year OS rate was 54.6% for patients who received axi-cel and 46.0% for patients who received chemoimmunotherapy (hazard ratio [HR]death, 0.73; 95% confidence interval [CI], 0.54–0.98; P = .03).[8][Level of evidence A1]
    • The median investigator-assessed PFS was 14.7 months in the axi-cel cohort and 3.7 months in the chemotherapy cohort (HR, 0.51; 95% CI, 0.38–0.67).
    • In the chemoimmunotherapy arm, 64% patients never received autologous SCT during the study because of inadequate response, progression, or death.[7]
    • Clinically meaningful and statistically significant differences in quality of life were obtained in the CAR T-cell arm at day 100 and day 150, compared with the standard of care.[7][Level of evidence A2]
    • Grade 3 or 4 cytokine release syndrome occurred in 6% of patients, and grade 3 or 4 neurotoxicity occurred in 21% of patients.
  2. A prospective randomized trial included 184 patients with primary refractory disease or relapse within 12 months of initial R-CHOP chemotherapy. Patients received the CAR T-cell therapy lisocabtagene maraleucel (liso-cel), with 63% of patients receiving bridging therapy or second-line chemoimmunotherapy followed by autologous SCT.[9]
    • With a median follow-up of 17.5 months, the median PFS was not reached for patients who received liso-cel and was 6.2 months for patients who received chemoimmunotherapy followed by autologous SCT (HR, 0.40; P < .0001).[9][Level of evidence B1]
    • On the chemoimmunotherapy arm of the study, 53% of patients never received autologous SCT because of inadequate response, progression, or death.[9]
    • Grade 3 cytokine release syndrome occurred in 1% of patients, and grade 3 neurotoxicity occurred in 4% of patients. There were no grade 4 or 5 occurrences.
  3. A prospective randomized trial included 322 patients with primary refractory disease or relapse within 12 months of initial R-CHOP chemotherapy. Patients received the CAR T-cell therapy tisagenlecleucel, with most patients receiving bridging therapy to achieve response, or second-line chemoimmunotherapy followed by autologous SCT.[10]
    • There was no difference in event-free survival (EFS) for patients in either arm (HR, 1.07; 95% CI, 0.82–1.40; P = .69).[10][Level of evidence B1]
    • In the CAR T-cell therapy arm, 48% of patients received two or more cycles of chemoimmunotherapy as part of bridging therapy. This approach to bridging therapy may have led to an unacceptable number of cases of progressive disease.

In summary:

  • For patients with high-risk relapsing DLBCL with primary refractory disease or relapse within 12 months of R-CHOP-based chemotherapy, axi-cel and liso-cel are superior induction regimens, compared with chemoimmunotherapy with regimens like R-ICE, R-DHAP, and R-GDP (rituximab, gemcitabine, dexamethasone, and cisplatin).
  • The interval until patients receive CAR T cells must be minimized, optimally by using only steroids, eliminating bridging chemoimmunotherapy, and infusing the CAR T-cell product as quickly as possible.
  • The preference for CAR T-cell therapy over chemoimmunotherapy followed by autologous SCT does not apply to patients who relapse more than 12 months after R-CHOP therapy.
  • The American Society of Clinical Oncology (ASCO) has compiled guidelines for the management of adverse events in patients treated with CAR T-cell therapy.[11]
  • Worse outcomes were reported when apheresis for CAR T-cell therapy occurred just after bendamustine therapy. In a retrospective multicenter review of 439 patients who were infused with CD-19–targeted CAR T cells, 80 patients had received prior bendamustine. With a median follow-up of 20.6 months after CAR T-cell infusion, the patients who had received prior bendamustine had a lower overall response rate (53% vs. 72%, P < .01), worse median PFS (3.1 vs. 6.2 months, P = .04), and worse median OS (4.6 vs. 23.5 months, P < .01).[12][Level of evidence C1]

BMT or SCT consolidation

BMT

BMT consolidation is a treatment option for patients with relapsed lymphoma.[13] Preliminary studies indicate that approximately 20% to 40% of patients will have a long-term disease-free status, but the precise percentage depends on patient selection and the specific treatment used. Preparative drug regimens have varied; some investigators also use total-body irradiation. Similar success has been achieved using autologous marrow, with or without marrow purging, and allogeneic marrow.[14–18]

Evidence (BMT):

  1. In a prospective randomized study (EORTC-PARMA), 215 patients in first or second relapse of aggressive lymphoma, younger than 60 years, and with no bone marrow or central nervous system involvement, were given two cycles of intensive combination chemotherapy. The 109 patients who responded were randomly assigned to receive four more cycles of chemotherapy and involved-field radiation therapy (IF-XRT) versus autologous BMT followed by IF-XRT. With a 5-year median follow-up, the EFS rate was significantly improved with transplant (46% vs. 12%). The OS rate was also significantly better with transplant (53% vs. 32%).[19][Level of evidence A1] Salvage BMT was unsuccessful for patients on the nontransplant arm whose disease relapsed.

    In general, patients who responded to initial therapy and who responded to conventional therapy for relapse before the BMT have had the best results.[20]

  2. In a prospective trial, patients who relapsed late (>12 months after diagnosis) had better OS than patients who relapsed earlier (the 8-year survival rate was 29% vs. 13%, P = .001).[21][Level of evidence C1]
Peripheral SCT

Peripheral SCT has yielded results equivalent to standard autologous SCT.[22,23] Even patients who never experienced complete remission with conventional chemotherapy may have prolonged PFS (31% at 5 years) after high-dose chemotherapy and hematopoietic SCT if they retain chemosensitivity to reinduction therapy.[24][Level of evidence C2] Some patients who relapse after a previous autologous SCT can have durable remissions after myeloablative or nonmyeloablative allogeneic SCT.[25,26]; [27][Level of evidence C3] Reduced-intensity conditioning for allogeneic SCT typically involves fludarabine plus busulfan or fludarabine plus cyclophosphamide, with or without 2 Gy of total-body irradiation.[28]

Evidence (peripheral SCT):

  1. In a randomized prospective trial, 396 patients with DLBCL in first relapse or who were refractory to first-line therapy received either R-ICE or R-DHAP followed by autologous SCT.[29]
  2. In a randomized prospective trial, 619 patients with relapsed or refractory aggressive lymphoma received either R-DHAP or R-GDP followed by autologous SCT.[30]
    • At a median follow-up of 53 months, there was no difference in EFS or OS, but patients who received R-GDP reported less toxicity.[30][Level of evidence A3]

CAR T-cell therapy for relapse after autologous SCT

In the event of disease relapse after autologous SCT, many patients receive consolidation with CAR T-cell therapy.

Multiple trials describe patients with refractory large B-cell lymphoma who underwent an infusion of T cells that were engineered to express a CAR to target the CD19 antigen expressed on the malignant B cells using three different constructs: axi-cel, tisagenlecleucel, and liso-cel.[31–35] Each study reported a complete response rate of 50% to 60% and a 2-year OS rate of 40% to 50%, but the long-term durability of response has yet to be determined in these highly-selected patients.[31–33][Level of evidence C3] This therapy is an option for patients with otherwise refractory or resistant disease. These results have been verified off-study in two reports that included 397 patients treated after U.S. Food and Drug Administration (FDA) approval.[36,37][Level of evidence C3] The highest risk patients who respond adequately may receive a subsequent allogeneic SCT consolidation in some cases if eligible.

ASCO has compiled guidelines for the management of adverse events in patients treated with CAR T-cell therapy.[11]

Tafasitamab plus lenalidomide

Tafasitamab is a humanized anti-CD19 monoclonal antibody with a fucosylated Fc region to enhance antibody-dependent cellular cytotoxicity. Tafasitamab has been studied mostly in combination with lenalidomide.

Evidence (tafasitamab plus lenalidomide):

  1. In a phase II study, 80 patients with SCT-ineligible relapsed or refractory DLBCL were treated with tafasitamab and lenalidomide. The study excluded patients with high-risk cytogenetics (MYC and BCL2 and/or BCL6 rearrangements) and those who had received more than four prior lines of therapy or prior CD19-directed therapy.[38]
    • The complete response rate was 43% and the objective response rate was 60%.

The FDA approved the combination of tafasitamab and lenalidomide for patients with relapsed or refractory DLBCL.[38][Level of evidence C3] It is unclear if using this CD19-directed therapy interferes with consolidation using CD19-CAR T cells.

Bispecific T-cell engagers

Bispecific T-cell engagers (BiTEs) bind to CD20 (or CD19) and to CD3 to direct T cells to eliminate malignant B cells.[39]

Epcoritamab

Epcoritamab is a CD20-directed BiTE. It is given subcutaneously every 28 days until disease progression or unacceptable toxicity with weekly step-up dosing during cycle 1.

Evidence (epcoritamab):

  1. A phase I/II trial (NCT03625037) included 157 patients with relapsed or refractory DLBCL after two or more prior lines of therapy.[40]
    • With a median follow-up of 10.7 months, the overall response rate was 63.1% (95% CI, 55.0%–70.6%), and the complete response rate was 38.9% (95% CI, 31.2%–46.9%).[40][Level of evidence C3]
    • The median PFS was 4.4 months (95% CI, 3.0–7.9).
    • The median OS was not reached (95% CI, 11.3–not reached).
    • Cytokine release syndrome occurred in 49.7% of patients, and it was grade 3 or higher in 2.5% of patients. Immune effector cell–associated neurotoxicity syndrome (ICANS) occurred in 6.4% of patients, and it was grade 3 or higher in 0.6% of patients.
    • Results were not significantly different among 61 recipients of prior CD19-directed CAR T-cell therapy.
Glofitamab

Glofitamab is a CD20-directed BiTE with bivalency for CD20. It is given intravenously every 21 days for a maximum of 12 cycles with weekly step-up dosing during cycle 1.

Evidence (glofitamab):

  1. A phase I/II trial included 155 patients with relapsed or refractory DLBCL after two or more prior lines of therapy.[39]
    • With a median follow up of 12.6 months, the overall response rate was 52% (95% CI, 43%–60%), and the complete response rate was 39% (95% CI, 32%–48%).[39][Level of evidence C3]
    • The median PFS was 4.9 months (95% CI, 3.4–8.1).
    • The estimated 12-month OS rate was 50% (95% CI, 41%–58%).
    • Cytokine release syndrome occurred in 63% of patients, and it was grade 3 or higher in 4% of patients. ICANS occurred in 8% of patients, and it was grade 3 or higher in 3% of patients.
    • Results were not significantly different among 52 recipients of prior CD19-directed CAR T-cell therapy.

Polatuzumab vedotin plus rituximab and bendamustine

Polatuzumab vedotin is a CD79b-directed monoclonal antibody conjugated to the cytotoxic agent vedotin (an antibody-drug conjugate).

Evidence (polatuzumab vedotin plus rituximab and bendamustine):

  1. In a randomized, prospective trial, 80 patients with SCT-ineligible relapsed or refractory DLBCL were treated with either polatuzumab vedotin combined with bendamustine and rituximab (BR) or BR alone, with a primary end point of complete response.[41]
    • The complete response rate by positron emission tomography−computed tomography scan was 40% for the polatuzumab vedotin-BR combination, compared with 18% for BR alone (P = .026).[41]
    • Similarly, the median PFS was higher for patients who received the polatuzumab vedotin combination (9.5 months) than for the patients who received BR alone (3.7 months) (HR, 0.36; 95% CI, 0.21−0.63; P < .001); the OS was 12.4 months for patients who received the polatuzumab vedotin combination versus 4.7 months for the patients who received BR alone (HR, 0.42; 95% CI, 0.24−0.75; P = .002).[41][Level of evidence C1]

The FDA approved the combination of polatuzumab vedotin and BR for patients with relapsed or refractory DLBCL.

Loncastuximab tesirine

Loncastuximab tesirine is a CD19-directed antibody conjugated to a pyrrolobenzodiazepine dimer cytotoxin (an antibody-drug conjugate).[42]

Evidence (loncastuximab tesirine):

  1. A phase I and subsequent phase II trial included 184 patients with SCT-ineligible relapsed or refractory DLBCL after two or more lines of therapy.
    • The overall response rate was 48.3% (95% CI, 39.9%–56.7%), and the complete response rate was 24%.[43,44][Level of evidence C3]

Rituximab plus lenalidomide

Evidence (rituximab plus lenalidomide):

  1. In two phase II trials, 49 patients showed a 19% to 35% overall response rate to lenalidomide with rituximab.[45,46][Level of evidence C3]

Palliative radiation therapy

In general, patients with aggressive lymphoma who relapse with indolent histology will benefit from palliative therapy.[47] Palliation may be achieved with very low-dose (4 Gy) IF-XRT for patients with indolent and aggressive relapsed disease.[48]

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

References
  1. Crump M, Neelapu SS, Farooq U, et al.: Outcomes in refractory diffuse large B-cell lymphoma: results from the international SCHOLAR-1 study. Blood 130 (16): 1800-1808, 2017. [PUBMED Abstract]
  2. Ayers EC, Li S, Medeiros LJ, et al.: Outcomes in patients with aggressive B-cell non-Hodgkin lymphoma after intensive frontline treatment failure. Cancer 126 (2): 293-303, 2020. [PUBMED Abstract]
  3. Schuster SJ, Tam CS, Borchmann P, et al.: Long-term clinical outcomes of tisagenlecleucel in patients with relapsed or refractory aggressive B-cell lymphomas (JULIET): a multicentre, open-label, single-arm, phase 2 study. Lancet Oncol 22 (10): 1403-1415, 2021. [PUBMED Abstract]
  4. Shah NN, Ahn KW, Litovich C, et al.: Is autologous transplant in relapsed DLBCL patients achieving only a PET+ PR appropriate in the CAR T-cell era? Blood 137 (10): 1416-1423, 2021. [PUBMED Abstract]
  5. Shadman M, Pasquini M, Ahn KW, et al.: Autologous transplant vs chimeric antigen receptor T-cell therapy for relapsed DLBCL in partial remission. Blood 139 (9): 1330-1339, 2022. [PUBMED Abstract]
  6. Cappell KM, Sherry RM, Yang JC, et al.: Long-Term Follow-Up of Anti-CD19 Chimeric Antigen Receptor T-Cell Therapy. J Clin Oncol 38 (32): 3805-3815, 2020. [PUBMED Abstract]
  7. Locke FL, Miklos DB, Jacobson CA, et al.: Axicabtagene Ciloleucel as Second-Line Therapy for Large B-Cell Lymphoma. N Engl J Med 386 (7): 640-654, 2022. [PUBMED Abstract]
  8. Westin JR, Oluwole OO, Kersten MJ, et al.: Survival with Axicabtagene Ciloleucel in Large B-Cell Lymphoma. N Engl J Med 389 (2): 148-157, 2023. [PUBMED Abstract]
  9. Abramson JS, Solomon SR, Arnason J, et al.: Lisocabtagene maraleucel as second-line therapy for large B-cell lymphoma: primary analysis of the phase 3 TRANSFORM study. Blood 141 (14): 1675-1684, 2023. [PUBMED Abstract]
  10. Bishop MR, Dickinson M, Purtill D, et al.: Second-Line Tisagenlecleucel or Standard Care in Aggressive B-Cell Lymphoma. N Engl J Med 386 (7): 629-639, 2022. [PUBMED Abstract]
  11. Santomasso BD, Nastoupil LJ, Adkins S, et al.: Management of Immune-Related Adverse Events in Patients Treated With Chimeric Antigen Receptor T-Cell Therapy: ASCO Guideline. J Clin Oncol 39 (35): 3978-3992, 2021. [PUBMED Abstract]
  12. Iacoboni G, Navarro V, Martín-López AÁ, et al.: Recent Bendamustine Treatment Before Apheresis Has a Negative Impact on Outcomes in Patients With Large B-Cell Lymphoma Receiving Chimeric Antigen Receptor T-Cell Therapy. J Clin Oncol 42 (2): 205-217, 2024. [PUBMED Abstract]
  13. Shipp MA, Abeloff MD, Antman KH, et al.: International Consensus Conference on high-dose therapy with hematopoietic stem-cell transplantation in aggressive non-Hodgkin’s lymphomas: report of the jury. Ann Oncol 10 (1): 13-9, 1999. [PUBMED Abstract]
  14. Freedman AS, Takvorian T, Anderson KC, et al.: Autologous bone marrow transplantation in B-cell non-Hodgkin’s lymphoma: very low treatment-related mortality in 100 patients in sensitive relapse. J Clin Oncol 8 (5): 784-91, 1990. [PUBMED Abstract]
  15. Phillips GL, Fay JW, Herzig RH, et al.: The treatment of progressive non-Hodgkin’s lymphoma with intensive chemoradiotherapy and autologous marrow transplantation. Blood 75 (4): 831-8, 1990. [PUBMED Abstract]
  16. Chopra R, Goldstone AH, Pearce R, et al.: Autologous versus allogeneic bone marrow transplantation for non-Hodgkin’s lymphoma: a case-controlled analysis of the European Bone Marrow Transplant Group Registry data. J Clin Oncol 10 (11): 1690-5, 1992. [PUBMED Abstract]
  17. Ratanatharathorn V, Uberti J, Karanes C, et al.: Prospective comparative trial of autologous versus allogeneic bone marrow transplantation in patients with non-Hodgkin’s lymphoma. Blood 84 (4): 1050-5, 1994. [PUBMED Abstract]
  18. Mills W, Chopra R, McMillan A, et al.: BEAM chemotherapy and autologous bone marrow transplantation for patients with relapsed or refractory non-Hodgkin’s lymphoma. J Clin Oncol 13 (3): 588-95, 1995. [PUBMED Abstract]
  19. Philip T, Guglielmi C, Hagenbeek A, et al.: Autologous bone marrow transplantation as compared with salvage chemotherapy in relapses of chemotherapy-sensitive non-Hodgkin’s lymphoma. N Engl J Med 333 (23): 1540-5, 1995. [PUBMED Abstract]
  20. Vellenga E, van Putten WL, van ‘t Veer MB, et al.: Rituximab improves the treatment results of DHAP-VIM-DHAP and ASCT in relapsed/progressive aggressive CD20+ NHL: a prospective randomized HOVON trial. Blood 111 (2): 537-43, 2008. [PUBMED Abstract]
  21. Guglielmi C, Gomez F, Philip T, et al.: Time to relapse has prognostic value in patients with aggressive lymphoma enrolled onto the Parma trial. J Clin Oncol 16 (10): 3264-9, 1998. [PUBMED Abstract]
  22. Vose JM, Anderson JR, Kessinger A, et al.: High-dose chemotherapy and autologous hematopoietic stem-cell transplantation for aggressive non-Hodgkin’s lymphoma. J Clin Oncol 11 (10): 1846-51, 1993. [PUBMED Abstract]
  23. Liberti G, Pearce R, Taghipour G, et al.: Comparison of peripheral blood stem-cell and autologous bone marrow transplantation for lymphoma patients: a case-controlled analysis of the EBMT Registry data. Lymphoma Working Party of the EBMT. Ann Oncol 5 (Suppl 2): 151-3, 1994. [PUBMED Abstract]
  24. Vose JM, Zhang MJ, Rowlings PA, et al.: Autologous transplantation for diffuse aggressive non-Hodgkin’s lymphoma in patients never achieving remission: a report from the Autologous Blood and Marrow Transplant Registry. J Clin Oncol 19 (2): 406-13, 2001. [PUBMED Abstract]
  25. van Kampen RJ, Canals C, Schouten HC, et al.: Allogeneic stem-cell transplantation as salvage therapy for patients with diffuse large B-cell non-Hodgkin’s lymphoma relapsing after an autologous stem-cell transplantation: an analysis of the European Group for Blood and Marrow Transplantation Registry. J Clin Oncol 29 (10): 1342-8, 2011. [PUBMED Abstract]
  26. Freytes CO, Loberiza FR, Rizzo JD, et al.: Myeloablative allogeneic hematopoietic stem cell transplantation in patients who experience relapse after autologous stem cell transplantation for lymphoma: a report of the International Bone Marrow Transplant Registry. Blood 104 (12): 3797-803, 2004. [PUBMED Abstract]
  27. Rezvani AR, Norasetthada L, Gooley T, et al.: Non-myeloablative allogeneic haematopoietic cell transplantation for relapsed diffuse large B-cell lymphoma: a multicentre experience. Br J Haematol 143 (3): 395-403, 2008. [PUBMED Abstract]
  28. Ghosh N, Ahmed S, Ahn KW, et al.: Association of Reduced-Intensity Conditioning Regimens With Overall Survival Among Patients With Non-Hodgkin Lymphoma Undergoing Allogeneic Transplant. JAMA Oncol 6 (7): 1011-1018, 2020. [PUBMED Abstract]
  29. Gisselbrecht C, Glass B, Mounier N, et al.: Salvage regimens with autologous transplantation for relapsed large B-cell lymphoma in the rituximab era. J Clin Oncol 28 (27): 4184-90, 2010. [PUBMED Abstract]
  30. Crump M, Kuruvilla J, Couban S, et al.: Randomized comparison of gemcitabine, dexamethasone, and cisplatin versus dexamethasone, cytarabine, and cisplatin chemotherapy before autologous stem-cell transplantation for relapsed and refractory aggressive lymphomas: NCIC-CTG LY.12. J Clin Oncol 32 (31): 3490-6, 2014. [PUBMED Abstract]
  31. Neelapu SS, Locke FL, Bartlett NL, et al.: Axicabtagene Ciloleucel CAR T-Cell Therapy in Refractory Large B-Cell Lymphoma. N Engl J Med 377 (26): 2531-2544, 2017. [PUBMED Abstract]
  32. Schuster SJ, Bishop MR, Tam CS, et al.: Tisagenlecleucel in Adult Relapsed or Refractory Diffuse Large B-Cell Lymphoma. N Engl J Med 380 (1): 45-56, 2019. [PUBMED Abstract]
  33. Locke FL, Ghobadi A, Jacobson CA, et al.: Long-term safety and activity of axicabtagene ciloleucel in refractory large B-cell lymphoma (ZUMA-1): a single-arm, multicentre, phase 1-2 trial. Lancet Oncol 20 (1): 31-42, 2019. [PUBMED Abstract]
  34. Abramson JS, Palomba ML, Gordon LI, et al.: Lisocabtagene maraleucel for patients with relapsed or refractory large B-cell lymphomas (TRANSCEND NHL 001): a multicentre seamless design study. Lancet 396 (10254): 839-852, 2020. [PUBMED Abstract]
  35. Lin JK, Muffly LS, Spinner MA, et al.: Cost Effectiveness of Chimeric Antigen Receptor T-Cell Therapy in Multiply Relapsed or Refractory Adult Large B-Cell Lymphoma. J Clin Oncol 37 (24): 2105-2119, 2019. [PUBMED Abstract]
  36. Jacobson CA, Hunter BD, Redd R, et al.: Axicabtagene Ciloleucel in the Non-Trial Setting: Outcomes and Correlates of Response, Resistance, and Toxicity. J Clin Oncol 38 (27): 3095-3106, 2020. [PUBMED Abstract]
  37. Nastoupil LJ, Jain MD, Feng L, et al.: Standard-of-Care Axicabtagene Ciloleucel for Relapsed or Refractory Large B-Cell Lymphoma: Results From the US Lymphoma CAR T Consortium. J Clin Oncol 38 (27): 3119-3128, 2020. [PUBMED Abstract]
  38. Salles G, Duell J, González Barca E, et al.: Tafasitamab plus lenalidomide in relapsed or refractory diffuse large B-cell lymphoma (L-MIND): a multicentre, prospective, single-arm, phase 2 study. Lancet Oncol 21 (7): 978-988, 2020. [PUBMED Abstract]
  39. Dickinson MJ, Carlo-Stella C, Morschhauser F, et al.: Glofitamab for Relapsed or Refractory Diffuse Large B-Cell Lymphoma. N Engl J Med 387 (24): 2220-2231, 2022. [PUBMED Abstract]
  40. Thieblemont C, Phillips T, Ghesquieres H, et al.: Epcoritamab, a Novel, Subcutaneous CD3xCD20 Bispecific T-Cell-Engaging Antibody, in Relapsed or Refractory Large B-Cell Lymphoma: Dose Expansion in a Phase I/II Trial. J Clin Oncol 41 (12): 2238-2247, 2023. [PUBMED Abstract]
  41. Sehn LH, Herrera AF, Flowers CR, et al.: Polatuzumab Vedotin in Relapsed or Refractory Diffuse Large B-Cell Lymphoma. J Clin Oncol 38 (2): 155-165, 2020. [PUBMED Abstract]
  42. Calabretta E, Hamadani M, Zinzani PL, et al.: The antibody-drug conjugate loncastuximab tesirine for the treatment of diffuse large B-cell lymphoma. Blood 140 (4): 303-308, 2022. [PUBMED Abstract]
  43. Caimi PF, Ai W, Alderuccio JP, et al.: Loncastuximab tesirine in relapsed or refractory diffuse large B-cell lymphoma (LOTIS-2): a multicentre, open-label, single-arm, phase 2 trial. Lancet Oncol 22 (6): 790-800, 2021. [PUBMED Abstract]
  44. Hamadani M, Radford J, Carlo-Stella C, et al.: Final results of a phase 1 study of loncastuximab tesirine in relapsed/refractory B-cell non-Hodgkin lymphoma. Blood 137 (19): 2634-2645, 2021. [PUBMED Abstract]
  45. Zinzani PL, Pellegrini C, Gandolfi L, et al.: Combination of lenalidomide and rituximab in elderly patients with relapsed or refractory diffuse large B-cell lymphoma: a phase 2 trial. Clin Lymphoma Myeloma Leuk 11 (6): 462-6, 2011. [PUBMED Abstract]
  46. Wiernik PH, Lossos IS, Tuscano JM, et al.: Lenalidomide monotherapy in relapsed or refractory aggressive non-Hodgkin’s lymphoma. J Clin Oncol 26 (30): 4952-7, 2008. [PUBMED Abstract]
  47. Lee AY, Connors JM, Klimo P, et al.: Late relapse in patients with diffuse large-cell lymphoma treated with MACOP-B. J Clin Oncol 15 (5): 1745-53, 1997. [PUBMED Abstract]
  48. Haas RL, Poortmans P, de Jong D, et al.: Effective palliation by low dose local radiotherapy for recurrent and/or chemotherapy refractory non-follicular lymphoma patients. Eur J Cancer 41 (12): 1724-30, 2005. [PUBMED Abstract]

Treatment of B-Cell Lymphoblastic Lymphoma/B-Cell Acute Lymphoblastic Leukemia

Lymphoblastic lymphoma (LBL) is a very aggressive form of non-Hodgkin lymphoma, which occurs often but not exclusively in young patients. LBL is the lymphomatous manifestation of acute lymphoblastic leukemia (ALL). The treatment paradigms are based on trials for ALL because LBL and ALL are considered different manifestations of the same biological disease. LBL is commonly associated with large mediastinal masses and has a high tendency to spread to bone marrow and the central nervous system. For more information, see Acute Lymphoblastic Leukemia Treatment.

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

Treatment of Diffuse Small Noncleaved-Cell/Burkitt Lymphoma

Diffuse small noncleaved-cell/Burkitt lymphoma typically involves younger patients and represents the most common type of pediatric non-Hodgkin lymphoma.[1,2] High-grade B-cell lymphoma, not otherwise specified, includes lymphomas with Burkitt-like or blastoid morphology without double hit cytogenetics, and with germinal center B-cell phenotype.[3] Up to one-half of patients have a single MYC rearrangement. Optimal treatment is poorly defined because the diagnosis is rare. Burkitt lymphoma regimens with central nervous system (CNS) prophylaxis are usually chosen.[3]

Treatment Options for Diffuse Small Noncleaved-Cell/Burkitt Lymphoma

Treatment options for diffuse small noncleaved-cell/Burkitt lymphoma include the following:

  1. Aggressive multidrug regimens.
  2. CNS prophylaxis.

Aggressive multidrug regimens

Treatment for diffuse small noncleaved-cell/Burkitt lymphoma is usually an aggressive multidrug regimen similar to those used for advanced-stage aggressive lymphomas (such as diffuse large cell).[4–6] Adverse prognostic factors include age older than 40 years, high serum lactate dehydrogenase (>3 times normal), Eastern Cooperative Oncology Group performance status of 2 or greater, and CNS involvement.[2] A retrospective review of 641 adult patients with Burkitt lymphoma from 30 U.S. cancer centers found a 3-year progression-free survival (PFS) rate of 64%. Nineteen percent of patients had CNS involvement, 14% had primary refractory disease, and the treatment-related mortality rate was 10%.[2]

Evidence (aggressive multidrug regimens):

  1. Aggressive combination chemotherapy modeled after that used in childhood Burkitt lymphoma has been successful for adult patients. More than 60% of advanced-stage patients were free of disease at 5 years.[6–9]
  2. Rituximab has been incorporated into these aggressive combination chemotherapy regimens. A nonrandomized, single-arm, prospective, multicenter trial of 363 patients, aged 16 years to 85 years, showed a 5-year PFS rate of 71% and a 5-year overall survival rate of 80%.[5][Level of evidence C1]

CNS prophylaxis

Patients with diffuse small noncleaved-cell/Burkitt lymphoma have a 20% to 30% lifetime risk of CNS involvement. CNS prophylaxis with methotrexate is recommended for all patients and is usually given as four to six intrathecal injections.[10] For more information, see Acute Lymphoblastic Leukemia Treatment.

Evidence (CNS prophylaxis):

  1. In a series of 41 patients treated with systemic and intrathecal chemotherapy, 44% of those who presented with CNS disease and 13% of those who relapsed with CNS involvement became long-term disease-free survivors.[11] CNS relapse patterns were similar whether or not patients received radiation therapy, but increased neurological deficits were noted among those who received radiation therapy.

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

References
  1. Blum KA, Lozanski G, Byrd JC: Adult Burkitt leukemia and lymphoma. Blood 104 (10): 3009-20, 2004. [PUBMED Abstract]
  2. Evens AM, Danilov A, Jagadeesh D, et al.: Burkitt lymphoma in the modern era: real-world outcomes and prognostication across 30 US cancer centers. Blood 137 (3): 374-386, 2021. [PUBMED Abstract]
  3. Olszewski AJ, Kurt H, Evens AM: Defining and treating high-grade B-cell lymphoma, NOS. Blood 140 (9): 943-954, 2022. [PUBMED Abstract]
  4. Thomas DA, Faderl S, O’Brien S, et al.: Chemoimmunotherapy with hyper-CVAD plus rituximab for the treatment of adult Burkitt and Burkitt-type lymphoma or acute lymphoblastic leukemia. Cancer 106 (7): 1569-80, 2006. [PUBMED Abstract]
  5. Hoelzer D, Walewski J, Döhner H, et al.: Improved outcome of adult Burkitt lymphoma/leukemia with rituximab and chemotherapy: report of a large prospective multicenter trial. Blood 124 (26): 3870-9, 2014. [PUBMED Abstract]
  6. Roschewski M, Dunleavy K, Abramson JS, et al.: Multicenter Study of Risk-Adapted Therapy With Dose-Adjusted EPOCH-R in Adults With Untreated Burkitt Lymphoma. J Clin Oncol 38 (22): 2519-2529, 2020. [PUBMED Abstract]
  7. Magrath I, Adde M, Shad A, et al.: Adults and children with small non-cleaved-cell lymphoma have a similar excellent outcome when treated with the same chemotherapy regimen. J Clin Oncol 14 (3): 925-34, 1996. [PUBMED Abstract]
  8. Hoelzer D, Ludwig WD, Thiel E, et al.: Improved outcome in adult B-cell acute lymphoblastic leukemia. Blood 87 (2): 495-508, 1996. [PUBMED Abstract]
  9. Mead GM, Sydes MR, Walewski J, et al.: An international evaluation of CODOX-M and CODOX-M alternating with IVAC in adult Burkitt’s lymphoma: results of United Kingdom Lymphoma Group LY06 study. Ann Oncol 13 (8): 1264-74, 2002. [PUBMED Abstract]
  10. Rizzieri DA, Johnson JL, Niedzwiecki D, et al.: Intensive chemotherapy with and without cranial radiation for Burkitt leukemia and lymphoma: final results of Cancer and Leukemia Group B Study 9251. Cancer 100 (7): 1438-48, 2004. [PUBMED Abstract]
  11. Magrath IT, Haddy TB, Adde MA: Treatment of patients with high grade non-Hodgkin’s lymphomas and central nervous system involvement: is radiation an essential component of therapy? Leuk Lymphoma 21 (1-2): 99-105, 1996. [PUBMED Abstract]

Latest Updates to This Summary (05/12/2025)

The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.

Editorial changes were made to this summary.

This summary is written and maintained by the PDQ Adult Treatment Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ® Cancer Information for Health Professionals pages.

About This PDQ Summary

Purpose of This Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of adult aggressive B-cell non-Hodgkin lymphoma. It is intended as a resource to inform and assist clinicians in the care of their patients. It does not provide formal guidelines or recommendations for making health care decisions.

Reviewers and Updates

This summary is reviewed regularly and updated as necessary by the PDQ Adult Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).

Board members review recently published articles each month to determine whether an article should:

  • be discussed at a meeting,
  • be cited with text, or
  • replace or update an existing article that is already cited.

Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.

The lead reviewers for Aggressive B-Cell Non-Hodgkin Lymphoma Treatment are:

  • Eric J. Seifter, MD (Johns Hopkins University)
  • Cole H. Sterling, MD (Johns Hopkins University)

Any comments or questions about the summary content should be submitted to Cancer.gov through the NCI website’s Email Us. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.

Levels of Evidence

Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Adult Treatment Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.

Permission to Use This Summary

PDQ is a registered trademark. Although the content of PDQ documents can be used freely as text, it cannot be identified as an NCI PDQ cancer information summary unless it is presented in its entirety and is regularly updated. However, an author would be permitted to write a sentence such as “NCI’s PDQ cancer information summary about breast cancer prevention states the risks succinctly: [include excerpt from the summary].”

The preferred citation for this PDQ summary is:

PDQ® Adult Treatment Editorial Board. PDQ Aggressive B-Cell Non-Hodgkin Lymphoma Treatment. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: /types/lymphoma/hp/aggressive-b-cell-lymphoma-treatment-pdq. Accessed <MM/DD/YYYY>. [PMID: 40203163]

Images in this summary are used with permission of the author(s), artist, and/or publisher for use within the PDQ summaries only. Permission to use images outside the context of PDQ information must be obtained from the owner(s) and cannot be granted by the National Cancer Institute. Information about using the illustrations in this summary, along with many other cancer-related images, is available in Visuals Online, a collection of over 2,000 scientific images.

Disclaimer

Based on the strength of the available evidence, treatment options may be described as either “standard” or “under clinical evaluation.” These classifications should not be used as a basis for insurance reimbursement determinations. More information on insurance coverage is available on Cancer.gov on the Managing Cancer Care page.

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More information about contacting us or receiving help with the Cancer.gov website can be found on our Contact Us for Help page. Questions can also be submitted to Cancer.gov through the website’s Email Us.

Photodynamic Therapy to Treat Cancer

Photodynamic Therapy to Treat Cancer

Photodynamic Therapy for Cancer

Cancer cells that have absorbed a drug called a photosensitizer. When activated by light, the drug kills the cancer cells.

Credit: National Cancer Institute

What is photodynamic therapy?

Photodynamic therapy uses a drug that is activated by light, called a photosensitizer or photosensitizing agent, to kill cancer cells. The light can come from a laser or other source, such as LEDs. Photodynamic therapy is also called PDT.

Photodynamic therapy is most often used as a local treatment, which means it treats a specific part of the body.

Cancer and precancers treated with photodynamic therapy

The FDA has approved photodynamic therapy to treat:

Photodynamic therapy is also used to relieve symptoms of some cancers, including:

  •  esophageal cancer when it blocks the throat
  • non-small cell lung cancer when it blocks the airways

How photodynamic therapy treats cancer

When cells that have absorbed photosensitizers are exposed to a specific wavelength of light, the photosensitizer produces a form of oxygen, called an oxygen radical, that kills them.

Photodynamic therapy may also damage blood vessels in the tumor, which prevents it from receiving the blood it needs to keep growing. And, it may trigger the immune system to attack tumor cells, even in other areas of the body.

How photodynamic therapy is given

Photodynamic therapy is a two-step process. First, you will first receive a photosensitizer. The drug may be taken by mouth, spread on the skin, or given through an IV, depending on where the tumor is in the body. After 24 to 72 hours, most of the drug will have left normal cells but remain in cancer or precancer cells. Then your tumor will be exposed to the light source.

Photodynamic Therapy Process Infographic
View and Print Infographic

How the light is applied depends on where the tumor is. For skin tumors, the light is aimed right at the cancer. For tumors in the throat, airways, and lungs, your doctor will insert an endoscope down your throat. An endoscope is a thin, lighted tube that can help the doctor see inside the body. Once the endoscope is in place, the doctor threads a fiber optic cable that transmits light through it to reach the treatment areas.

One type of photodynamic therapy called extracorporeal photopheresis (ECP) is used to treat abnormal white blood cells that can cause skin symptoms in people with cutaneous T-cell lymphoma. In ECP, a machine collects your blood cells, treats them with a photosensitizer, exposes them to light, and then returns them to your body through a needle in a vein.

Most often, you will have photodynamic therapy as an outpatient, which means you go home after treatment and do not spend the night in the hospital. You may have photodynamic therapy by itself, or you may have it along with other cancer treatments.

Benefits of photodynamic therapy

Photodynamic therapy limits damage to healthy cells because the photosensitizers tend to build up in abnormal cells and the light is focused directly on them.

Photodynamic therapy does not cause scarring, which makes it good for people with skin cancers and precancers.

Drawbacks of photodynamic therapy

Photodynamic therapy can harm normal cells in the treatment area and cause side effects.

The light used in photodynamic therapy can’t pass through more than about 1/3-inch of tissue, or 1 centimeter. So, photodynamic therapy can only be used to treat tumors that are on or just under the skin or on the lining of internal organs or cavities.

Because the light can’t reach very far into large tumors, photodynamic therapy is less helpful in treating them.

Side effects of photodynamic therapy

Damage to normal cells is limited but photodynamic therapy can still cause burns, swelling, pain, and scarring in the treatment area. Other side effects may occur depending on the area that is treated, including:

  • cough
  • trouble swallowing
  • stomach pain
  • painful breathing
  • shortness of breath
  • skin problems, such as redness, stinging, swelling, or itching

A type of photosensitizer called porfimer sodium makes the skin and eyes sensitive to light for about 6 weeks. During this time, you should avoid direct sunlight and bright indoor light.

ECP can cause:

Side effects improve once treatment is over.

Where to go for photodynamic therapy

A small number of hospitals and cancer centers throughout the country have skilled doctors and the machines needed to perform photodynamic therapy. Talk with your doctor or contact hospitals and cancer centers in your area to find out if they are using this treatment.

Photodynamic therapy research

Researchers are looking for ways to expand photodynamic therapy to other cancers, including improving the equipment used and the delivery of the light.

Studies are underway to see if ECP may be used for other blood cancers and to help reduce rejection after stem cell transplants.

Researchers are also developing a new type of PDT called photoimmunotherapy, or PIT.  In this treatment, a photosensitizer is combined with an immune protein that delivers the photosynthesizer to cancer cells. When light is applied, the photosynthesizer kills the cancer cells. This process also causes an immune response inside the tumor that can cause more cancer cells to die. Studies of PIT are going on with people with head and neck cancers. Other research is focused on finding photosensitizers that:

  • are more powerful
  • target cancer cells more precisely
  • are triggered by light that can go through tissue to treat deep or large tumors
  • cause fewer side effects

If you are interested in finding a clinical trial that uses photodynamic therapy, use the advanced clinical trials search form or contact NCI’s Cancer Information Service.

Skin Cancer Treatment (PDQ®)–Patient Version

Skin Cancer Treatment (PDQ®)–Patient Version

General Information About Skin Cancer

Go to Health Professional Version

Key Points

  • Skin cancer is a disease in which malignant (cancer) cells form in the tissues of the skin.
  • Different types of cancer start in the skin.
  • Having a fair complexion and being exposed to sunlight are risk factors for basal cell carcinoma and squamous cell carcinoma of the skin.
  • Basal cell carcinoma, squamous cell carcinoma of the skin, and actinic keratosis often appear as a change in the skin.
  • Tests or procedures that examine the skin are used to diagnose basal cell carcinoma and squamous cell carcinoma of the skin.
  • Certain factors affect prognosis (chance of recovery) and treatment options.

Skin cancer is a disease in which malignant (cancer) cells form in the tissues of the skin.

The skin is the body’s largest organ. It protects against heat, sunlight, injury, and infection. Skin also helps control body temperature and stores water, fat, and vitamin D. The skin has several layers, but the two main layers are the epidermis (upper or outer layer) and the dermis (lower or inner layer). Skin cancer begins in the epidermis, which is made up of three kinds of cells:

  • Squamous cells: Thin, flat cells that form the top layer of the epidermis.
  • Basal cells: Round cells under the squamous cells.
  • Melanocytes: Cells that make melanin and are found in the lower part of the epidermis. Melanin is the pigment that gives skin its natural color. When skin is exposed to the sun, melanocytes make more pigment and cause the skin to darken.
EnlargeAnatomy of the skin; drawing shows the epidermis (including the squamous cell and basal cell layers), dermis, and subcutaneous tissue. Also shown are the hair shafts, hair follicles, oil glands, lymph vessels, nerves, fatty tissue, veins, arteries, and sweat glands.
Anatomy of the skin showing the epidermis (including the squamous cell and basal cell layers), dermis, subcutaneous tissue, and other parts of the skin.

Skin cancer can occur anywhere on the body, but it is most common in skin that is often exposed to sunlight, such as the face, neck, and hands.

Different types of cancer start in the skin.

Skin cancer may form in basal cells or squamous cells. Basal cell carcinoma and squamous cell carcinoma are the most common types of skin cancer. They are also called nonmelanoma skin cancer. Actinic keratosis is a skin condition that sometimes becomes squamous cell carcinoma.

Melanoma is less common than basal cell carcinoma or squamous cell carcinoma. It is more likely to invade nearby tissues and spread to other parts of the body.

This summary is about basal cell carcinoma, squamous cell carcinoma of the skin, and actinic keratosis.

Having a fair complexion and being exposed to sunlight are risk factors for basal cell carcinoma and squamous cell carcinoma of the skin.

Anything that increases a person’s chance of getting a disease is called a risk factor. Not every person with one or more of these risk factors will develop skin cancer, and it will develop in people who don’t have any known risk factors. Talk with your doctor if you think you may be at risk.

Risk factors for basal cell carcinoma and squamous cell carcinoma of the skin include the following:

  • Being exposed to natural sunlight or artificial sunlight (such as from tanning beds) over long periods of time.
  • Having a fair complexion, which includes the following:
    • Fair skin that freckles and burns easily, does not tan, or tans poorly.
    • Blue, green, or other light-colored eyes.
    • Red or blond hair.

    Although having a fair complexion is a risk factor for skin cancer, people of all skin colors can get skin cancer.

  • Having a history of sunburns.
  • Having a personal or family history of basal cell carcinoma, squamous cell carcinoma of the skin, actinic keratosis, familial dysplastic nevus syndrome, or unusual moles.
  • Having certain changes in the genes or hereditary syndromes, such as basal cell nevus syndrome, that are linked to skin cancer.
  • Having skin inflammation that has lasted for long periods of time.
  • Having a weakened immune system.
  • Being exposed to arsenic.
  • Past treatment with radiation.

Older age is the main risk factor for most cancers. The chance of getting cancer increases as you get older.

Basal cell carcinoma, squamous cell carcinoma of the skin, and actinic keratosis often appear as a change in the skin.

Not all changes in the skin are a sign of basal cell carcinoma, squamous cell carcinoma of the skin, or actinic keratosis. Check with your doctor if you notice any changes in your skin.

Signs of basal cell carcinoma and squamous cell carcinoma of the skin include the following:

  • A sore that does not heal.
  • Areas of the skin that are:
    • Raised, smooth, shiny, and look pearly.
    • Firm and look like a scar, and may be white, yellow, or waxy.
    • Raised and red or reddish-brown.
    • Scaly, bleeding, or crusty.

Basal cell carcinoma and squamous cell carcinoma of the skin occur most often in areas of the skin exposed to the sun, such as the nose, ears, lower lip, or top of the hands.

Signs of actinic keratosis include the following:

  • A rough, red, pink, or brown, scaly patch on the skin that may be flat or raised.
  • Cracking or peeling of the lower lip that is not helped by lip balm or petroleum jelly.

Actinic keratosis occurs most commonly on the face or the top of the hands.

Tests or procedures that examine the skin are used to diagnose basal cell carcinoma and squamous cell carcinoma of the skin.

In addition to asking about your personal and family health history and doing a physical exam, your doctor may perform the following tests and procedures:

  • Skin exam: An exam of the skin for bumps or spots that look abnormal in color, size, shape, or texture.
  • Skin biopsy: All or part of the abnormal-looking growth is cut from the skin and viewed under a microscope by a pathologist to check for signs of cancer. There are four main types of skin biopsies:
    • Shave biopsy: A sterile razor blade is used to “shave-off” the abnormal-looking growth.
    • Punch biopsy: A special instrument called a punch or a trephine is used to remove a circle of tissue from the abnormal-looking growth.
      EnlargePunch biopsy; drawing shows a sharp, hollow, circular instrument being inserted into a lesion on the skin of a patient’s forearm. The instrument is turned clockwise and counterclockwise to cut into the skin and remove a small, round piece of tissue. A pullout shows that the instrument cuts about 4 millimeters (mm) down to the layer of fatty tissue below the skin.
      Punch biopsy. A sharp, hollow, circular instrument is used to remove a small, round piece of tissue from a lesion on the skin. The instrument is turned clockwise and counterclockwise to cut about 4 millimeters (mm) down to the layer of fatty tissue below the skin and remove the sample of tissue. Skin thickness is different on different parts of the body.
    • Incisional biopsy: A scalpel is used to remove part of a growth.
    • Excisional biopsy: A scalpel is used to remove the entire growth.

Certain factors affect prognosis (chance of recovery) and treatment options.

The prognosis for squamous cell carcinoma of the skin depends mostly on the following:

Treatment options for basal cell carcinoma and squamous cell carcinoma of the skin depend on the following:

  • The type of cancer.
  • The stage of the cancer, for squamous cell carcinoma.
  • The size of the tumor and what part of the body it affects.
  • The patient’s general health.

Stages of Skin Cancer

Key Points

  • After squamous cell cancer of the skin has been diagnosed, tests are done to find out if cancer cells have spread within the skin or to other parts of the body.
  • There are three ways that cancer spreads in the body.
  • Cancer may spread from where it began to other parts of the body.
  • Staging for basal cell carcinoma and squamous cell carcinoma of the skin depends on where the cancer formed.
  • The following stages are used for basal cell carcinoma and squamous cell carcinoma of the skin that is on the head or neck but not on the eyelid:
    • Stage 0 (Carcinoma in situ)
    • Stage I
    • Stage II
    • Stage III
    • Stage IV
  • The following stages are used for basal cell carcinoma and squamous cell carcinoma of the skin on the eyelid:
    • Stage 0 (Carcinoma in situ)
    • Stage I
    • Stage II
    • Stage III
    • Stage IV
  • Treatment depends on the type of skin cancer or other skin condition diagnosed:
    • Basal cell carcinoma
    • Squamous cell carcinoma
    • Actinic keratosis

After squamous cell cancer of the skin has been diagnosed, tests are done to find out if cancer cells have spread within the skin or to other parts of the body.

The process used to find out if cancer has spread within the skin or to other parts of the body is called staging. The information gathered from the staging process determines the stage of the disease. It is important to know the stage in order to plan treatment for squamous cell carcinoma of the skin.

Basal cell carcinoma of the skin rarely spreads to other parts of the body. Staging tests to check whether basal cell carcinoma of the skin has spread are usually not needed.

The following tests and procedures may be used in the staging process for squamous cell carcinoma of the skin:

  • CT scan (CAT scan): A procedure that makes a series of detailed pictures of areas inside the body, such as the head, neck, and chest, taken from different angles. The pictures are made by a computer linked to an x-ray machine. A dye may be injected into a vein or swallowed to help the organs or tissues show up more clearly. This procedure is also called computed tomography, computerized tomography, or computerized axial tomography.
  • Chest x-ray: An x-ray of the organs and bones inside the chest. An x-ray is a type of energy beam that can go through the body and onto film, making a picture of areas inside the body.
  • PET scan (positron emission tomography scan): A procedure to find malignant tumor cells in the body. A small amount of radioactive glucose (sugar) is injected into a vein. The PET scanner rotates around the body and makes a picture of where glucose is being used in the body. Malignant tumor cells show up brighter in the picture because they are more active and take up more glucose than normal cells do. Sometimes a PET scan and CT scan are done at the same time.
  • Ultrasound exam: A procedure in which high-energy sound waves (ultrasound) are bounced off internal tissues, such as lymph nodes, or organs and make echoes. The echoes form a picture of body tissues called a sonogram. The picture can be printed to be looked at later. An ultrasound exam of the regional lymph nodes may be done for basal cell carcinoma and squamous cell carcinoma of the skin.
  • Eye exam with dilated pupil: An exam of the eye in which the pupil is dilated (opened wider) with medicated eye drops to allow the doctor to look through the lens and pupil to the retina and optic nerve. The inside of the eye, including the retina and the optic nerve, is examined with a light.
  • Lymph node biopsy: The removal of all or part of a lymph node. A pathologist views the lymph node tissue under a microscope to check for cancer cells. A lymph node biopsy may be done for squamous cell carcinoma of the skin.

There are three ways that cancer spreads in the body.

Cancer can spread through tissue, the lymph system, and the blood:

  • Tissue. The cancer spreads from where it began by growing into nearby areas.
  • Lymph system. The cancer spreads from where it began by getting into the lymph system. The cancer travels through the lymph vessels to other parts of the body.
  • Blood. The cancer spreads from where it began by getting into the blood. The cancer travels through the blood vessels to other parts of the body.

Cancer may spread from where it began to other parts of the body.

When cancer spreads to another part of the body, it is called metastasis. Cancer cells break away from where they began (the primary tumor) and travel through the lymph system or blood.

  • Lymph system. The cancer gets into the lymph system, travels through the lymph vessels, and forms a tumor (metastatic tumor) in another part of the body.
  • Blood. The cancer gets into the blood, travels through the blood vessels, and forms a tumor (metastatic tumor) in another part of the body.

The metastatic tumor is the same type of cancer as the primary tumor. For example, if skin cancer spreads to the lung, the cancer cells in the lung are actually skin cancer cells. The disease is metastatic skin cancer, not lung cancer.

Many cancer deaths are caused when cancer moves from the original tumor and spreads to other tissues and organs. This is called metastatic cancer. This animation shows how cancer cells travel from the place in the body where they first formed to other parts of the body.

Staging for basal cell carcinoma and squamous cell carcinoma of the skin depends on where the cancer formed.

Staging for basal cell carcinoma and squamous cell carcinoma of the eyelid is different from staging for basal cell carcinoma and squamous cell carcinoma found on other areas of the head or neck. There is no staging system for basal cell carcinoma or squamous cell carcinoma that is not found on the head or neck.

Surgery to remove the primary tumor and abnormal lymph nodes is done so that tissue samples can be studied under a microscope. This is called pathologic staging and the findings are used for staging as described below. If staging is done before surgery to remove the tumor, it is called clinical staging. The clinical stage may be different from the pathologic stage.

The following stages are used for basal cell carcinoma and squamous cell carcinoma of the skin that is on the head or neck but not on the eyelid:

Stage 0 (Carcinoma in situ)

In stage 0, abnormal cells are found in the squamous cell or basal cell layer of the epidermis. These abnormal cells may become cancer and spread into nearby normal tissue. Stage 0 is also called carcinoma in situ.

EnlargeNonmelanoma skin cancer of the head and neck (carcinoma in situ); drawing shows abnormal squamous cells and basal cells in the epidermis. Also shown are the dermis and the subcutaneous tissue below the dermis. There are two insets: the inset on the left shows a close up of normal and abnormal squamous cells; the inset on the right shows a close up of normal and abnormal basal cells.
Nonmelanoma skin cancer of the head and neck (carcinoma in situ). Abnormal cells are found in the squamous cell or basal cell layer of the epidermis. These abnormal cells may become cancer and spread into nearby normal tissue.

Stage I

In stage I, cancer has formed and the tumor is 2 centimeters or smaller.

EnlargeStage I nonmelanoma skin cancer of the head and neck; drawing shows cancer in the epidermis (the outer layer of the skin). An inset shows that the tumor is 2 centimeters or smaller and that 2 centimeters is about the size of a peanut. Also shown are the dermis (the inner layer of the skin) and the subcutaneous tissue below the dermis.
Stage I nonmelanoma skin cancer of the head and neck. The tumor is 2 centimeters or smaller.

Stage II

In stage II, the tumor is larger than 2 centimeters but not larger than 4 centimeters.

EnlargeStage II nonmelanoma skin cancer of the head and neck; drawing shows cancer in the epidermis and the dermis. An inset shows that the tumor is larger than 2 centimeters but not larger than 4 centimeters and that 2 centimeters is about the size of a peanut and 4 centimeters is about the size of a walnut. Also shown is the subcutaneous tissue below the dermis.
Stage II nonmelanoma skin cancer of the head and neck. The tumor is larger than 2 centimeters but not larger than 4 centimeters.

Stage III

EnlargeStage III nonmelanoma skin cancer of the head and neck (1); drawing shows (a) an inset showing that the tumor is larger than 4 centimeters and that 4 centimeters is about the size of a walnut. Also shown is cancer spreading through the epidermis to (b) tissue covering the nerves below the dermis; (c) below the subcutaneous tissue; and (d) bone.
Stage III nonmelanoma skin cancer of the head and neck (1). The tumor is (a) larger than 4 centimeters; or cancer has spread to (b) tissue covering the nerves below the dermis; or (c) below the subcutaneous tissue; or (d) the bone and the bone has minor damage. Cancer may have spread to one lymph node on the same side of the body as the tumor and the node is 3 centimeters or smaller, and cancer has not spread through to the outside covering of the lymph node (not shown).

or

EnlargeStage III nonmelanoma skin cancer of the head and neck (2); drawing shows a primary tumor on the face and cancer in one lymph node on the same side of the body as the tumor. The top inset shows that the tumor is 4 centimeters or smaller and that 4 centimeters is about the size of a walnut. The bottom inset shows that the lymph node with cancer is 3 centimeters or smaller and that 3 centimeters is about the size of a grape.
Stage III nonmelanoma skin cancer of the head and neck (2). The tumor is 4 centimeters or smaller. Cancer has spread to one lymph node on the same side of the body as the tumor and the node is 3 centimeters or smaller.

In stage III, one of the following is found:

  • the tumor is larger than 4 centimeters, or cancer has spread to tissue covering the nerves below the dermis, or has spread below the subcutaneous tissue, or has spread to the bone and the bone has minor damage. Cancer may have also spread to one lymph node on the same side of the body as the tumor and the node is 3 centimeters or smaller, and cancer has not spread through to the outside covering of the lymph node; or
  • the tumor is 4 centimeters or smaller. Cancer has spread to one lymph node on the same side of the body as the tumor and the node is 3 centimeters or smaller.

Stage IV

EnlargeStage IV nonmelanoma skin cancer of the head and neck (1); drawing shows a primary tumor on the face and cancer that has spread to: (a) one lymph node on the same side of the body as the tumor, the node is 3 centimeters or smaller, and cancer has spread through to the outside covering of the lymph node; (b) one lymph node on the same side of the body as the tumor and the node is larger than 3 centimeters but not larger than 6 centimeters; (c) more than one lymph node on the same side of the body as the tumor and the nodes are 6 centimeters or smaller; and (d) one or more lymph nodes on the opposite or both sides of the body as the tumor and the nodes are 6 centimeters or smaller. Also shown is a 10-centimeter ruler and a 4-inch ruler.
Stage IV nonmelanoma skin cancer of the head and neck (1). The tumor is any size. Cancer may have spread to the bone and the bone has minor damage, or to tissue covering the nerves below the dermis, or below the subcutaneous tissue. Cancer has spread to: (a) one lymph node on the same side of the body as the tumor, the node is 3 centimeters or smaller, and cancer has spread through to the outside covering of the lymph node; or (b) one lymph node on the same side of the body as the tumor, the node is larger than 3 centimeters but not larger than 6 centimeters, and cancer has not spread through to the outside covering of the lymph node; or (c) more than one lymph node on the same side of the body as the tumor, the nodes are 6 centimeters or smaller, and cancer has not spread through to the outside covering of the lymph nodes; or (d) one or more lymph nodes on the opposite side of the body as the tumor or on both sides of the body, the nodes are 6 centimeters or smaller, and cancer has not spread through to the outside covering of the lymph nodes.

or

EnlargeStage IV nonmelanoma skin cancer of the head and neck (2); drawing shows a primary skin tumor on the face and cancer that has spread to: (a) one lymph node that is larger than 6 centimeters; (b) one lymph node on the same side of the body as the tumor, the affected node is larger than 3 centimeters, and cancer has spread through to the outside covering of the lymph node; (c) one lymph node on the opposite side of the body as the tumor, the affected node is any size, and cancer has spread through to the outside covering of the lymph node; and (d) more than one lymph node on one or both sides of the body and cancer has spread through to the outside covering of the lymph nodes. Also shown is a 10-centimeter ruler and a 4-inch ruler.
Stage IV nonmelanoma skin cancer of the head and neck (2). The tumor is any size and cancer has spread to: (a) one lymph node that is larger than 6 centimeters and cancer has not spread through to the outside covering of the lymph node; or (b) one lymph node on the same side of the body as the tumor, the affected node is larger than 3 centimeters, and cancer has spread through to the outside covering of the lymph node; or (c) one lymph node on the opposite side of the body as the tumor, the affected node is any size, and cancer has spread through to the outside covering of the lymph node; or (d) more than one lymph node on one or both sides of the body and cancer has spread through to the outside covering of the lymph nodes.

or

EnlargeStage IV nonmelanoma skin cancer of the head and neck (3); drawing shows a primary skin tumor on the face and other parts of the body where nonmelanoma skin cancer may spread, including the base of the skull, the lung, the bone, and the bone marrow. An inset shows cancer cells spreading through the blood and lymph system to another part of the body where metastatic cancer has formed.
Stage IV nonmelanoma skin cancer of the head and neck (3). The tumor is any size and cancer has spread to bone marrow or to bone, including the base of the skull, and the bone has been damaged; or cancer has spread to other parts of the body, such as the lung.

In stage IV, one of the following is found:

  • the tumor is any size and cancer may have spread to the bone and the bone has minor damage, or to tissue covering the nerves below the dermis, or below the subcutaneous tissue. Cancer has spread to the lymph nodes as follows:
    • one lymph node on the same side of the body as the tumor, the affected node is 3 centimeters or smaller, and cancer has spread through to the outside covering of the lymph node; or
    • one lymph node on the same side of the body as the tumor, the affected node is larger than 3 centimeters but not larger than 6 centimeters, and cancer has not spread through to the outside covering of the lymph node; or
    • more than one lymph node on the same side of the body as the tumor, the affected nodes are 6 centimeters or smaller, and cancer has not spread through to the outside covering of the lymph nodes; or
    • one or more lymph nodes on the opposite side of the body as the tumor or on both sides of the body, the affected nodes are 6 centimeters or smaller, and cancer has not spread through to the outside covering of the lymph nodes.
  • the tumor is any size and cancer may have spread to tissue covering the nerves below the dermis, or below the subcutaneous tissue, or to bone marrow or to bone, including the bottom of the skull. Also:
    • cancer has spread to one lymph node that is larger than 6 centimeters and cancer has not spread through to the outside covering of the lymph node; or
    • cancer has spread to one lymph node on the same side of the body as the tumor, the affected node is larger than 3 centimeters, and cancer has spread through to the outside covering of the lymph node; or
    • cancer has spread to one lymph node on the opposite side of the body as the tumor, the affected node is any size, and cancer has spread through to the outside covering of the lymph node; or
    • cancer has spread to more than one lymph node on one or both sides of the body and cancer has spread through to the outside covering of the lymph nodes.
  • the tumor is any size and cancer has spread to bone marrow or to bone, including the bottom of the skull, and the bone has been damaged. Cancer may have also spread to the lymph nodes; or
  • cancer has spread to other parts of the body, such as the lung.

The following stages are used for basal cell carcinoma and squamous cell carcinoma of the skin on the eyelid:

Stage 0 (Carcinoma in situ)

In stage 0, abnormal cells are found in the epidermis, usually in the basal cell layer. These abnormal cells may become cancer and spread into nearby normal tissue. Stage 0 is also called carcinoma in situ.

Stage I

In stage I, cancer has formed. Stage I is divided into stages IA and IB.

  • Stage IA: The tumor is 10 millimeters or smaller and may have spread to the edge of the eyelid where the lashes are, to the connective tissue in the eyelid, or to the full thickness of the eyelid.
  • Stage IB: The tumor is larger than 10 millimeters but not larger than 20 millimeters and the tumor has not spread to the edge of the eyelid where the lashes are, or to the connective tissue in the eyelid.

Stage II

Stage II is divided into stages IIA and IIB.

  • In stage IIA, one of the following is found:
    • the tumor is larger than 10 millimeters but not larger than 20 millimeters and has spread to the edge of the eyelid where the lashes are, to the connective tissue in the eyelid, or to the full thickness of the eyelid; or
    • the tumor is larger than 20 millimeters but not larger than 30 millimeters and may have spread to the edge of the eyelid where the lashes are, to the connective tissue in the eyelid, or to the full thickness of the eyelid.
  • In stage IIB, the tumor may be any size and has spread to the eye, eye socket, sinuses, tear ducts, or brain, or to the tissues that support the eye.

Stage III

Stage III is divided into stages IIIA and IIIB.

  • Stage IIIA: The tumor may be any size and may have spread to the edge of the eyelid where the lashes are, to the connective tissue in the eyelid, or to the full thickness of the eyelid, or to the eye, eye socket, sinuses, tear ducts, or brain, or to the tissues that support the eye. Cancer has spread to one lymph node on the same side of the body as the tumor and the node is 3 centimeters or smaller.
  • Stage IIIB: The tumor may be any size and may have spread to the edge of the eyelid where the lashes are, to the connective tissue in the eyelid, or to the full thickness of the eyelid, or to the eye, eye socket, sinuses, tear ducts, or brain, or to the tissues that support the eye. Cancer has spread to lymph nodes as follows:
    • one lymph node on the same side of the body as the tumor and the node is larger than 3 centimeters; or
    • more than one lymph node on the opposite side of the body as the tumor or on both sides of the body.

Stage IV

In stage IV, the tumor has spread to other parts of the body, such as the lung or liver.

Treatment depends on the type of skin cancer or other skin condition diagnosed:

Basal cell carcinoma

EnlargePhotographs showing a skin cancer lesion that looks reddish brown and slightly raised (left panel) and the back of a person’s ear with a skin cancer lesion that looks like an open sore with a pearly rim (right panel).
Basal cell carcinoma. A skin cancer lesion that looks reddish brown and slightly raised (left panel) and a skin cancer lesion that looks like an open sore with a pearly rim (right panel).

Basal cell carcinoma is the most common type of skin cancer. It usually occurs on areas of the skin that have been in the sun, most often the nose. Often this cancer appears as a raised bump that looks smooth and pearly. A less common type looks like a scar or it is flat and firm and may be skin-colored, yellow, or waxy. Basal cell carcinoma may spread to tissues around the cancer, but it usually does not spread to other parts of the body.

Squamous cell carcinoma

EnlargePhotographs showing the side of a person’s face with a skin cancer lesion that looks raised and crusty (left panel) and a person’s leg with a skin cancer lesion that looks pink and raised (right panel).
Squamous cell carcinoma. A skin cancer lesion on the face that looks raised and crusty (left panel) and a skin cancer lesion on the leg that looks pink and raised (right panel).

Squamous cell carcinoma occurs on areas of the skin that have been damaged by the sun, such as the ears, lower lip, and the back of the hands. Squamous cell carcinoma may also appear on areas of the skin that have been sunburned or exposed to chemicals or radiation. Often this cancer looks like a firm red bump. The tumor may feel scaly, bleed, or form a crust. Squamous cell tumors may spread to nearby lymph nodes. Squamous cell carcinoma that has not spread can usually be cured.

Actinic keratosis

Actinic keratosis is a skin condition that is not cancer, but sometimes changes into squamous cell carcinoma. One or more lesions may occur in areas that have been exposed to the sun, such as the face, the back of the hands, and the lower lip. It looks like rough, red, pink, or brown scaly patches on the skin that may be flat or raised, or as a cracked and peeling lower lip that is not helped by lip balm or petroleum jelly. Actinic keratosis may disappear without treatment.

Treatment Option Overview

Key Points

  • There are different types of treatment for patients with basal cell carcinoma, squamous cell carcinoma of the skin, and actinic keratosis.
  • The following types of treatment are used:
    • Surgery
    • Radiation therapy
    • Chemotherapy
    • Photodynamic therapy
    • Immunotherapy
    • Targeted therapy
    • Chemical peel
    • Other drug therapy
  • New types of treatment are being tested in clinical trials.
  • Treatment for skin cancer may cause side effects.
  • Patients may want to think about taking part in a clinical trial.
  • Patients can enter clinical trials before, during, or after starting their cancer treatment.
  • Follow-up tests may be needed.

There are different types of treatment for patients with basal cell carcinoma, squamous cell carcinoma of the skin, and actinic keratosis.

Different types of treatment are available for patients with basal cell carcinoma, squamous cell carcinoma of the skin, and actinic keratosis. Some treatments are standard (the currently used treatment), and some are being tested in clinical trials. A treatment clinical trial is a research study meant to help improve current treatments or obtain information on new treatments for patients with cancer. When clinical trials show that a new treatment is better than the standard treatment, the new treatment may become the standard treatment. Patients may want to think about taking part in a clinical trial. Some clinical trials are open only to patients who have not started treatment.

The following types of treatment are used:

Surgery

One or more of the following surgical procedures may be used to treat basal cell carcinoma, squamous cell carcinoma of the skin, or actinic keratosis:

  • Simple excision: The tumor, along with some of the normal tissue around it, is cut from the skin.
  • Mohs micrographic surgery: The tumor is cut from the skin in thin layers. During the procedure, the edges of the tumor and each layer of tumor removed are viewed through a microscope to check for cancer cells. Layers continue to be removed until no more cancer cells are seen. This type of surgery removes as little normal tissue as possible. It is often used to remove skin cancer on the face, fingers, or genitals and skin cancer that does not have a clear border.
    EnlargeMohs surgery; drawing shows a patient with skin cancer on the face. The pullout shows a block of skin with cancer in the epidermis (outer layer of the skin) and the dermis (inner layer of the skin). A visible lesion is shown on the skin’s surface. Four numbered blocks show the removal of thin layers of the skin one at a time until all the cancer is removed.
    Mohs surgery. A surgical procedure to remove skin cancer in several steps. First, a thin layer of cancerous tissue is removed. Then, a second thin layer of tissue is removed and viewed under a microscope to check for cancer cells. More layers are removed one at a time until the tissue viewed under a microscope shows no remaining cancer. This type of surgery is used to remove as little normal tissue as possible and is often used to remove skin cancer on the face.
  • Shave excision: The abnormal area is shaved off the surface of the skin with a small blade.
  • Curettage and electrodesiccation: The tumor is cut from the skin with a curette (a sharp, spoon-shaped tool). A needle-shaped electrode is then used to treat the area with an electric current that stops the bleeding and destroys cancer cells that remain around the edge of the wound. The process may be repeated one to three times during the surgery to remove all of the cancer. This type of treatment is also called electrosurgery.
  • Cryosurgery: A treatment that uses an instrument to freeze and destroy abnormal tissue, such as carcinoma in situ. This type of treatment is also called cryotherapy.
    EnlargeCryosurgery; drawing shows an instrument with a nozzle held over an abnormal area on the lower arm of a patient. Inset shows a spray of liquid nitrogen or liquid carbon dioxide coming from the nozzle and covering the abnormal lesion. Freezing destroys the lesion.
    Cryosurgery. An instrument with a nozzle is used to spray liquid nitrogen or liquid carbon dioxide to freeze and destroy abnormal tissue.
  • Laser surgery: A surgical procedure that uses a laser beam (a narrow beam of intense light) as a knife to make bloodless cuts in tissue or to remove a surface lesion such as a tumor.
  • Dermabrasion: Removal of the top layer of skin using a rotating wheel or small particles to rub away skin cells.

Simple excision, Mohs micrographic surgery, curettage and electrodesiccation, and cryosurgery are used to treat basal cell carcinoma and squamous cell carcinoma of the skin. Laser surgery is rarely used to treat basal cell carcinoma. Simple excision, shave excision, curettage and desiccation, dermabrasion, and laser surgery are used to treat actinic keratosis.

Radiation therapy

Radiation therapy is a cancer treatment that uses high-energy x-rays or other types of radiation to kill cancer cells or keep them from growing. External radiation therapy uses a machine outside the body to send radiation toward the area of the body with cancer.

External radiation therapy is used to treat basal cell carcinoma and squamous cell carcinoma of the skin.

Chemotherapy

Chemotherapy is a cancer treatment that uses drugs to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing.

Chemotherapy for basal cell carcinoma, squamous cell carcinoma of the skin, and actinic keratosis is usually topical (applied to the skin in a cream or lotion). Topical fluorouracil (5-FU) is used to treat basal cell carcinoma.

See Drugs Approved for Basal Cell Carcinoma for more information.

Photodynamic therapy

Photodynamic therapy (PDT) is a cancer treatment that uses a drug and a certain type of light to kill cancer cells. A drug that is not active until it is exposed to light is injected into a vein or put on the skin. The drug collects more in cancer cells than in normal cells. For skin cancer, laser light is shined onto the skin and the drug becomes active and kills the cancer cells. Photodynamic therapy causes little damage to healthy tissue.

Photodynamic therapy is also used to treat actinic keratoses.

Immunotherapy

Immunotherapy is a treatment that uses the patient’s immune system to fight cancer. Substances made by the body or made in a laboratory are used to boost, direct, or restore the body’s natural defenses against cancer.

There are different types of immunotherapy used to treat skin cancer:

  • Immune checkpoint inhibitors block proteins called checkpoints that are made by some types of immune system cells, such as T cells, and some cancer cells. PD-1 is a protein on the surface of T cells that helps keep the body’s immune responses in check. PD-L1 is a protein found on some types of cancer cells. When PD-1 attaches to PD-L1, it stops the T cell from killing the cancer cell. PD-1 and PD-L1 inhibitors keep PD-1 and PD-L1 proteins from attaching to each other. This allows the T cells to kill cancer cells.
    • Cemiplimab and pembrolizumab are types of PD-1 inhibitors used to treat squamous cell carcinoma of the skin that is locally advanced or has spread to other parts of the body.
    EnlargeImmune checkpoint inhibitor; the panel on the left shows the binding of proteins PD-L1 (on the tumor cell) to PD-1 (on the T cell), which keeps T cells from killing tumor cells in the body. Also shown are a tumor cell antigen and T cell receptor. The panel on the right shows immune checkpoint inhibitors (anti-PD-L1 and anti-PD-1) blocking the binding of PD-L1 to PD-1, which allows the T cells to kill tumor cells.
    Immune checkpoint inhibitor. Checkpoint proteins, such as PD-L1 on tumor cells and PD-1 on T cells, help keep immune responses in check. The binding of PD-L1 to PD-1 keeps T cells from killing tumor cells in the body (left panel). Blocking the binding of PD-L1 to PD-1 with an immune checkpoint inhibitor (anti-PD-L1 or anti-PD-1) allows the T cells to kill tumor cells (right panel).
    Immunotherapy uses the body’s immune system to fight cancer. This animation explains one type of immunotherapy that uses immune checkpoint inhibitors to treat cancer.

See Drugs Approved for Basal Cell Carcinoma for more information.

Targeted therapy

Targeted therapy is a type of treatment that uses drugs or other substances to identify and attack specific cancer cells.

See Drugs Approved for Basal Cell Carcinoma for more information.

Chemical peel

A chemical peel is a procedure used to improve the way certain skin conditions look. A chemical solution is put on the skin to dissolve the top layers of skin cells. Chemical peels may be used to treat actinic keratosis. This type of treatment is also called chemabrasion and chemexfoliation.

Other drug therapy

Retinoids (drugs related to vitamin A) are sometimes used to treat squamous cell carcinoma of the skin. Diclofenac and ingenol are topical drugs used to treat actinic keratosis.

New types of treatment are being tested in clinical trials.

Information about clinical trials is available from the NCI website.

Treatment for skin cancer may cause side effects.

For information about side effects caused by treatment for cancer, visit our Side Effects page.

Patients may want to think about taking part in a clinical trial.

For some patients, taking part in a clinical trial may be the best treatment choice. Clinical trials are part of the cancer research process. Clinical trials are done to find out if new cancer treatments are safe and effective or better than the standard treatment.

Many of today’s standard treatments for cancer are based on earlier clinical trials. Patients who take part in a clinical trial may receive the standard treatment or be among the first to receive a new treatment.

Patients who take part in clinical trials also help improve the way cancer will be treated in the future. Even when clinical trials do not lead to effective new treatments, they often answer important questions and help move research forward.

Patients can enter clinical trials before, during, or after starting their cancer treatment.

Some clinical trials only include patients who have not yet received treatment. Other trials test treatments for patients whose cancer has not gotten better. There are also clinical trials that test new ways to stop cancer from recurring (coming back) or reduce the side effects of cancer treatment.

Clinical trials are taking place in many parts of the country. Information about clinical trials supported by NCI can be found on NCI’s clinical trials search webpage. Clinical trials supported by other organizations can be found on the ClinicalTrials.gov website.

Follow-up tests may be needed.

As you go through treatment, you will have follow-up tests or check-ups. Some tests that were done to diagnose or stage the cancer may be repeated to see how well the treatment is working. Decisions about whether to continue, change, or stop treatment may be based on the results of these tests.

Some of the tests will continue to be done from time to time after treatment has ended. The results of these tests can show if your condition has changed or if the cancer has recurred (come back).

If basal cell carcinoma and squamous cell carcinoma recur (come back), it is usually within 5 years of initial treatment. Talk to your doctor about how often you should have your skin checked for signs of cancer.

Treatment of Basal Cell Carcinoma

For information about the treatments listed below, see the Treatment Option Overview section.

Treatment of basal cell carcinoma that is localized may include the following:

Treatment of basal cell carcinoma that is metastatic or cannot be treated with local therapy may include the following:

Treatment of recurrent basal cell carcinoma that is not metastatic may include the following:

  • Simple excision.
  • Mohs micrographic surgery.

Use our clinical trial search to find NCI-supported cancer clinical trials that are accepting patients. You can search for trials based on the type of cancer, the age of the patient, and where the trials are being done. General information about clinical trials is also available.

Treatment of Squamous Cell Carcinoma of the Skin

Treatment of squamous cell carcinoma that is localized may include the following:

Treatment of squamous cell carcinoma that is metastatic or cannot be treated with local therapy may include the following:

Treatment of recurrent squamous cell carcinoma that is not metastatic may include the following:

  • Simple excision.
  • Mohs micrographic surgery.
  • Radiation therapy.

Use our clinical trial search to find NCI-supported cancer clinical trials that are accepting patients. You can search for trials based on the type of cancer, the age of the patient, and where the trials are being done. General information about clinical trials is also available.

Treatment of Actinic Keratosis

For information about the treatments listed below, see the Treatment Option Overview section.

Actinic keratosis is not cancer but is treated because it may develop into cancer. Treatment of actinic keratosis may include the following:

Use our clinical trial search to find NCI-supported cancer clinical trials that are accepting patients. You can search for trials based on the type of cancer, the age of the patient, and where the trials are being done. General information about clinical trials is also available.

To Learn More About Skin Cancer

For more information from the National Cancer Institute about skin cancer, visit:

For general cancer information and other resources from the National Cancer Institute, visit:

About This PDQ Summary

About PDQ

Physician Data Query (PDQ) is the National Cancer Institute’s (NCI’s) comprehensive cancer information database. The PDQ database contains summaries of the latest published information on cancer prevention, detection, genetics, treatment, supportive care, and complementary and alternative medicine. Most summaries come in two versions. The health professional versions have detailed information written in technical language. The patient versions are written in easy-to-understand, nontechnical language. Both versions have cancer information that is accurate and up to date and most versions are also available in Spanish.

PDQ is a service of the NCI. The NCI is part of the National Institutes of Health (NIH). NIH is the federal government’s center of biomedical research. The PDQ summaries are based on an independent review of the medical literature. They are not policy statements of the NCI or the NIH.

Purpose of This Summary

This PDQ cancer information summary has current information about the treatment of skin cancer. It is meant to inform and help patients, families, and caregivers. It does not give formal guidelines or recommendations for making decisions about health care.

Reviewers and Updates

Editorial Boards write the PDQ cancer information summaries and keep them up to date. These Boards are made up of experts in cancer treatment and other specialties related to cancer. The summaries are reviewed regularly and changes are made when there is new information. The date on each summary (“Updated”) is the date of the most recent change.

The information in this patient summary was taken from the health professional version, which is reviewed regularly and updated as needed, by the PDQ Adult Treatment Editorial Board.

Clinical Trial Information

A clinical trial is a study to answer a scientific question, such as whether one treatment is better than another. Trials are based on past studies and what has been learned in the laboratory. Each trial answers certain scientific questions in order to find new and better ways to help cancer patients. During treatment clinical trials, information is collected about the effects of a new treatment and how well it works. If a clinical trial shows that a new treatment is better than one currently being used, the new treatment may become “standard.” Patients may want to think about taking part in a clinical trial. Some clinical trials are open only to patients who have not started treatment.

Clinical trials can be found online at NCI’s website. For more information, call the Cancer Information Service (CIS), NCI’s contact center, at 1-800-4-CANCER (1-800-422-6237).

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PDQ is a registered trademark. The content of PDQ documents can be used freely as text. It cannot be identified as an NCI PDQ cancer information summary unless the whole summary is shown and it is updated regularly. However, a user would be allowed to write a sentence such as “NCI’s PDQ cancer information summary about breast cancer prevention states the risks in the following way: [include excerpt from the summary].”

The best way to cite this PDQ summary is:

PDQ® Adult Treatment Editorial Board. PDQ Skin Cancer Treatment. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: /types/skin/patient/skin-treatment-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389265]

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Mycosis Fungoides (Including Sézary Syndrome) Treatment (PDQ®)–Patient Version

Mycosis Fungoides (Including Sézary Syndrome) Treatment (PDQ®)–Patient Version

General Information About Mycosis Fungoides (Including Sézary Syndrome)

Go to Health Professional Version

Key Points

  • Mycosis fungoides and Sézary syndrome are diseases in which lymphocytes (a type of white blood cell) become malignant (cancerous) and affect the skin.
  • Mycosis fungoides and Sézary syndrome are types of cutaneous T-cell lymphoma.
  • A sign of mycosis fungoides is a red rash on the skin.
  • In Sézary syndrome, cancerous T-cells are found in the blood.
  • Tests that examine the skin and blood are used to diagnose mycosis fungoides and Sézary syndrome.
  • Certain factors affect prognosis (chance of recovery) and treatment options.

Mycosis fungoides and Sézary syndrome are diseases in which lymphocytes (a type of white blood cell) become malignant (cancerous) and affect the skin.

Normally, the bone marrow makes blood stem cells (immature cells) that become mature blood stem cells over time. A blood stem cell may become a myeloid stem cell or a lymphoid stem cell. A myeloid stem cell becomes a red blood cell, white blood cell, or platelet. A lymphoid stem cell becomes a lymphoblast and then one of three types of lymphocytes (white blood cells):

EnlargeBlood cell development; drawing shows the steps a blood stem cell goes through to become a red blood cell, platelet, or white blood cell. A myeloid stem cell becomes a red blood cell, a platelet, or a myeloblast, which then becomes a granulocyte (the types of granulocytes are eosinophils, basophils, and neutrophils). A lymphoid stem cell becomes a lymphoblast and then becomes a B-lymphocyte, T-lymphocyte, or natural killer cell.
Blood cell development. A blood stem cell goes through several steps to become a red blood cell, platelet, or white blood cell.

In mycosis fungoides, T-cell lymphocytes become cancerous and affect the skin. When these lymphocytes occur in the blood, they are called Sézary cells. In Sézary syndrome, cancerous T-cell lymphocytes affect the skin and large numbers of Sézary cells are found in the blood.

Mycosis fungoides and Sézary syndrome are types of cutaneous T-cell lymphoma.

Mycosis fungoides and Sézary syndrome are the two most common types of cutaneous T-cell lymphoma (a type of non-Hodgkin lymphoma). For information about other types of skin cancer or non-Hodgkin lymphoma, see the following PDQ summaries:

A sign of mycosis fungoides is a red rash on the skin.

Mycosis fungoides may go through the following phases:

  • Premycotic phase: A scaly, red rash in areas of the body that usually are not exposed to the sun. This rash does not cause symptoms and may last for months or years. It is hard to diagnose the rash as mycosis fungoides during this phase.
  • Patch phase: Thin, reddened, eczema-like rash.
  • Plaque phase: Small raised bumps (papules) or hardened lesions on the skin, which may be reddened.
  • Tumor phase: Tumors form on the skin. These tumors may develop ulcers and the skin may get infected.

Check with your doctor if you have any of these signs.

In Sézary syndrome, cancerous T-cells are found in the blood.

Also, skin all over the body is reddened, itchy, peeling, and painful. There may also be patches, plaques, or tumors on the skin. It is not known if Sézary syndrome is an advanced form of mycosis fungoides or a separate disease.

Tests that examine the skin and blood are used to diagnose mycosis fungoides and Sézary syndrome.

The following tests and procedures may be used:

  • Physical exam and health history: An exam of the body to check general signs of health, including checking for signs of disease, such as lumps, the number and type of skin lesions, or anything else that seems unusual. Pictures of the skin and a history of the patient’s health habits and past illnesses and treatments will also be taken.
  • Complete blood count with differential: A procedure in which a sample of blood is drawn and checked for the following:
    • The number of red blood cells and platelets.
    • The number and type of white blood cells.
    • The amount of hemoglobin (the protein that carries oxygen) in the red blood cells.
    • The portion of the blood sample made up of red blood cells.
    EnlargeComplete blood count (CBC); left panel shows blood being drawn from a vein on the inside of the elbow using a tube attached to a syringe; right panel shows a laboratory test tube with blood cells separated into layers: plasma, white blood cells, platelets, and red blood cells.
    Complete blood count (CBC). Blood is collected by inserting a needle into a vein and allowing the blood to flow into a tube. The blood sample is sent to the laboratory and the red blood cells, white blood cells, and platelets are counted. The CBC is used to test for, diagnose, and monitor many different conditions.
  • Sézary blood cell count: A procedure in which a sample of blood is viewed under a microscope to count the number of Sézary cells.
  • HIV test: A test to measure the level of HIV antibodies in a sample of blood. Antibodies are made by the body when it is invaded by a foreign substance. A high level of HIV antibodies may mean the body has been infected with HIV.
  • Skin biopsy: The removal of cells or tissues so they can be viewed under a microscope to check for signs of cancer. The doctor may remove a growth from the skin, which will be examined by a pathologist. More than one skin biopsy may be needed to diagnose mycosis fungoides. Other tests that may be done on the cells or tissue sample include the following:
    • Immunophenotyping: A laboratory test that uses antibodies to identify cancer cells based on the types of antigens or markers on the surface of the cells. This test is used to help diagnose specific types of lymphoma.
    • Flow cytometry: A laboratory test that measures the number of cells in a sample, the percentage of live cells in a sample, and certain characteristics of the cells, such as size, shape, and the presence of tumor (or other) markers on the cell surface. The cells from a sample of a patient’s blood, bone marrow, or other tissue are stained with a fluorescent dye, placed in a fluid, and then passed one at a time through a beam of light. The test results are based on how the cells that were stained with the fluorescent dye react to the beam of light. This test is used to help diagnose and manage certain types of cancers, such as leukemia and lymphoma.
    • T-cell receptor (TCR) gene rearrangement test: A laboratory test in which cells in a sample of blood or bone marrow are checked to see if there are certain changes in the genes that make receptors on T cells (white blood cells). Testing for these gene changes can tell whether large numbers of T cells with a certain T-cell receptor are being made.

Certain factors affect prognosis (chance of recovery) and treatment options.

The prognosis and treatment options depend on the following:

  • The stage of the cancer.
  • The type of lesion (patches, plaques, or tumors).
  • The patient’s age and sex.

Mycosis fungoides and Sézary syndrome are hard to cure. Treatment is usually palliative, to relieve symptoms and improve the quality of life. Patients with earlystage disease may live many years.

Stages of Mycosis Fungoides (Including Sézary Syndrome)

Key Points

  • After mycosis fungoides and Sézary syndrome have been diagnosed, tests are done to find out if cancer cells have spread from the skin to other parts of the body.
  • There are three ways that cancer spreads in the body.
  • Cancer may spread from where it began to other parts of the body.
  • The following stages are used for mycosis fungoides and Sézary syndrome:
    • Stage I Mycosis Fungoides
    • Stage II Mycosis Fungoides
    • Stage III Mycosis Fungoides
    • Stage IV Mycosis Fungoides/Sézary Syndrome
  • Mycosis fungoides and Sézary syndrome can recur (come back) after they have been treated.

After mycosis fungoides and Sézary syndrome have been diagnosed, tests are done to find out if cancer cells have spread from the skin to other parts of the body.

The process used to find out if cancer has spread from the skin to other parts of the body is called staging. The information gathered from the staging process determines the stage of the disease. It is important to know the stage in order to plan treatment.

The following procedures may be used in the staging process:

  • Chest x-ray: An x-ray of the organs and bones inside the chest. An x-ray is a type of energy beam that can go through the body and onto film, making a picture of areas inside the body.
  • CT scan (CAT scan): A procedure that makes a series of detailed pictures of areas inside the body, such as the lymph nodes, chest, abdomen, and pelvis, taken from different angles. The pictures are made by a computer linked to an x-ray machine. A dye may be injected into a vein or swallowed to help the organs or tissues show up more clearly. This procedure is also called computed tomography, computerized tomography, or computerized axial tomography.
  • PET scan (positron emission tomography scan): A procedure to find malignant tumor cells in the body. A small amount of radioactive glucose (sugar) is injected into a vein. The PET scanner rotates around the body and makes a picture of where glucose is being used in the body. Malignant tumor cells show up brighter in the picture because they are more active and take up more glucose than normal cells do.
  • Lymph node biopsy: The removal of all or part of a lymph node. A pathologist views the lymph node tissue under a microscope to check for cancer cells.
  • Bone marrow aspiration and biopsy: The removal of bone marrow and a small piece of bone by inserting a hollow needle into the hipbone or breastbone. A pathologist views the bone marrow and bone under a microscope to look for signs of cancer.

There are three ways that cancer spreads in the body.

Cancer can spread through tissue, the lymph system, and the blood:

  • Tissue. The cancer spreads from where it began by growing into nearby areas.
  • Lymph system. The cancer spreads from where it began by getting into the lymph system. The cancer travels through the lymph vessels to other parts of the body.
  • Blood. The cancer spreads from where it began by getting into the blood. The cancer travels through the blood vessels to other parts of the body.

Cancer may spread from where it began to other parts of the body.

When cancer spreads to another part of the body, it is called metastasis. Cancer cells break away from where they began (the primary tumor) and travel through the lymph system or blood.

  • Lymph system. The cancer gets into the lymph system, travels through the lymph vessels, and forms a tumor (metastatic tumor) in another part of the body.
  • Blood. The cancer gets into the blood, travels through the blood vessels, and forms a tumor (metastatic tumor) in another part of the body.

The metastatic tumor is the same type of cancer as the primary tumor. For example, if mycosis fungoides spreads to the liver, the cancer cells in the liver are actually mycosis fungoides cells. The disease is metastatic mycosis fungoides, not liver cancer.

Many cancer deaths are caused when cancer moves from the original tumor and spreads to other tissues and organs. This is called metastatic cancer. This animation shows how cancer cells travel from the place in the body where they first formed to other parts of the body.

The following stages are used for mycosis fungoides and Sézary syndrome:

Stage I Mycosis Fungoides

Stage I is divided into stages IA and IB as follows:

  • Stage IA: Patches, papules, and/or plaques cover less than 10% of the skin surface.
  • Stage IB: Patches, papules, and/or plaques cover 10% or more of the skin surface.

There may be a low number of Sézary cells in the blood.

Stage II Mycosis Fungoides

Stage II is divided into stages IIA and IIB as follows:

There may be a low number of Sézary cells in the blood.

Stage III Mycosis Fungoides

In stage III, 80% or more of the skin surface is reddened and may have patches, papules, plaques, or tumors. Lymph nodes may be abnormal, but they are not cancerous.

There may be a low number of Sézary cells in the blood.

Stage IV Mycosis Fungoides/Sézary Syndrome

When there is a high number of Sézary cells in the blood, the disease is called Sézary syndrome.

Stage IV is divided into stages IVA1, IVA2, and IVB as follows:

  • Stage IVA1: Patches, papules, plaques, or tumors may cover any amount of the skin surface, and 80% or more of the skin surface may be reddened. The lymph nodes may be abnormal, but they are not cancerous. There is a high number of Sézary cells in the blood.
  • Stage IVA2: Patches, papules, plaques, or tumors may cover any amount of the skin surface, and 80% or more of the skin surface may be reddened. The lymph nodes are very abnormal, or cancer has formed in the lymph nodes. There may be a high number of Sézary cells in the blood.
  • Stage IVB: Cancer has spread to other organs in the body, such as the spleen or liver. Patches, papules, plaques, or tumors may cover any amount of the skin surface, and 80% or more of the skin surface may be reddened. The lymph nodes may be abnormal or cancerous. There may be a high number of Sézary cells in the blood.

Mycosis fungoides and Sézary syndrome can recur (come back) after they have been treated.

Mycosis fungoides and Sézary syndrome may come back in the skin or in other parts of the body, such as the spleen or liver.

Treatment Option Overview

Key Points

  • There are different types of treatment for patients with mycosis fungoides and cancer.
  • Seven types of standard treatment are used:
    • Photodynamic therapy
    • Radiation therapy
    • Chemotherapy
    • Other drug therapy
    • Immunotherapy
    • Targeted therapy
    • High-dose chemotherapy and radiation therapy with stem cell transplant
  • New types of treatment are being tested in clinical trials.
    • Immune checkpoint inhibitor therapy
  • Treatment for mycosis fungoides and Sézary syndrome may cause side effects.
  • Patients may want to think about taking part in a clinical trial.
  • Patients can enter clinical trials before, during, or after starting their cancer treatment.
  • Follow-up tests may be needed.

There are different types of treatment for patients with mycosis fungoides and cancer.

Different types of treatment are available for patients with mycosis fungoides and . Some treatments are standard (the currently used treatment), and some are being tested in clinical trials. A treatment clinical trial is a research study meant to help improve current treatments or obtain information on new treatments for patients with cancer. When clinical trials show that a new treatment is better than the standard treatment, the new treatment may become the standard treatment. Patients may want to think about taking part in a clinical trial. Some clinical trials are open only to patients who have not started treatment.

Seven types of standard treatment are used:

Photodynamic therapy

Photodynamic therapy is a cancer treatment that uses a drug and a certain type of laser light to kill cancer cells. A drug that is not active until it is exposed to light is injected into a vein. The drug collects more in cancer cells than in normal cells. For skin cancer, laser light is shined onto the skin and the drug becomes active and kills the cancer cells. Photodynamic therapy causes little damage to healthy tissue. Patients undergoing photodynamic therapy will need to limit the amount of time spent in sunlight. There are different types of photodynamic therapy:

Radiation therapy

Radiation therapy is a cancer treatment that uses high-energy x-rays or other types of radiation to kill cancer cells or keep them from growing. External radiation therapy uses a machine outside the body to send radiation toward the area of the body with cancer. Sometimes, total skin electron beam (TSEB) radiation therapy is used to treat mycosis fungoides and Sézary syndrome. This is a type of external radiation treatment in which a radiation therapy machine aims electrons (tiny, invisible particles) at the skin covering the whole body . External radiation therapy may also be used as palliative therapy to relieve symptoms and improve quality of life.

Ultraviolet A (UVA) radiation therapy or ultraviolet B (UVB) radiation therapy may be given using a special lamp or laser that directs radiation at the skin.

Chemotherapy

Chemotherapy is a cancer treatment that uses drugs to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. When chemotherapy is taken by mouth or injected into a vein or muscle, the drugs enter the bloodstream and can reach cancer cells throughout the body (systemic chemotherapy). Sometimes the chemotherapy is topical (put on the skin in a cream, lotion, or ointment).

See Drugs Approved for Non-Hodgkin Lymphoma for more information. (Mycosis fungoides and Sézary syndrome are types of non-Hodgkin lymphoma.)

Other drug therapy

Topical corticosteroids are used to relieve red, swollen, and inflamed skin. They are a type of steroid. Topical corticosteroids may be in a cream, lotion, or ointment.

Retinoids, such as bexarotene, are drugs related to vitamin A that can slow the growth of certain types of cancer cells. The retinoids may be taken by mouth or put on the skin.

Lenalidomide is a drug that helps the immune system kill abnormal blood cells or cancer cells and may prevent the growth of new blood vessels that tumors need to grow.

Vorinostat and romidepsin are two of the histone deacetylase (HDAC) inhibitors used to treat mycosis fungoides and Sézary syndrome. HDAC inhibitors cause a chemical change that stops tumor cells from dividing.

See Drugs Approved for Non-Hodgkin Lymphoma for more information. (Mycosis fungoides and Sézary syndrome are types of non-Hodgkin lymphoma.)

Immunotherapy

Immunotherapy is a treatment that uses the patient’s immune system to fight cancer. Substances made by the body or made in a laboratory are used to boost, direct, or restore the body’s natural defenses against cancer. This cancer treatment is a type of biologic therapy.

  • Interferon: This treatment interferes with the division of mycosis fungoides and Sézary cells and can slow tumor growth.

See Drugs Approved for Non-Hodgkin Lymphoma for more information. (Mycosis fungoides and Sézary syndrome are types of non-Hodgkin lymphoma.)

Targeted therapy

Targeted therapy is a type of treatment that uses drugs or other substances to identify and attack specific cancer cells. Targeted therapies usually cause less harm to normal cells than chemotherapy or radiation therapy do.

  • Monoclonal antibodies: Monoclonal antibodies are immune system proteins made in the laboratory to treat many diseases, including cancer. As a cancer treatment, these antibodies can attach to a specific target on cancer cells or other cells that may help cancer cells grow. The antibodies are able to then kill the cancer cells, block their growth, or keep them from spreading. Monoclonal antibodies are given by infusion. They may be used alone or to carry drugs, toxins, or radioactive material directly to cancer cells.

    Types of monoclonal antibodies include:

    • Brentuximab vedotin, which contains a monoclonal antibody that binds to a protein, called CD30, found on some types of lymphoma cells. It also contains an anticancer drug that may help kill cancer cells.
    • Mogamulizumab, which contains a monoclonal antibody that binds to a protein, called CCR4, found on some types of lymphoma cells. It may block this protein and help the immune system kill cancer cells. It is used to treat mycosis fungoides and Sézary syndrome that came back or did not get better after treatment with at least one systemic therapy.
    How do monoclonal antibodies work to treat cancer? This video shows how monoclonal antibodies, such as trastuzumab, pembrolizumab, and rituximab, block molecules cancer cells need to grow, flag cancer cells for destruction by the body’s immune system, or deliver harmful substances to cancer cells.

High-dose chemotherapy and radiation therapy with stem cell transplant

High doses of chemotherapy and sometimes radiation therapy are given to kill cancer cells. Healthy cells, including blood-forming cells, are also destroyed by the cancer treatment. Stem cell transplant is a treatment to replace the blood-forming cells. Stem cells (immature blood cells) are removed from the blood or bone marrow of the patient or a donor and are frozen and stored. After the patient completes chemotherapy and radiation therapy, the stored stem cells are thawed and given back to the patient through an infusion. These reinfused stem cells grow into (and restore) the body’s blood cells.

New types of treatment are being tested in clinical trials.

This summary section describes treatments that are being studied in clinical trials. It may not mention every new treatment being studied. Information about clinical trials is available from the NCI website.

Immune checkpoint inhibitor therapy

  • Immune checkpoint inhibitor therapy: Immune checkpoint inhibitors block proteins called checkpoints that are made by some types of immune system cells, such as T cells, and some cancer cells. These checkpoints help keep immune responses from being too strong and sometimes can keep T cells from killing cancer cells. When these checkpoints are blocked, T cells can kill cancer cells better.
  • PD-1 and PD-L1 inhibitor therapy: PD-1 is a protein on the surface of T cells that helps keep the body’s immune responses in check. PD-L1 is a protein found on some types of cancer cells. When PD-1 attaches to PD-L1, it stops the T cell from killing the cancer cell. PD-1 and PD-L1 inhibitors keep PD-1 and PD-L1 proteins from attaching to each other. This allows the T cells to kill cancer cells. Pembrolizumab is a type of PD-1 inhibitor.
EnlargeImmune checkpoint inhibitor; the panel on the left shows the binding of proteins PD-L1 (on the tumor cell) to PD-1 (on the T cell), which keeps T cells from killing tumor cells in the body. Also shown are a tumor cell antigen and T cell receptor. The panel on the right shows immune checkpoint inhibitors (anti-PD-L1 and anti-PD-1) blocking the binding of PD-L1 to PD-1, which allows the T cells to kill tumor cells.
Immune checkpoint inhibitor. Checkpoint proteins, such as PD-L1 on tumor cells and PD-1 on T cells, help keep immune responses in check. The binding of PD-L1 to PD-1 keeps T cells from killing tumor cells in the body (left panel). Blocking the binding of PD-L1 to PD-1 with an immune checkpoint inhibitor (anti-PD-L1 or anti-PD-1) allows the T cells to kill tumor cells (right panel).
Immunotherapy uses the body’s immune system to fight cancer. This animation explains one type of immunotherapy that uses immune checkpoint inhibitors to treat cancer.

Information about clinical trials is available from the NCI website.

Treatment for mycosis fungoides and Sézary syndrome may cause side effects.

For information about side effects caused by treatment for cancer, visit our Side Effects page.

Patients may want to think about taking part in a clinical trial.

For some patients, taking part in a clinical trial may be the best treatment choice. Clinical trials are part of the cancer research process. Clinical trials are done to find out if new cancer treatments are safe and effective or better than the standard treatment.

Many of today’s standard treatments for cancer are based on earlier clinical trials. Patients who take part in a clinical trial may receive the standard treatment or be among the first to receive a new treatment.

Patients who take part in clinical trials also help improve the way cancer will be treated in the future. Even when clinical trials do not lead to effective new treatments, they often answer important questions and help move research forward.

Patients can enter clinical trials before, during, or after starting their cancer treatment.

Some clinical trials only include patients who have not yet received treatment. Other trials test treatments for patients whose cancer has not gotten better. There are also clinical trials that test new ways to stop cancer from recurring (coming back) or reduce the side effects of cancer treatment.

Clinical trials are taking place in many parts of the country. Information about clinical trials supported by NCI can be found on NCI’s clinical trials search webpage. Clinical trials supported by other organizations can be found on the ClinicalTrials.gov website.

Follow-up tests may be needed.

As you go through treatment, you will have follow-up tests or check-ups. Some tests that were done to diagnose or stage the cancer may be repeated to see how well the treatment is working. Decisions about whether to continue, change, or stop treatment may be based on the results of these tests.

Some of the tests will continue to be done from time to time after treatment has ended. The results of these tests can show if your condition has changed or if the cancer has recurred (come back).

Treatment of Stage I and Stage II Mycosis Fungoides

For information about the treatments listed below, see the Treatment Option Overview section.

Treatment of newly diagnosed stage I and stage II mycosis fungoides may include the following:

Use our clinical trial search to find NCI-supported cancer clinical trials that are accepting patients. You can search for trials based on the type of cancer, the age of the patient, and where the trials are being done. General information about clinical trials is also available.

Treatment of Stage III and Stage IV Mycosis Fungoides (Including Sézary Syndrome)

For information about the treatments listed below, see the Treatment Option Overview section.

Treatment of newly diagnosed stage III and stage IV mycosis fungoides including Sézary syndrome is palliative (to relieve symptoms and improve the quality of life) and may include the following:

Use our clinical trial search to find NCI-supported cancer clinical trials that are accepting patients. You can search for trials based on the type of cancer, the age of the patient, and where the trials are being done. General information about clinical trials is also available.

Treatment Recurrent Mycosis Fungoides (Including and Sézary Syndrome)

For information about the treatments listed below, see the Treatment Option Overview section.

Treatment of recurrent mycosis fungoides including Sézary syndrome may be within a clinical trial and may include the following:

Use our clinical trial search to find NCI-supported cancer clinical trials that are accepting patients. You can search for trials based on the type of cancer, the age of the patient, and where the trials are being done. General information about clinical trials is also available.

To Learn More About Mycosis Fungoides Sézary Syndrome

For more information from the National Cancer Institute about mycosis fungoides and Sézary syndrome, see the following:

For general cancer information and other resources from the National Cancer Institute, visit:

About This PDQ Summary

About PDQ

Physician Data Query (PDQ) is the National Cancer Institute’s (NCI’s) comprehensive cancer information database. The PDQ database contains summaries of the latest published information on cancer prevention, detection, genetics, treatment, supportive care, and complementary and alternative medicine. Most summaries come in two versions. The health professional versions have detailed information written in technical language. The patient versions are written in easy-to-understand, nontechnical language. Both versions have cancer information that is accurate and up to date and most versions are also available in Spanish.

PDQ is a service of the NCI. The NCI is part of the National Institutes of Health (NIH). NIH is the federal government’s center of biomedical research. The PDQ summaries are based on an independent review of the medical literature. They are not policy statements of the NCI or the NIH.

Purpose of This Summary

This PDQ cancer information summary has current information about the treatment of mycosis fungoides (including Sézary Syndrome). It is meant to inform and help patients, families, and caregivers. It does not give formal guidelines or recommendations for making decisions about health care.

Reviewers and Updates

Editorial Boards write the PDQ cancer information summaries and keep them up to date. These Boards are made up of experts in cancer treatment and other specialties related to cancer. The summaries are reviewed regularly and changes are made when there is new information. The date on each summary (“Updated”) is the date of the most recent change.

The information in this patient summary was taken from the health professional version, which is reviewed regularly and updated as needed, by the PDQ Adult Treatment Editorial Board.

Clinical Trial Information

A clinical trial is a study to answer a scientific question, such as whether one treatment is better than another. Trials are based on past studies and what has been learned in the laboratory. Each trial answers certain scientific questions in order to find new and better ways to help cancer patients. During treatment clinical trials, information is collected about the effects of a new treatment and how well it works. If a clinical trial shows that a new treatment is better than one currently being used, the new treatment may become “standard.” Patients may want to think about taking part in a clinical trial. Some clinical trials are open only to patients who have not started treatment.

Clinical trials can be found online at NCI’s website. For more information, call the Cancer Information Service (CIS), NCI’s contact center, at 1-800-4-CANCER (1-800-422-6237).

Permission to Use This Summary

PDQ is a registered trademark. The content of PDQ documents can be used freely as text. It cannot be identified as an NCI PDQ cancer information summary unless the whole summary is shown and it is updated regularly. However, a user would be allowed to write a sentence such as “NCI’s PDQ cancer information summary about breast cancer prevention states the risks in the following way: [include excerpt from the summary].”

The best way to cite this PDQ summary is:

PDQ® Adult Treatment Editorial Board. PDQ Mycosis Fungoides (Including Sézary Syndrome) Treatment. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: /types/lymphoma/patient/mycosis-fungoides-treatment-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389317]

Images in this summary are used with permission of the author(s), artist, and/or publisher for use in the PDQ summaries only. If you want to use an image from a PDQ summary and you are not using the whole summary, you must get permission from the owner. It cannot be given by the National Cancer Institute. Information about using the images in this summary, along with many other images related to cancer can be found in Visuals Online. Visuals Online is a collection of more than 3,000 scientific images.

Disclaimer

The information in these summaries should not be used to make decisions about insurance reimbursement. More information on insurance coverage is available on Cancer.gov on the Managing Cancer Care page.

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More information about contacting us or receiving help with the Cancer.gov website can be found on our Contact Us for Help page. Questions can also be submitted to Cancer.gov through the website’s E-mail Us.

Primary CNS Lymphoma Treatment (PDQ®)–Patient Version

Primary CNS Lymphoma Treatment (PDQ®)–Patient Version

General Information About Primary CNS Lymphoma

Go to Health Professional Version

Key Points

  • Primary central nervous system (CNS) lymphoma is a disease in which malignant (cancer) cells form in the lymph tissue of the brain and/or spinal cord.
  • Having a weakened immune system may increase the risk of developing primary CNS lymphoma.
  • Signs and symptoms of primary CNS lymphoma may include nausea and vomiting or seizures.
  • Tests that examine the eyes, brain, and spinal cord are used to diagnose primary CNS lymphoma.
  • Certain factors affect prognosis (chance of recovery) and treatment options.

Primary central nervous system (CNS) lymphoma is a disease in which malignant (cancer) cells form in the lymph tissue of the brain and/or spinal cord.

Lymphoma is a disease in which malignant (cancer) cells form in the lymph system. The lymph system is part of the immune system and is made up of the lymph, lymph vessels, lymph nodes, spleen, thymus, tonsils, and bone marrow. Lymphocytes (carried in the lymph) travel in and out of the central nervous system (CNS). It is thought that some of these lymphocytes become malignant and cause lymphoma to form in the CNS. Primary CNS lymphoma can start in the brain, spinal cord, or meninges (the layers that form the outer covering of the brain). Because the eye is so close to the brain, primary CNS lymphoma can also start in the eye (called ocular lymphoma).

EnlargeLymphatic system; drawing shows the lymph vessels and lymph organs, including the lymph nodes, tonsils, thymus, spleen, and bone marrow. Also shown is the small intestine (one site of mucosal-associated lymphoid tissue). There are also two pullouts: one showing a close up of the inside structure of a lymph node and the attached artery, vein, and lymph vessels with arrows showing how the lymph (clear, watery fluid) moves into and out of the lymph node, and another showing a close up of bone marrow with blood cells.
The lymph system is part of the body’s immune system and is made up of tissues and organs that help protect the body from infection and disease. These include the tonsils, adenoids (not shown), thymus, spleen, bone marrow, lymph vessels, and lymph nodes. Lymph tissue is also found in many other parts of the body, including the small intestine.

Having a weakened immune system may increase the risk of developing primary CNS lymphoma.

Anything that increases a person’s chance of getting a disease is called a risk factor. Not every person with one or more of these risk factors will develop primary CNS lymphoma, and it will develop in people who don’t have any known risk factors. Talk with your doctor if you think you may be at risk.

Primary CNS lymphoma may occur in patients who have HIV, AIDS, Epstein-Barr virus, or other disorders of the immune system, or who have had an organ transplant. For more information about lymphoma in patients with AIDS, see AIDS-Related Lymphoma Treatment.

Signs and symptoms of primary CNS lymphoma may include nausea and vomiting or seizures.

These and other signs and symptoms may be caused by primary CNS lymphoma or by other conditions. Check with your doctor if you have any of the following:

Tests that examine the eyes, brain, and spinal cord are used to diagnose primary CNS lymphoma.

In addition to asking about your personal and family health history and doing a physical exam, your doctor may perform the following tests and procedures:

  • Neurological exam: A series of questions and tests to check the brain, spinal cord, and nerve function. The exam checks a person’s mental status, coordination, ability to walk normally, and how well the muscles, senses, and reflexes work. This may also be called a neuro exam or a neurologic exam.
  • Eye exam with dilated pupil: An exam of the eye in which the pupil is dilated (enlarged) with medicated eye drops to allow the doctor to look through the lens and pupil to the retina. The inside of the eye, including the retina and the optic nerve, is checked. Pictures may be taken over time to keep track of changes in the size of the tumor. There are several types of eye exams:
    • Ophthalmoscopy: An exam of the inside of the back of the eye to check the retina and optic nerve using a small magnifying lens and a light.
    • Slit-lamp biomicroscopy: An exam of the inside of the eye to check the retina, optic nerve, and other parts of the eye using a strong beam of light and a microscope.
  • MRI (magnetic resonance imaging): A procedure that uses a magnet, radio waves, and a computer to make a series of detailed pictures of areas inside the brain and spinal cord. A substance called gadolinium is injected into the patient through a vein. The gadolinium collects around the cancer cells so they show up brighter in the picture. This procedure is also called nuclear magnetic resonance imaging (NMRI).
  • Lumbar puncture: A procedure used to collect cerebrospinal fluid (CSF) from the spinal column. This is done by placing a needle between two bones in the spine and into the CSF around the spinal cord and removing a sample of the fluid. The sample of CSF is checked under a microscope for signs of tumor cells. The sample may also be checked for the amounts of protein and glucose. A higher than normal amount of protein or lower than normal amount of glucose may be a sign of a tumor. This procedure is also called an LP or spinal tap.
    EnlargeLumbar puncture; drawing shows a patient lying in a curled position on a table and a spinal needle (a long, thin needle) being inserted into the lower back. Inset shows a close-up of the spinal needle inserted into the cerebrospinal fluid (CSF) in the lower part of the spinal column.
    Lumbar puncture. A patient lies in a curled position on a table. After a small area on the lower back is numbed, a spinal needle (a long, thin needle) is inserted into the lower part of the spinal column to remove cerebrospinal fluid (CSF, shown in blue). The fluid may be sent to a laboratory for testing.
  • Stereotactic biopsy: A biopsy procedure that uses a computer and a 3-dimensional (3-D) scanning device to find a tumor site and guide the removal of tissue so it can be viewed under a microscope to check for signs of cancer.

    The following tests may be done on the samples of tissue that are removed:

    • Flow cytometry: A laboratory test that measures the number of cells in a sample, the percentage of live cells in a sample, and certain characteristics of the cells, such as size, shape, and the presence of tumor (or other) markers on the cell surface. The cells from a sample of a patient’s blood, bone marrow, or other tissue are stained with a fluorescent dye, placed in a fluid, and then passed one at a time through a beam of light. The test results are based on how the cells that were stained with the fluorescent dye react to the beam of light. This test is used to help diagnose and manage certain types of cancers, such as leukemia and lymphoma.
    • Immunohistochemistry: A laboratory test that uses antibodies to check for certain antigens (markers) in a sample of a patient’s tissue. The antibodies are usually linked to an enzyme or a fluorescent dye. After the antibodies bind to a specific antigen in the tissue sample, the enzyme or dye is activated, and the antigen can then be seen under a microscope. This type of test is used to help diagnose cancer and to help tell one type of cancer from another type of cancer.
    • Cytogenetic analysis: A laboratory test in which the chromosomes of cells in a sample of blood or bone marrow are counted and checked for any changes, such as broken, missing, rearranged, or extra chromosomes. Changes in certain chromosomes may be a sign of cancer. Cytogenetic analysis is used to help diagnose cancer, plan treatment, or find out how well treatment is working.
    • FISH (fluorescence in situ hybridization): A laboratory test used to look at and count genes or chromosomes in cells and tissues. Pieces of DNA that contain fluorescent dyes are made in the laboratory and added to a sample of a patient’s cells or tissues. When these dyed pieces of DNA attach to certain genes or areas of chromosomes in the sample, they light up when viewed under a fluorescent microscope. The FISH test is used to help diagnose cancer and help plan treatment.
  • Complete blood count (CBC) with differential: A procedure in which a sample of blood is drawn and checked for the following:
    EnlargeComplete blood count (CBC); left panel shows blood being drawn from a vein on the inside of the elbow using a tube attached to a syringe; right panel shows a laboratory test tube with blood cells separated into layers: plasma, white blood cells, platelets, and red blood cells.
    Complete blood count (CBC). Blood is collected by inserting a needle into a vein and allowing the blood to flow into a tube. The blood sample is sent to the laboratory and the red blood cells, white blood cells, and platelets are counted. The CBC is used to test for, diagnose, and monitor many different conditions.
  • Blood chemistry studies: A procedure in which a blood sample is checked to measure the amounts of certain substances released into the blood by organs and tissues in the body. An unusual (higher or lower than normal) amount of a substance can be a sign of disease.
  • HIV test: A test to measure the level of HIV antibodies in a sample of blood. Antibodies are made by the body when it is invaded by a foreign substance. A high level of HIV antibodies may mean the body has been infected with HIV.

Certain factors affect prognosis (chance of recovery) and treatment options.

The prognosis depends on the following:

  • Whether the patient has HIV.
  • The patient’s age and general health.
  • Whether the tumor is in the central nervous system, eye, or both.
  • The level of certain substances in the blood and cerebrospinal fluid (CSF).

Treatment options depend on the following:

  • Whether the tumor is in the central nervous system, eye, or both.
  • The patient’s age and general health.
  • Whether the cancer has just been diagnosed or has recurred (come back).

Treatment of primary CNS lymphoma works best when the tumor has not spread outside the cerebrum (the largest part of the brain) and the patient is younger than 60 years, able to carry out most daily activities, and does not have AIDS or other diseases that weaken the immune system.

Staging Primary CNS Lymphoma

Key Points

  • After primary central nervous system (CNS) lymphoma has been diagnosed, tests are done to find out if cancer cells have spread within the brain and spinal cord or to the eye.
  • There is no standard staging system for primary CNS lymphoma.
  • Primary CNS lymphoma often recurs (comes back) after it has been treated.

After primary central nervous system (CNS) lymphoma has been diagnosed, tests are done to find out if cancer cells have spread within the brain and spinal cord or to the eye.

Primary CNS lymphoma usually does not spread beyond the central nervous system or the eye. The process used to find out if cancer has spread is called staging. There is no standard system for staging primary CNS lymphoma.

The following tests and procedures may be used to help plan treatment:

  • CT scan (CAT scan): A procedure that makes a series of detailed pictures of areas inside the body, taken from different angles. The pictures are made by a computer linked to an x-ray machine. A dye may be injected into a vein or swallowed to help the organs or tissues show up more clearly. This procedure is also called computed tomography, computerized tomography, or computerized axial tomography.
  • PET scan (positron emission tomography scan): A procedure to find malignant tumor cells in the body. A small amount of radioactive glucose (sugar) is injected into a vein. The PET scanner rotates around the body and makes a picture of where glucose is being used in the body. Malignant tumor cells show up brighter in the picture because they are more active and take up more glucose than normal cells do. A PET scan and CT scan may be done at the same time. This is called a PET-CT.
  • MRI (magnetic resonance imaging): A procedure that uses a magnet, radio waves, and a computer to make a series of detailed pictures of areas inside the body. This procedure is also called nuclear magnetic resonance imaging (NMRI).
  • Bone marrow aspiration and biopsy: The removal of bone marrow, blood, and a small piece of bone by inserting a hollow needle into the hipbone or breastbone. A pathologist views the bone marrow, blood, and bone under a microscope to look for signs of cancer.
    EnlargeBone marrow aspiration and biopsy; drawing shows a patient lying face down on a table and a bone marrow needle being inserted into the hip bone. An inset shows a close up of the needle being inserted through the skin and hip bone into the bone marrow.
    Bone marrow aspiration and biopsy. After a small area of skin is numbed, a long, hollow needle is inserted through the patient’s skin and hip bone into the bone marrow. A sample of bone marrow and a small piece of bone are removed for examination under a microscope.

There is no standard staging system for primary CNS lymphoma.

Primary CNS lymphoma often recurs (comes back) after it has been treated.

Primary CNS lymphoma often recurs in the brain, spinal cord, or the eye.

Treatment Option Overview

Key Points

  • There are different types of treatment for patients with primary central nervous system (CNS) lymphoma.
  • The following types of treatments are used:
    • Radiation therapy
    • Chemotherapy
    • Steroid therapy
    • Targeted therapy
    • High-dose chemotherapy with stem cell transplant
    • Immunotherapy
  • New types of treatment are being tested in clinical trials.
  • Treatment for primary CNS lymphoma may cause side effects.
  • Patients may want to think about taking part in a clinical trial.
  • Patients can enter clinical trials before, during, or after starting their cancer treatment.
  • Follow-up tests may be needed.

There are different types of treatment for patients with primary central nervous system (CNS) lymphoma.

Different types of treatment are available for patients with primary CNS lymphoma. Some treatments are standard (the currently used treatment), and some are being tested in clinical trials. A treatment clinical trial is a research study meant to help improve current treatments or obtain information on new treatments for patients with cancer. When clinical trials show that a new treatment is better than the standard treatment, the new treatment may become the standard treatment. Patients may want to think about taking part in a clinical trial. Some clinical trials are open only to patients who have not started treatment.

Surgery is not used to treat primary CNS lymphoma.

The following types of treatments are used:

Radiation therapy

Radiation therapy is a cancer treatment that uses high-energy x-rays or other types of radiation to kill cancer cells or keep them from growing. External radiation therapy uses a machine outside the body to send radiation toward the area of the body with cancer. Because primary CNS lymphoma spreads throughout the brain, external radiation therapy is given to the whole brain. This is called whole-brain radiation therapy.

High-dose radiation therapy to the brain can damage healthy tissue and cause disorders that can affect thinking, learning, problem solving, reading, writing, speech, and memory. Clinical trials have tested the use of chemotherapy alone or before radiation therapy to reduce the damage to healthy brain tissue that occurs with the use of radiation therapy.

Chemotherapy

Chemotherapy is a cancer treatment that uses drugs to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. When chemotherapy is taken by mouth or injected into a vein or muscle, the drugs enter the bloodstream and can reach cancer cells throughout the body (systemic chemotherapy). When chemotherapy is placed directly into the cerebrospinal fluid (intrathecal chemotherapy), an organ, or a body cavity such as the abdomen, the drugs mainly affect cancer cells in those areas (regional chemotherapy).

The way the chemotherapy is given depends on where the tumor is in the CNS or eye. Primary CNS lymphoma may be treated with systemic chemotherapy, intrathecal chemotherapy, and/or intraventricular chemotherapy, in which anticancer drugs are placed into the ventricles (fluid-filled cavities) of the brain. If primary CNS lymphoma is found in the eye, anticancer drugs are injected directly into the vitreous humor (jelly-like substance) inside the eye.

EnlargeIntrathecal chemotherapy; drawing shows the cerebrospinal fluid (CSF) in the brain and spinal cord, and an Ommaya reservoir (a dome-shaped container that is placed under the scalp during surgery; it holds the drugs as they flow through a small tube into the brain). Top section shows a syringe and needle injecting anticancer drugs into the Ommaya reservoir. Bottom section shows a syringe and needle injecting anticancer drugs directly into the cerebrospinal fluid in the lower part of the spinal column.
Intrathecal chemotherapy. Anticancer drugs are injected into the intrathecal space, which is the space that holds the cerebrospinal fluid (CSF, shown in blue). There are two different ways to do this. One way, shown in the top part of the figure, is to inject the drugs into an Ommaya reservoir (a dome-shaped container that is placed under the scalp during surgery; it holds the drugs as they flow through a small tube into the brain). The other way, shown in the bottom part of the figure, is to inject the drugs directly into the CSF in the lower part of the spinal column, after a small area on the lower back is numbed.

Steroid therapy

Steroids are hormones made naturally in the body. They can also be made in a laboratory and used as drugs. Glucocorticoids are steroid drugs that have an anticancer effect in lymphomas.

Targeted therapy

Targeted therapy is a type of treatment that uses drugs or other substances to identify and attack specific cancer cells.

  • Monoclonal antibodies: Monoclonal antibodies are immune system proteins made in the laboratory to treat many diseases, including cancer. As a cancer treatment, these antibodies can attach to a specific target on cancer cells or other cells that may help cancer cells grow. The antibodies are able to then kill the cancer cells, block their growth, or keep them from spreading. Monoclonal antibodies are given by infusion. They may be used alone or to carry drugs, toxins, or radioactive material directly to cancer cells. Rituximab and nivolumab are types of monoclonal antibodies used to treat newly diagnosed or recurrent primary CNS lymphoma.
    How do monoclonal antibodies work to treat cancer? This video shows how monoclonal antibodies, such as trastuzumab, pembrolizumab, and rituximab, block molecules cancer cells need to grow, flag cancer cells for destruction by the body’s immune system, or deliver harmful substances to cancer cells.
  • Tyrosine kinase inhibitors: These small-molecule drugs go through the cell membrane and work inside cancer cells to block signals that cancer cells need to grow and divide. Ibrutinib is a type of tyrosine kinase inhibitor used to treat newly diagnosed or recurrent primary CNS lymphoma.

High-dose chemotherapy with stem cell transplant

High doses of chemotherapy are given to kill cancer cells. Healthy cells, including blood-forming cells, are also destroyed by the cancer treatment. Stem cell transplant is a treatment to replace the blood-forming cells. Stem cells (immature blood cells) are removed from the blood or bone marrow of the patient or a donor and are frozen and stored. After the patient completes chemotherapy, the stored stem cells are thawed and given back to the patient through an infusion. These reinfused stem cells grow into (and restore) the body’s blood cells.

Immunotherapy

Immunotherapy is a treatment that uses the patient’s immune system to fight cancer. Substances made by the body or made in a laboratory are used to boost, direct, or restore the body’s natural defenses against cancer.

  • CAR T-cell therapy: This treatment changes the patient’s T cells (a type of immune system cell) so they will attack certain proteins on the surface of cancer cells. T cells are taken from the patient, and special receptors are added to their surface in the laboratory. The changed cells are called chimeric antigen receptor (CAR) T cells. The CAR T cells are grown in the laboratory and given to the patient by infusion. The CAR T cells multiply in the patient’s blood and attack cancer cells.
    EnlargeCAR T-cell therapy; drawing of blood being removed from a vein in a patient’s arm to get T cells. Also shown is a special receptor called a chimeric antigen receptor (CAR) being made in the laboratory; the gene for CAR is inserted into the T cells and then millions of CAR T cells are grown. Drawing also shows the CAR T cells being given to the patient by infusion and binding to antigens on the cancer cells and killing them.
    CAR T-cell therapy. A type of treatment in which a patient’s T cells (a type of immune cell) are changed in the laboratory so they will bind to cancer cells and kill them. Blood from a vein in the patient’s arm flows through a tube to an apheresis machine (not shown), which removes the white blood cells, including the T cells, and sends the rest of the blood back to the patient. Then, the gene for a special receptor called a chimeric antigen receptor (CAR) is inserted into the T cells in the laboratory. Millions of the CAR T cells are grown in the laboratory and then given to the patient by infusion. The CAR T cells are able to bind to an antigen on the cancer cells and kill them.

New types of treatment are being tested in clinical trials.

Information about clinical trials is available from the NCI website.

Treatment for primary CNS lymphoma may cause side effects.

For information about side effects caused by treatment for cancer, visit our Side Effects page.

Patients may want to think about taking part in a clinical trial.

For some patients, taking part in a clinical trial may be the best treatment choice. Clinical trials are part of the cancer research process. Clinical trials are done to find out if new cancer treatments are safe and effective or better than the standard treatment.

Many of today’s standard treatments for cancer are based on earlier clinical trials. Patients who take part in a clinical trial may receive the standard treatment or be among the first to receive a new treatment.

Patients who take part in clinical trials also help improve the way cancer will be treated in the future. Even when clinical trials do not lead to effective new treatments, they often answer important questions and help move research forward.

Patients can enter clinical trials before, during, or after starting their cancer treatment.

Some clinical trials only include patients who have not yet received treatment. Other trials test treatments for patients whose cancer has not gotten better. There are also clinical trials that test new ways to stop cancer from recurring (coming back) or reduce the side effects of cancer treatment.

Clinical trials are taking place in many parts of the country. Information about clinical trials supported by NCI can be found on NCI’s clinical trials search webpage. Clinical trials supported by other organizations can be found on the ClinicalTrials.gov website.

Follow-up tests may be needed.

As you go through treatment, you will have follow-up tests or check-ups. Some tests that were done to diagnose or stage the cancer may be repeated to see how well the treatment is working. Decisions about whether to continue, change, or stop treatment may be based on the results of these tests.

Some of the tests will continue to be done from time to time after treatment has ended. The results of these tests can show if your condition has changed or if the cancer has recurred (come back).

Treatment of Primary CNS Lymphoma

For information about the treatments listed below, see the Treatment Option Overview section.

Treatment of newly diagnosed primary central nervous system (CNS) lymphoma may include the following:

Use our clinical trial search to find NCI-supported cancer clinical trials that are accepting patients. You can search for trials based on the type of cancer, the age of the patient, and where the trials are being done. General information about clinical trials is also available.

Treatment of Recurrent Primary CNS Lymphoma

For information about the treatments listed below, see the Treatment Option Overview section.

Treatment of recurrent primary central nervous system (CNS) lymphoma may include the following:

Treatment of Primary Intraocular Lymphoma

For information about the treatments listed below, see the Treatment Option Overview section.

Treatment of newly diagnosed primary intraocular lymphoma may include the following:

To Learn More About Primary CNS Lymphoma

For more information from the National Cancer Institute about primary central nervous system (CNS) lymphoma, see the following:

For general cancer information and other resources from the National Cancer Institute, visit:

About This PDQ Summary

About PDQ

Physician Data Query (PDQ) is the National Cancer Institute’s (NCI’s) comprehensive cancer information database. The PDQ database contains summaries of the latest published information on cancer prevention, detection, genetics, treatment, supportive care, and complementary and alternative medicine. Most summaries come in two versions. The health professional versions have detailed information written in technical language. The patient versions are written in easy-to-understand, nontechnical language. Both versions have cancer information that is accurate and up to date and most versions are also available in Spanish.

PDQ is a service of the NCI. The NCI is part of the National Institutes of Health (NIH). NIH is the federal government’s center of biomedical research. The PDQ summaries are based on an independent review of the medical literature. They are not policy statements of the NCI or the NIH.

Purpose of This Summary

This PDQ cancer information summary has current information about the treatment of primary CNS lymphoma. It is meant to inform and help patients, families, and caregivers. It does not give formal guidelines or recommendations for making decisions about health care.

Reviewers and Updates

Editorial Boards write the PDQ cancer information summaries and keep them up to date. These Boards are made up of experts in cancer treatment and other specialties related to cancer. The summaries are reviewed regularly and changes are made when there is new information. The date on each summary (“Updated”) is the date of the most recent change.

The information in this patient summary was taken from the health professional version, which is reviewed regularly and updated as needed, by the PDQ Adult Treatment Editorial Board.

Clinical Trial Information

A clinical trial is a study to answer a scientific question, such as whether one treatment is better than another. Trials are based on past studies and what has been learned in the laboratory. Each trial answers certain scientific questions in order to find new and better ways to help cancer patients. During treatment clinical trials, information is collected about the effects of a new treatment and how well it works. If a clinical trial shows that a new treatment is better than one currently being used, the new treatment may become “standard.” Patients may want to think about taking part in a clinical trial. Some clinical trials are open only to patients who have not started treatment.

Clinical trials can be found online at NCI’s website. For more information, call the Cancer Information Service (CIS), NCI’s contact center, at 1-800-4-CANCER (1-800-422-6237).

Permission to Use This Summary

PDQ is a registered trademark. The content of PDQ documents can be used freely as text. It cannot be identified as an NCI PDQ cancer information summary unless the whole summary is shown and it is updated regularly. However, a user would be allowed to write a sentence such as “NCI’s PDQ cancer information summary about breast cancer prevention states the risks in the following way: [include excerpt from the summary].”

The best way to cite this PDQ summary is:

PDQ® Adult Treatment Editorial Board. PDQ Primary CNS Lymphoma Treatment. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: /types/lymphoma/patient/primary-cns-lymphoma-treatment-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389274]

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AIDS-Related Lymphoma Treatment (PDQ®)–Patient Version

AIDS-Related Lymphoma Treatment (PDQ®)–Patient Version

General Information About AIDS-Related Lymphoma

Go to Health Professional Version

Key Points

  • AIDS-related lymphoma is a disease in which malignant (cancer) cells form in the lymph system of patients who have acquired immunodeficiency syndrome (AIDS).
  • There are many different types of lymphoma.
  • Signs of AIDS-related lymphoma include weight loss, fever, and drenching night sweats.
  • Tests that examine the lymph system and other parts of the body are used to diagnose AIDS-related lymphoma.
  • Certain factors affect prognosis (chance of recovery) and treatment options.

AIDS-related lymphoma is a disease in which malignant (cancer) cells form in the lymph system of patients who have acquired immunodeficiency syndrome (AIDS).

AIDS is caused by the human immunodeficiency virus (HIV), which attacks and weakens the body’s immune system. A weakened immune system is unable to fight infection and disease. People with HIV disease have an increased risk of infection and lymphoma or other types of cancer. A person with HIV and certain types of infection or cancer, such as lymphoma, is diagnosed as having AIDS. Sometimes, people are diagnosed with AIDS and AIDS-related lymphoma at the same time. For information about AIDS and its treatment, see the AIDSinfo website.

AIDS-related lymphoma is a type of cancer that affects the lymph system. The lymph system is part of the immune system. It helps protect the body from infection and disease.

The lymph system is made up of the following:

  • Lymph: Colorless, watery fluid that travels through the lymph vessels and carries T and B lymphocytes. Lymphocytes are a type of white blood cell.
  • Lymph vessels: A network of thin tubes that collect lymph from different parts of the body and return it to the bloodstream.
  • Lymph nodes: Small, bean-shaped structures that filter lymph and store white blood cells that help fight infection and disease. Lymph nodes are found along a network of lymph vessels throughout the body. Groups of lymph nodes are found in the neck, underarm, mediastinum, abdomen, pelvis, and groin.
  • Spleen: An organ that makes lymphocytes, stores red blood cells and lymphocytes, filters the blood, and destroys old blood cells. The spleen is on the left side of the abdomen near the stomach.
  • Thymus: An organ in which T lymphocytes mature and multiply. The thymus is in the chest behind the breastbone.
  • Tonsils: Two small masses of lymph tissue at the back of the throat. There is one tonsil on each side of the throat.
  • Bone marrow: The soft, spongy tissue in the center of certain bones, such as the hip bone and breastbone. White blood cells, red blood cells, and platelets are made in the bone marrow.

Lymph tissue is also found in other parts of the body such as the brain, stomach, thyroid gland, and skin.

Sometimes AIDS-related lymphoma occurs outside the lymph nodes in the bone marrow, liver, meninges (thin membranes that cover the brain) and gastrointestinal tract. Less often, it may occur in the anus, heart, bile duct, gingiva, and muscles.

EnlargeLymphatic system; drawing shows the lymph vessels and lymph organs, including the lymph nodes, tonsils, thymus, spleen, and bone marrow. Also shown is the small intestine (one site of mucosal-associated lymphoid tissue). There are also two pullouts: one showing a close up of the inside structure of a lymph node and the attached artery, vein, and lymph vessels with arrows showing how the lymph (clear, watery fluid) moves into and out of the lymph node, and another showing a close up of bone marrow with blood cells.
The lymph system is part of the body’s immune system and is made up of tissues and organs that help protect the body from infection and disease. These include the tonsils, adenoids (not shown), thymus, spleen, bone marrow, lymph vessels, and lymph nodes. Lymph tissue is also found in many other parts of the body, including the small intestine.

There are many different types of lymphoma.

Lymphomas are divided into two general types:

Both non-Hodgkin lymphoma and Hodgkin lymphoma may occur in patients with AIDS, but non-Hodgkin lymphoma is more common. When a person with AIDS has non-Hodgkin lymphoma, it is called AIDS-related lymphoma. When AIDS-related lymphoma occurs in the central nervous system (CNS), it is called AIDS-related primary CNS lymphoma.

Non-Hodgkin lymphomas are grouped by the way their cells look under a microscope. They may be indolent (slow-growing) or aggressive (fast-growing). AIDS-related lymphomas are aggressive. There are two main types of AIDS-related non-Hodgkin lymphoma:

For more information about lymphoma or AIDS-related cancers, see the following:

Signs of AIDS-related lymphoma include weight loss, fever, and drenching night sweats.

These and other signs and symptoms may be caused by AIDS-related lymphoma or by other conditions. Check with your doctor if you have any of the following:

  • Weight loss or fever for no known reason.
  • Drenching night sweats.
  • Painless, swollen lymph nodes in the neck, chest, underarm, or groin.
  • A feeling of fullness below the ribs.

Tests that examine the lymph system and other parts of the body are used to diagnose AIDS-related lymphoma.

The following tests and procedures may be used:

  • Physical exam and health history: An exam of the body to check general signs of health, including checking for signs of disease, such as lumps or anything else that seems unusual. A history of the patient’s health, including fever, drenching night sweats, and weight loss, health habits, and past illnesses and treatments will also be taken.
  • Complete blood count (CBC): A procedure in which a sample of blood is drawn and checked for the following:
    • The number of red blood cells, white blood cells, and platelets.
    • The amount of hemoglobin (the protein that carries oxygen) in the red blood cells.
    • The portion of the sample made up of red blood cells.
    EnlargeComplete blood count (CBC); left panel shows blood being drawn from a vein on the inside of the elbow using a tube attached to a syringe; right panel shows a laboratory test tube with blood cells separated into layers: plasma, white blood cells, platelets, and red blood cells.
    Complete blood count (CBC). Blood is collected by inserting a needle into a vein and allowing the blood to flow into a tube. The blood sample is sent to the laboratory and the red blood cells, white blood cells, and platelets are counted. The CBC is used to test for, diagnose, and monitor many different conditions.
  • Blood chemistry studies: A procedure in which a blood sample is checked to measure the amounts of certain substances released into the blood by organs and tissues in the body. An unusual (higher or lower than normal) amount of a substance can be a sign of disease.
  • LDH test: A procedure in which a blood sample is checked to measure the amount of lactic dehydrogenase. An increased amount of LDH in the blood may be a sign of tissue damage, lymphoma, or other diseases.
  • Hepatitis B and hepatitis C test: A procedure in which a sample of blood is checked to measure the amounts of hepatitis B virus-specific antigens and/or antibodies and the amounts of hepatitis C virus-specific antibodies. These antigens or antibodies are called markers. Different markers or combinations of markers are used to determine whether a patient has a hepatitis B or C infection, has had a prior infection or vaccination, or is susceptible to infection.
  • HIV test: A test to measure the level of HIV antibodies in a sample of blood. Antibodies are made by the body when it is invaded by a foreign substance. A high level of HIV antibodies may mean the body has been infected with HIV.
  • CT scan (CAT scan): A procedure that makes a series of detailed pictures of areas inside the body, such as the neck, chest, abdomen, pelvis, and lymph nodes, taken from different angles. The pictures are made by a computer linked to an x-ray machine. A dye may be injected into a vein or swallowed to help the organs or tissues show up more clearly. This procedure is also called computed tomography, computerized tomography, or computerized axial tomography.
  • PET scan (positron emission tomography scan): A procedure to find malignant tumor cells in the body. A small amount of radioactive glucose (sugar) is injected into a vein. The PET scanner rotates around the body and makes a picture of where glucose is being used in the body. Malignant tumor cells show up brighter in the picture because they are more active and take up more glucose than normal cells do.
  • Bone marrow aspiration and biopsy: The removal of bone marrow and a small piece of bone by inserting a hollow needle into the hipbone or breastbone. A pathologist views the bone marrow and bone under a microscope to look for signs of cancer.
    EnlargeBone marrow aspiration and biopsy; drawing shows a patient lying face down on a table and a bone marrow needle being inserted into the hip bone. An inset shows a close up of the needle being inserted through the skin and hip bone into the bone marrow.
    Bone marrow aspiration and biopsy. After a small area of skin is numbed, a long, hollow needle is inserted through the patient’s skin and hip bone into the bone marrow. A sample of bone marrow and a small piece of bone are removed for examination under a microscope.
  • Lymph node biopsy: The removal of all or part of a lymph node. A pathologist views the tissue under a microscope to look for cancer cells. One of the following types of biopsies may be done:

    Other areas of the body, such as the liver, lung, bone, bone marrow, and brain, may also have a sample of tissue removed and checked by a pathologist for signs of cancer.

If cancer is found, the following tests may be done to study the cancer cells:

  • Immunohistochemistry: A laboratory test that uses antibodies to check for certain antigens (markers) in a sample of a patient’s tissue. The antibodies are usually linked to an enzyme or a fluorescent dye. After the antibodies bind to a specific antigen in the tissue sample, the enzyme or dye is activated, and the antigen can then be seen under a microscope. This type of test is used to help diagnose cancer and to help tell one type of cancer from another type of cancer.
  • Cytogenetic analysis: A laboratory test in which the chromosomes of cells in a sample of blood or bone marrow are counted and checked for any changes, such as broken, missing, rearranged, or extra chromosomes. Changes in certain chromosomes may be a sign of cancer. Cytogenetic analysis is used to help diagnose cancer, plan treatment, or find out how well treatment is working.
  • FISH (fluorescence in situ hybridization): A laboratory test used to look at and count genes or chromosomes in cells and tissues. Pieces of DNA that contain fluorescent dyes are made in the laboratory and added to a sample of a patient’s cells or tissues. When these dyed pieces of DNA attach to certain genes or areas of chromosomes in the sample, they light up when viewed under a fluorescent microscope. The FISH test is used to help diagnose cancer and help plan treatment.
  • Immunophenotyping: A laboratory test that uses antibodies to identify cancer cells based on the types of antigens or markers on the surface of the cells. This test is used to help diagnose specific types of lymphoma.

Certain factors affect prognosis (chance of recovery) and treatment options.

The prognosis and treatment options depend on the following:

  • The stage of the cancer.
  • The age of the patient.
  • The number of CD4 lymphocytes (a type of white blood cell) in the blood.
  • The number of places in the body lymphoma is found outside the lymph system.
  • Whether the patient has a history of intravenous (IV) drug use.
  • The patient’s ability to carry out regular daily activities.

Stages of AIDS-Related Lymphoma

Key Points

  • After AIDS-related lymphoma has been diagnosed, tests are done to find out if cancer cells have spread within the lymph system or to other parts of the body.
  • There are three ways that cancer spreads in the body.
  • The following stages are used for AIDS-related lymphoma:
    • Stage I
    • Stage II
    • Stage III
    • Stage IV
  • For treatment, AIDS-related lymphomas are grouped based on where they started in the body, as follows:
    • Peripheral/systemic lymphoma
    • Primary CNS lymphoma

After AIDS-related lymphoma has been diagnosed, tests are done to find out if cancer cells have spread within the lymph system or to other parts of the body.

The process used to find out if cancer cells have spread within the lymph system or to other parts of the body is called staging. The information gathered from the staging process determines the stage of the disease. It is important to know the stage in order to plan treatment, but AIDS-related lymphoma is usually advanced when it is diagnosed.

The following tests and procedures may be used to find out if the cancer has spread:

  • MRI (magnetic resonance imaging) with gadolinium: A procedure that uses a magnet, radio waves, and a computer to make a series of detailed pictures of areas inside the body, such as the brain and spinal cord. A substance called gadolinium is injected into the patient through a vein. The gadolinium collects around the cancer cells so they show up brighter in the picture. This procedure is also called nuclear magnetic resonance imaging (NMRI).
  • Lumbar puncture: A procedure used to collect cerebrospinal fluid (CSF) from the spinal column. This is done by placing a needle between two bones in the spine and into the CSF around the spinal cord and removing a sample of the fluid. The sample of CSF is checked under a microscope for signs that the cancer has spread to the brain and spinal cord. The sample may also be checked for Epstein-Barr virus. This procedure is also called an LP or spinal tap.
    EnlargeLumbar puncture; drawing shows a patient lying in a curled position on a table and a spinal needle (a long, thin needle) being inserted into the lower back. Inset shows a close-up of the spinal needle inserted into the cerebrospinal fluid (CSF) in the lower part of the spinal column.
    Lumbar puncture. A patient lies in a curled position on a table. After a small area on the lower back is numbed, a spinal needle (a long, thin needle) is inserted into the lower part of the spinal column to remove cerebrospinal fluid (CSF, shown in blue). The fluid may be sent to a laboratory for testing.

There are three ways that cancer spreads in the body.

Cancer can spread through tissue, the lymph system, and the blood:

  • Tissue. The cancer spreads from where it began by growing into nearby areas.
  • Lymph system. The cancer spreads from where it began by getting into the lymph system. The cancer travels through the lymph vessels to other parts of the body.
  • Blood. The cancer spreads from where it began by getting into the blood. The cancer travels through the blood vessels to other parts of the body.

The following stages are used for AIDS-related lymphoma:

Stage I

EnlargeStage I adult lymphoma; drawing shows cancer in one lymph node group and in the spleen. Also shown are the Waldeyer’s ring and the thymus. An inset shows a lymph node with a lymph vessel, an artery, and a vein. Cancer cells are shown in the lymph node.
Stage I adult lymphoma. Cancer is found in one or more lymph nodes in a group of lymph nodes or, in rare cases, cancer is found in the Waldeyer’s ring, thymus, or spleen. In stage IE (not shown), cancer has spread to one area outside the lymph system.

Stage I AIDS-related lymphoma is divided into stages I and IE.

Stage II

Stage II AIDS-related lymphoma is divided into stages II and IIE.

  • In stage II, cancer is found in two or more groups of lymph nodes that are either above the diaphragm or below the diaphragm.
    EnlargeStage II adult lymphoma; drawing shows cancer in two lymph node groups above the diaphragm and below the diaphragm. An inset shows a lymph node with a lymph vessel, an artery, and a vein. Cancer cells are shown in the lymph node.
    Stage II adult lymphoma. Cancer is found in two or more groups of lymph nodes that are either above the diaphragm or below the diaphragm.
  • In stage IIE, cancer has spread from a group of lymph nodes to a nearby area that is outside the lymph system. Cancer may have spread to other lymph node groups on the same side of the diaphragm.
    EnlargeStage IIE adult lymphoma; drawing shows cancer that has spread from a group of lymph nodes to a nearby area. Also shown is a lung and the diaphragm. An inset shows a lymph node with a lymph vessel, an artery, and a vein. Cancer cells are shown in the lymph node.
    Stage IIE adult lymphoma. Cancer has spread from a group of lymph nodes to a nearby area that is outside the lymph system. Cancer may have spread to other lymph node groups on the same side of the diaphragm.

In stage II, the term bulky disease refers to a larger tumor mass. The size of the tumor mass that is referred to as bulky disease varies based on the type of lymphoma.

Stage III

EnlargeStage III adult lymphoma; drawing shows the right and left sides of the body. The right side of the body shows cancer in a group of lymph nodes above the diaphragm and below the diaphragm. The left side of the body shows cancer in a group of lymph nodes above the diaphragm and cancer in the spleen.
Stage III adult lymphoma. Cancer is found in groups of lymph nodes both above and below the diaphragm; or in a group of lymph nodes above the diaphragm and in the spleen.

In stage III AIDS-related lymphoma, cancer is found:

Stage IV

EnlargeStage IV adult lymphoma; drawing shows four panels: (a) the top left panel shows cancer in the liver; (b) the top right panel shows cancer in the left lung and in two groups of lymph nodes below the diaphragm; (c) the bottom left panel shows cancer in the left lung and in a group of lymph nodes above the diaphragm and below the diaphragm; and (d) the bottom right panel shows cancer in both lungs, the liver, and the bone marrow (pullout). Also shown is primary cancer in the lymph nodes and a pullout of the brain with cerebrospinal fluid (in blue).
Stage IV adult lymphoma. Cancer (a) has spread throughout one or more organs outside the lymph system; or (b) is found in two or more groups of lymph nodes that are either above the diaphragm or below the diaphragm and in one organ that is outside the lymph system and not near the affected lymph nodes; or (c) is found in groups of lymph nodes above the diaphragm and below the diaphragm and in any organ that is outside the lymph system; or (d) is found in the liver, bone marrow, more than one place in the lung, or cerebrospinal fluid (CSF). The cancer has not spread directly into the liver, bone marrow, lung, or CSF from nearby lymph nodes.

In stage IV AIDS-related lymphoma, cancer:

  • has spread throughout one or more organs outside the lymph system; or
  • is found in two or more groups of lymph nodes that are either above the diaphragm or below the diaphragm and in one organ that is outside the lymph system and not near the affected lymph nodes; or
  • is found in groups of lymph nodes both above and below the diaphragm and in any organ that is outside the lymph system; or
  • is found in the liver, bone marrow, more than one place in the lung, or cerebrospinal fluid (CSF). The cancer has not spread directly into the liver, bone marrow, lung, or CSF from nearby lymph nodes.

Patients who are infected with the Epstein-Barr virus or whose AIDS-related lymphoma affects the bone marrow have an increased risk of the cancer spreading to the central nervous system (CNS).

For treatment, AIDS-related lymphomas are grouped based on where they started in the body, as follows:

Peripheral/systemic lymphoma

Lymphoma that starts in the lymph system or elsewhere in the body, other than the brain, is called peripheral/systemic lymphoma. It may spread throughout the body, including to the brain or bone marrow. It is often diagnosed in an advanced stage.

Primary CNS lymphoma

Primary CNS lymphoma starts in the central nervous system (brain and spinal cord). It is linked to the Epstein-Barr virus. Lymphoma that starts somewhere else in the body and spreads to the central nervous system is not primary CNS lymphoma.

Treatment Option Overview

Key Points

  • There are different types of treatment for patients with AIDS-related lymphoma.
  • Treatment of AIDS-related lymphoma combines treatment of the lymphoma with treatment for AIDS.
  • The following types of treatment are used:
    • Chemotherapy
    • Radiation therapy
    • High-dose chemotherapy with stem cell transplant
    • Targeted therapy
  • New types of treatment are being tested in clinical trials.
  • Treatment for AIDS-related lymphoma may cause side effects.
  • Patients may want to think about taking part in a clinical trial.
  • Patients can enter clinical trials before, during, or after starting their cancer treatment.
  • Follow-up tests may be needed.

There are different types of treatment for patients with AIDS-related lymphoma.

Different types of treatment are available for patients with AIDS-related lymphoma. Some treatments are standard (the currently used treatment), and some are being tested in clinical trials. A treatment clinical trial is a research study meant to help improve current treatments or obtain information on new treatments for patients with cancer. When clinical trials show that a new treatment is better than the standard treatment, the new treatment may become the standard treatment. Patients may want to think about taking part in a clinical trial. Some clinical trials are open only to patients who have not started treatment.

Treatment of AIDS-related lymphoma combines treatment of the lymphoma with treatment for AIDS.

Patients with AIDS have weakened immune systems and treatment can cause the immune system to become even weaker. For this reason, treating patients who have AIDS-related lymphoma is difficult and some patients may be treated with lower doses of drugs than lymphoma patients who do not have AIDS.

Highly active antiretroviral therapy (HAART) is used to lessen the damage to the immune system caused by HIV. Treatment with HAART may allow some patients with AIDS-related lymphoma to safely receive anticancer drugs in standard or higher doses. In these patients, treatment may work as well as it does in lymphoma patients who do not have AIDS. Medicine to prevent and treat infections, which can be serious, is also used.

For more information about AIDS and its treatment, see the AIDSinfo website.

The following types of treatment are used:

Chemotherapy

Chemotherapy is a cancer treatment that uses drugs to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. When chemotherapy is taken by mouth or injected into a vein or muscle, the drugs enter the bloodstream and can reach cancer cells throughout the body (systemic chemotherapy). When chemotherapy is placed directly into the cerebrospinal fluid (intrathecal chemotherapy), an organ, or a body cavity such as the abdomen, the drugs mainly affect cancer cells in those areas (regional chemotherapy). Combination chemotherapy is treatment using more than one anticancer drug.

Intrathecal chemotherapy may be used in patients who are more likely to have lymphoma in the central nervous system (CNS).

EnlargeIntrathecal chemotherapy; drawing shows the cerebrospinal fluid (CSF) in the brain and spinal cord, and an Ommaya reservoir (a dome-shaped container that is placed under the scalp during surgery; it holds the drugs as they flow through a small tube into the brain). Top section shows a syringe and needle injecting anticancer drugs into the Ommaya reservoir. Bottom section shows a syringe and needle injecting anticancer drugs directly into the cerebrospinal fluid in the lower part of the spinal column.
Intrathecal chemotherapy. Anticancer drugs are injected into the intrathecal space, which is the space that holds the cerebrospinal fluid (CSF, shown in blue). There are two different ways to do this. One way, shown in the top part of the figure, is to inject the drugs into an Ommaya reservoir (a dome-shaped container that is placed under the scalp during surgery; it holds the drugs as they flow through a small tube into the brain). The other way, shown in the bottom part of the figure, is to inject the drugs directly into the CSF in the lower part of the spinal column, after a small area on the lower back is numbed.

Chemotherapy is used in the treatment of AIDS-related peripheral/systemic lymphoma. It is not yet known whether it is best to give HAART at the same time as chemotherapy or after chemotherapy ends.

Colony-stimulating factors are sometimes given together with chemotherapy. This helps lessen the side effects chemotherapy may have on the bone marrow.

Radiation therapy

Radiation therapy is a cancer treatment that uses high-energy x-rays or other types of radiation to kill cancer cells or keep them from growing. External radiation therapy uses a machine outside the body to send radiation toward the area of the body with cancer.

High-dose chemotherapy with stem cell transplant

High doses of chemotherapy are given to kill cancer cells. Healthy cells, including blood-forming cells, are also destroyed by the cancer treatment. Stem cell transplant is a treatment to replace the blood-forming cells. Stem cells (immature blood cells) are removed from the blood or bone marrow of the patient and are frozen and stored. After the patient completes chemotherapy, the stored stem cells are thawed and given back to the patient through an infusion. These reinfused stem cells grow into (and restore) the body’s blood cells.

Targeted therapy

Targeted therapy is a type of treatment that uses drugs or other substances to identify and attack specific cancer cells. Targeted therapies usually cause less harm to normal cells than chemotherapy or radiation therapy do.

  • Monoclonal antibodies: Monoclonal antibodies are immune system proteins made in the laboratory to treat many diseases, including cancer. As a cancer treatment, these antibodies can attach to a specific target on cancer cells or other cells that may help cancer cells grow. The antibodies are able to then kill the cancer cells, block their growth, or keep them from spreading. Monoclonal antibodies are given by infusion. These may be used alone or to carry drugs, toxins, or radioactive material directly to cancer cells. Rituximab is used in the treatment of AIDS-related peripheral/systemic lymphoma.
    How do monoclonal antibodies work to treat cancer? This video shows how monoclonal antibodies, such as trastuzumab, pembrolizumab, and rituximab, block molecules cancer cells need to grow, flag cancer cells for destruction by the body’s immune system, or deliver harmful substances to cancer cells.

New types of treatment are being tested in clinical trials.

Information about clinical trials is available from the NCI website.

Treatment for AIDS-related lymphoma may cause side effects.

For information about side effects caused by treatment for cancer, visit our Side Effects page.

Patients may want to think about taking part in a clinical trial.

For some patients, taking part in a clinical trial may be the best treatment choice. Clinical trials are part of the cancer research process. Clinical trials are done to find out if new cancer treatments are safe and effective or better than the standard treatment.

Many of today’s standard treatments for cancer are based on earlier clinical trials. Patients who take part in a clinical trial may receive the standard treatment or be among the first to receive a new treatment.

Patients who take part in clinical trials also help improve the way cancer will be treated in the future. Even when clinical trials do not lead to effective new treatments, they often answer important questions and help move research forward.

Patients can enter clinical trials before, during, or after starting their cancer treatment.

Some clinical trials only include patients who have not yet received treatment. Other trials test treatments for patients whose cancer has not gotten better. There are also clinical trials that test new ways to stop cancer from recurring (coming back) or reduce the side effects of cancer treatment.

Clinical trials are taking place in many parts of the country. Information about clinical trials supported by NCI can be found on NCI’s clinical trials search webpage. Clinical trials supported by other organizations can be found on the ClinicalTrials.gov website.

Follow-up tests may be needed.

As you go through treatment, you will have follow-up tests or check-ups. Some tests that were done to diagnose or stage the cancer may be repeated to see how well the treatment is working. Decisions about whether to continue, change, or stop treatment may be based on the results of these tests.

Some of the tests will continue to be done from time to time after treatment has ended. The results of these tests can show if your condition has changed or if the cancer has recurred (come back).

Treatment of AIDS-Related Peripheral/Systemic Lymphoma

For information about the treatments listed below, see the Treatment Option Overview section.

Treatment of AIDS-related peripheral/systemic lymphoma may include the following:

Use our clinical trial search to find NCI-supported cancer clinical trials that are accepting patients. You can search for trials based on the type of cancer, the age of the patient, and where the trials are being done. General information about clinical trials is also available.

Treatment of AIDS-Related Primary Central Nervous System Lymphoma

For information about the treatments listed below, see the Treatment Option Overview section.

Treatment of AIDS-related primary central nervous system lymphoma may include the following:

Use our clinical trial search to find NCI-supported cancer clinical trials that are accepting patients. You can search for trials based on the type of cancer, the age of the patient, and where the trials are being done. General information about clinical trials is also available.

To Learn More About AIDS-Related Lymphoma

For more information from the National Cancer Institute about AIDS-related lymphoma, see the following:

For general cancer information and other resources from the National Cancer Institute, visit:

About This PDQ Summary

About PDQ

Physician Data Query (PDQ) is the National Cancer Institute’s (NCI’s) comprehensive cancer information database. The PDQ database contains summaries of the latest published information on cancer prevention, detection, genetics, treatment, supportive care, and complementary and alternative medicine. Most summaries come in two versions. The health professional versions have detailed information written in technical language. The patient versions are written in easy-to-understand, nontechnical language. Both versions have cancer information that is accurate and up to date and most versions are also available in Spanish.

PDQ is a service of the NCI. The NCI is part of the National Institutes of Health (NIH). NIH is the federal government’s center of biomedical research. The PDQ summaries are based on an independent review of the medical literature. They are not policy statements of the NCI or the NIH.

Purpose of This Summary

This PDQ cancer information summary has current information about the treatment of AIDS-related lymphoma. It is meant to inform and help patients, families, and caregivers. It does not give formal guidelines or recommendations for making decisions about health care.

Reviewers and Updates

Editorial Boards write the PDQ cancer information summaries and keep them up to date. These Boards are made up of experts in cancer treatment and other specialties related to cancer. The summaries are reviewed regularly and changes are made when there is new information. The date on each summary (“Updated”) is the date of the most recent change.

The information in this patient summary was taken from the health professional version, which is reviewed regularly and updated as needed, by the PDQ Adult Treatment Editorial Board.

Clinical Trial Information

A clinical trial is a study to answer a scientific question, such as whether one treatment is better than another. Trials are based on past studies and what has been learned in the laboratory. Each trial answers certain scientific questions in order to find new and better ways to help cancer patients. During treatment clinical trials, information is collected about the effects of a new treatment and how well it works. If a clinical trial shows that a new treatment is better than one currently being used, the new treatment may become “standard.” Patients may want to think about taking part in a clinical trial. Some clinical trials are open only to patients who have not started treatment.

Clinical trials can be found online at NCI’s website. For more information, call the Cancer Information Service (CIS), NCI’s contact center, at 1-800-4-CANCER (1-800-422-6237).

Permission to Use This Summary

PDQ is a registered trademark. The content of PDQ documents can be used freely as text. It cannot be identified as an NCI PDQ cancer information summary unless the whole summary is shown and it is updated regularly. However, a user would be allowed to write a sentence such as “NCI’s PDQ cancer information summary about breast cancer prevention states the risks in the following way: [include excerpt from the summary].”

The best way to cite this PDQ summary is:

PDQ® Adult Treatment Editorial Board. PDQ AIDS-Related Lymphoma Treatment. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: /types/lymphoma/patient/aids-related-treatment-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389358]

Images in this summary are used with permission of the author(s), artist, and/or publisher for use in the PDQ summaries only. If you want to use an image from a PDQ summary and you are not using the whole summary, you must get permission from the owner. It cannot be given by the National Cancer Institute. Information about using the images in this summary, along with many other images related to cancer can be found in Visuals Online. Visuals Online is a collection of more than 3,000 scientific images.

Disclaimer

The information in these summaries should not be used to make decisions about insurance reimbursement. More information on insurance coverage is available on Cancer.gov on the Managing Cancer Care page.

Contact Us

More information about contacting us or receiving help with the Cancer.gov website can be found on our Contact Us for Help page. Questions can also be submitted to Cancer.gov through the website’s E-mail Us.

Advances in Lymphoma Research

Advances in Lymphoma Research

Illustration of T cells attacking cancer cells

Artist’s rendering of T cells (red and blue spheres) attacking cancer cells. T-cell therapy has been effective in treating certain lymphoma patients.

Credit: iStock

NCI-funded researchers are working to advance our understanding of how to treat lymphoma. All lymphomas start in the cells of the lymph system, which is part of the body’s immune system. Lymphomas are grouped into two main types: Hodgkin lymphoma and non-Hodgkin lymphoma (sometimes called NHL). But more than 70 different subtypes of the disease exist. Advances in understanding the gene changes that can lead to lymphoma are now helping scientists design more personalized treatments for these subtypes.

This page highlights some of the latest lymphoma research, including clinical advances that may soon translate into improved care and research findings from recent studies.

Treatment of Non-Hodgkin Lymphoma (NHL)

Most people diagnosed with lymphoma have a subtype of non-Hodgkin lymphoma. Non-Hodgkin lymphoma can either be aggressive or indolent.

Aggressive non-Hodgkin lymphoma grows and spreads quickly and usually requires immediate treatment. With modern treatment regimens, almost 70% of people with aggressive non-Hodgkin lymphoma will be considered cured. Research is now largely focused on finding better treatments for the minority of people with aggressive lymphoma who are not cured with initial therapy.

Indolent non-Hodgkin lymphoma grows slowly, and in some cases may not cause symptoms for years. People with indolent disease can often postpone treatment until their symptoms worsen, with no negative effects on survival. Sometimes, an indolent lymphoma can turn into aggressive lymphoma, which requires immediate treatment.

Indolent non-Hodgkin lymphoma largely cannot be cured with currently available therapies. The past two decades have seen improvements in extending the survival of people who are treated for this type of lymphoma. However, researchers are studying how to improve long-term survival further and working toward potentially curative treatments.

Chemotherapy,  radiation therapy, targeted therapy, and immunotherapy are all used in the treatment of non-Hodgkin lymphoma. A stem cell transplant is sometimes used for lymphoma that has recurred, but this procedure has serious side effects. Four CAR T-cell therapies have been approved to treat some types of recurrent lymphoma. However, these newer therapies still can’t cure many people with recurrent lymphoma.

Most research on treatment for non-Hodgkin lymphoma is now focused on targeted therapy and immunotherapy. Researchers are also trying to identify gene changes in different types of lymphoma that might be targets for new drug development.

For example, in 2018, a study led by NCI researchers identified genetic subtypes of diffuse large B-cell lymphoma (the most common type of non-Hodgkin lymphoma) that could help explain why some patients with the disease respond to treatment and others don’t. Further studies may lead to more tailored treatments for patients with this type of lymphoma.

New targeted therapies

A signaling pathway is a series of chemical reactions that control one or more cell functions. Many types of non-Hodgkin lymphoma are driven by a signaling pathway called the B-cell receptor signaling pathway. A drug called ibrutinib (Imbruvica) has been developed to shut down that pathway. It is being used and tested in a number of ways:

The FDA has approved three other drugs that target the B-cell receptor signaling pathway: acalabrutib (Calquence), zanubrutinib (Brukinsa), and pirtobrutinib (Jaypirca).

Many other targeted therapies are being studied in non-Hodgkin lymphoma. Some that are approved for specific subtypes are listed below.

However, in lymphoma, resistance to a single agent can develop quickly. Researchers are now testing combinations of targeted therapies to treat non-Hodgkin lymphoma to try to overcome resistance. For example, ongoing trials led by NCI researchers are testing a five-drug regimen and a six-drug regimen in people with aggressive or indolent B-cell lymphomas whose cancer has relapsed or is resistant to treatment.

Early results showed that the five-drug regimen, called ViPOR, shrank tumors substantially in about half of participants. Over a third of patients’ tumors disappeared entirely, called a complete response. Two years after treatment, most people who had a complete response remained in remission. These benefits were seen mainly in people with two specific subtypes of B-cell lymphoma.

Researchers are also trying to make standard treatment regimens less toxic. In one study, NCI researchers found that the intensity of standard chemotherapy could be reduced in adults with lower risk Burkitt lymphoma, an aggressive type of non-Hodgkin lymphoma, without compromising the potential for a cure.

Immunotherapy

Immunotherapy uses substances to stimulate or suppress the immune system to help the body fight cancer. Several immunotherapies have shown promise in treating different types of lymphoma. 

CAR T cells. CAR T cells are a type of immunotherapy in which a patient’s T cells, a type of immune cell, are changed in the laboratory so they will better attack cancer cells. Four CAR T-cell therapies have been approved for the treatment of non-Hodgkin lymphoma:

To date, CAR T cells have provided long-term remissions for about one third of adults with aggressive lymphoma who receive them. Large randomized trials have been comparing CAR T-cell therapy to autologous stem cell transplantation at first relapse. In two of these trials, people who received the CAR T-cell therapy were less likely to have died or had a disease relapse after treatment compared with people who received chemotherapy followed by stem cell transplantation. Participants in one other trial are still being followed to see if differences in survival emerge over time.

Early results from a phase 2 trial tested CAR T cells as initial therapy in people at very high risk of relapse showed that over three-quarters of patients had their cancer go into remission. However, long term results are not yet available and CAR T cells are not FDA approved in this setting.

CAR T cells are also being tested in other lymphoma subtypes, both aggressive and indolent, as well as in patients with lymphoma that has spread to the central nervous system. 

Immunomodulating drugs. Immunomodulators are drugs that either stimulate or suppress the immune system. One such drug, lenalidomide (Revlimid), has been approved in combination with targeted therapies for previously treated follicular lymphoma and marginal zone lymphoma. It is also often used to treat diffuse large B-cell lymphoma.

Novel immunotherapies. Researchers are also testing novel ways to stimulate the immune system to fight lymphoma. For example, in 2018, a small trial showed that combining radiation therapy with the injection of a compound that stimulates the immune system could shrink some indolent B-cell lymphomas.

Immunotherapy drugs called bispecific antibodies are also under development. These drugs bind to lymphoma cells and the body’s own immune cells at the same time to bring them together. This allows the immune cells to kill the lymphoma cells. Five bispecific antibodies are in clinical trials for various types of lymphoma, including:

Glofitamab, epcoritamab, and mosunetuzumab have all received accelerated approval from the FDA for the treatment of some lymphomas that have returned or gotten worse after at least two other treatments.

Hodgkin Lymphoma Treatment

An illustration of a cytokine binding to a receptor on the cell surface and how it causes JAK proteins inside the cell to cause gene transcription.

JAK Inhibitors Boost Immunotherapy in Clinical Trials

The combination shrank lymphoma and lung tumors in people and in mice.

Hodgkin lymphoma is much less common than non-Hodgkin lymphoma. It is mostly seen in early adulthood (age 20–39) and in late adulthood (age 65 and older). More than 75% of all adults newly diagnosed with Hodgkin lymphoma can be cured with standard chemotherapy, radiation therapy, or both. Over the last 5 decades, deaths from Hodgkin lymphoma among adults have fallen more rapidly than deaths from any other cancer type. 

Researchers are now focusing on adjusting standard treatment regimens to reduce the long-term side effects and improve quality of life for survivors. They are also testing better ways to treat the minority of patients whose cancer does recur. 

Targeted therapies

A protein called CD30 is commonly found on the surface of Hodgkin lymphoma cells. A drug called brentuximab vedotin (Adcetris) that targets this protein has been approved as part of initial treatment for people with advanced Hodgkin lymphoma. Use of this new drug may help older patients avoid what had been the standard treatment with an especially toxic chemotherapy drug.

Clinical trials are now testing brentuximab vedotin combined with other chemotherapy drugs and with immunotherapies. The drug has also been approved by the FDA in combination with chemotherapy for some children and adolescents with Hodgkin lymphoma. 

Immunotherapy

Immune checkpoint inhibitors that help T cells to better kill cancer cells have been effective in some people with recurrent Hodgkin lymphoma. Two such drugs—nivolumab (Opdivo) and pembrolizumab (Keytruda)—have been approved for some patients with Hodgkin lymphoma that has recurred after previous treatments.

Researchers are now testing these drugs in combination with other therapies, as well as earlier in treatment for some people with cancer that is likely to recur. For example, a large clinical trial recently found a benefit to giving nivolumab as part of initial treatment to teens and adults with advanced forms of classic Hodgkin lymphoma. More than 90% of trial participants who received nivolumab plus chemotherapy and targeted therapy were alive without their cancer starting to grow again 2 years after treatment, compared with 83% of those who received chemotherapy and targeted therapy alone

NCI-Supported Research Programs

The Lymphoma Specialized Programs of Research Excellence (Lymphoma SPOREs) are designed to quickly move basic scientific findings into clinical settings. The Lymphoma SPOREs support the development of new immunotherapies, novel targeted therapies, and new methods for determining prognosis for individual patients.

The goal of the International Lymphoma Epidemiology Consortium (InterLymph) is to enhance collaboration among epidemiologists studying lymphoma, provide a forum for the exchange of research ideas, and create a framework for collaborating on analyses that compile data from multiple studies. 

The Lymphoma Epidemiology of Outcomes (LEO) Cohort Study was established to address the current and long-term health needs of non-Hodgkin lymphoma patients and survivors. The goal is to support a broad research agenda aimed at identifying novel clinical, epidemiologic, host, genetic, tumor, and treatment factors that significantly influence non-Hodgkin lymphoma prognosis and survivorship.

The Cancer Genome Characterization Initiative (CGCI) is supporting research to identify common gene changes in adult and pediatric cancers. Its results are freely available to the wider cancer research community, to spur the development of new targeted drugs. The HIV+ Tumor Molecular Characterization Project (HTMCP) and Burkitt Lymphoma Genome Sequencing Project (BLGSP) are two active CGCI projects.

Within the Center for Cancer Research, the Lymphoid Malignancies Branch focuses on identifying abnormalities in the immune system and looking at molecular disorders that underlie lymphoid malignancies. 

The Clinical Trial Sequencing Project (CTSP) promotes the use of genomics in NCI-supported clinical trials. CTSP’s goal is to clarify the molecular basis of response and resistance to therapies studied. Diffuse large B-cell lymphoma is one of the cancer types under study, along with breast and renal cell carcinoma. 

Clinical Trials

NCI funds and oversees both early- and late-phase clinical trials to develop new treatments and improve patient care. Trials are available for lymphoma treatment.

Lymphoma Research Results

The following are some of NCI’s latest news articles on lymphoma research:

View the full list of Lymphoma Research Results and Study Updates.
 

Mycosis Fungoides and Other Cutaneous T-Cell Lymphomas Treatment (PDQ®)–Health Professional Version

Mycosis Fungoides and Other Cutaneous T-Cell Lymphomas Treatment (PDQ®)–Health Professional Version

General Information About Mycosis Fungoides and Other Cutaneous T-Cell Lymphomas

Go to Patient Version

Clinical Presentation

Cutaneous T-cell lymphomas, which include mycosis fungoides and Sézary syndrome, are neoplasias of malignant T lymphocytes that usually possess the helper/inducer cell surface phenotype and initially present as skin involvement.[1] Cutaneous T-cell lymphomas should be distinguished from other T-cell lymphomas that involve the skin, such as anaplastic large cell lymphoma (CD30 positive), peripheral T-cell lymphoma (CD30 negative, with no epidermal involvement), or adult T-cell leukemia/lymphoma (usually with systemic involvement).[2,3] For more information about these types of T-cell lymphomas, see Peripheral T-Cell Non-Hodgkin Lymphoma Treatment.

Typically, the natural history of cutaneous T-cell lymphoma is indolent.[4] Symptoms of the disease may be present for long periods, in a range of 2 to 10 years, because cutaneous eruptions wax and wane before being confirmed by biopsy. Cutaneous T-cell lymphomas are treatable with available topical therapy, systemic therapy, or both. Curative modalities have proven elusive, with the possible exception of patients with minimal disease confined to the skin.

In addition, several benign or indolent conditions can be confused with mycosis fungoides. It is important to consult with a pathologist who has expertise in distinguishing these conditions.[1]

Prognosis and Survival

The prognosis of patients with cutaneous T-cell lymphomas is based on the extent of disease (stage) at presentation.[5] The presence of lymphadenopathy and involvement of peripheral blood and viscera increase in likelihood with worsening cutaneous involvement and define poor prognostic groups.[5–8] The Cutaneous Lymphoma International Consortium retrospectively reviewed 1,275 patients and found that the following four independent prognostic markers indicate a worse survival:[9]

  • Stage IV disease.
  • Age older than 60 years.
  • Large cell transformation.
  • Elevated lactate dehydrogenase.

The median survival following diagnosis varies according to stage. Patients with stage IA disease have a median survival of 20 years or more. Most deaths for this group are not caused by, nor are they related to, mycosis fungoides.[10,11] In contrast, more than 50% of patients with stage III through stage IV disease die of mycosis fungoides, with a median survival of approximately 5 years.[7,9,12,13] The Cutaneous Lymphoma International Prognostic index used male sex, age older than 60 years, plaques, lymph nodes, blood involvement, and visceral involvement as poor prognostic factors to define predicted overall survival (OS) and progression-free survival in both early-stage and advanced-stage groups.[14]

A report on 1,798 patients from the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) Program database found an increase in second malignancies in patients with mycosis fungoides (standardized incidence ratio, 1.32; 95% confidence interval [CI], 1.15–1.52), especially for Hodgkin lymphoma, non-Hodgkin lymphoma, and myeloma.[15] Another report on 4,459 patients from the SEER database found that the 19.2% of African American patients with mycosis fungoides had shorter OS, potentially attributable to disease characteristics, socioeconomic status, and type of therapy (hazard ratio, 1.47; 95% CI, 1.25–1.74; P < .001).[16]

Cutaneous disease can manifest as an eczematous patch or plaque stage covering less than 10% of the body surface (T1), a plaque stage covering 10% or more of the body surface (T2), or as tumors (T3) that frequently undergo necrotic ulceration.[17,18] Several retrospective studies showed that 20% of patients have disease that progresses from stage I or II to stage III or IV.[19–21] Sézary syndrome presents with generalized erythroderma (T4) and peripheral blood involvement. However, there is some disagreement about whether mycosis fungoides and Sézary syndrome are actually variants of the same disease.[22] The same retrospective study with a median follow-up of 14.5 years found that only 3% of 1,422 patients progressed from mycosis fungoides to Sézary syndrome.[19]

There is consensus that patients with Sézary syndrome (leukemic involvement) have a poor prognosis (median survival, 4 years), with or without the typical generalized erythroderma.[23,24] Cytologic transformation from a low-grade lymphoma to a high-grade lymphoma (large cell transformation) occurs rarely (<5%) during the course of these diseases and is associated with a poor prognosis.[25–27] A retrospective analysis of 100 cases with large cell transformation found reduced disease-specific survival with extracutaneous transformation, increased extent of skin lesions, and CD30 negativity.[28] A common cause of death during the tumor phase is septicemia caused by chronic skin infection with staph species, herpes simplex, herpes zoster, and fungal skin infections.[29,30]

Folliculotropic mycosis fungoides is a variant of mycosis fungoides marked by folliculotropic, rather than epidermotropic, neoplastic infiltrates, with preferential location in the head and neck area.[31] Early plaque-stage folliculotropic mycosis fungoides have a very indolent prognosis, while extracutaneous disease portends a very poor prognosis.[31]

References
  1. Wilcox RA: Cutaneous T-cell lymphoma: 2017 update on diagnosis, risk-stratification, and management. Am J Hematol 92 (10): 1085-1102, 2017. [PUBMED Abstract]
  2. Willemze R, Kerl H, Sterry W, et al.: EORTC classification for primary cutaneous lymphomas: a proposal from the Cutaneous Lymphoma Study Group of the European Organization for Research and Treatment of Cancer. Blood 90 (1): 354-71, 1997. [PUBMED Abstract]
  3. Harris NL, Jaffe ES, Stein H, et al.: A revised European-American classification of lymphoid neoplasms: a proposal from the International Lymphoma Study Group. Blood 84 (5): 1361-92, 1994. [PUBMED Abstract]
  4. Diamandidou E, Cohen PR, Kurzrock R: Mycosis fungoides and Sezary syndrome. Blood 88 (7): 2385-409, 1996. [PUBMED Abstract]
  5. Agar NS, Wedgeworth E, Crichton S, et al.: Survival outcomes and prognostic factors in mycosis fungoides/Sézary syndrome: validation of the revised International Society for Cutaneous Lymphomas/European Organisation for Research and Treatment of Cancer staging proposal. J Clin Oncol 28 (31): 4730-9, 2010. [PUBMED Abstract]
  6. Talpur R, Singh L, Daulat S, et al.: Long-term outcomes of 1,263 patients with mycosis fungoides and Sézary syndrome from 1982 to 2009. Clin Cancer Res 18 (18): 5051-60, 2012. [PUBMED Abstract]
  7. Kim YH, Liu HL, Mraz-Gernhard S, et al.: Long-term outcome of 525 patients with mycosis fungoides and Sezary syndrome: clinical prognostic factors and risk for disease progression. Arch Dermatol 139 (7): 857-66, 2003. [PUBMED Abstract]
  8. Alberti-Violetti S, Talpur R, Schlichte M, et al.: Advanced-stage mycosis fungoides and Sézary syndrome: survival and response to treatment. Clin Lymphoma Myeloma Leuk 15 (6): e105-12, 2015. [PUBMED Abstract]
  9. Scarisbrick JJ, Prince HM, Vermeer MH, et al.: Cutaneous Lymphoma International Consortium Study of Outcome in Advanced Stages of Mycosis Fungoides and Sézary Syndrome: Effect of Specific Prognostic Markers on Survival and Development of a Prognostic Model. J Clin Oncol 33 (32): 3766-73, 2015. [PUBMED Abstract]
  10. Kim YH, Jensen RA, Watanabe GL, et al.: Clinical stage IA (limited patch and plaque) mycosis fungoides. A long-term outcome analysis. Arch Dermatol 132 (11): 1309-13, 1996. [PUBMED Abstract]
  11. Vollmer RT: A review of survival in mycosis fungoides. Am J Clin Pathol 141 (5): 706-11, 2014. [PUBMED Abstract]
  12. Zackheim HS, Amin S, Kashani-Sabet M, et al.: Prognosis in cutaneous T-cell lymphoma by skin stage: long-term survival in 489 patients. J Am Acad Dermatol 40 (3): 418-25, 1999. [PUBMED Abstract]
  13. de Coninck EC, Kim YH, Varghese A, et al.: Clinical characteristics and outcome of patients with extracutaneous mycosis fungoides. J Clin Oncol 19 (3): 779-84, 2001. [PUBMED Abstract]
  14. Benton EC, Crichton S, Talpur R, et al.: A cutaneous lymphoma international prognostic index (CLIPi) for mycosis fungoides and Sezary syndrome. Eur J Cancer 49 (13): 2859-68, 2013. [PUBMED Abstract]
  15. Huang KP, Weinstock MA, Clarke CA, et al.: Second lymphomas and other malignant neoplasms in patients with mycosis fungoides and Sezary syndrome: evidence from population-based and clinical cohorts. Arch Dermatol 143 (1): 45-50, 2007. [PUBMED Abstract]
  16. Su C, Nguyen KA, Bai HX, et al.: Racial disparity in mycosis fungoides: An analysis of 4495 cases from the US National Cancer Database. J Am Acad Dermatol 77 (3): 497-502.e2, 2017. [PUBMED Abstract]
  17. Siegel RS, Pandolfino T, Guitart J, et al.: Primary cutaneous T-cell lymphoma: review and current concepts. J Clin Oncol 18 (15): 2908-25, 2000. [PUBMED Abstract]
  18. Lorincz AL: Cutaneous T-cell lymphoma (mycosis fungoides) Lancet 347 (9005): 871-6, 1996. [PUBMED Abstract]
  19. Quaglino P, Pimpinelli N, Berti E, et al.: Time course, clinical pathways, and long-term hazards risk trends of disease progression in patients with classic mycosis fungoides: a multicenter, retrospective follow-up study from the Italian Group of Cutaneous Lymphomas. Cancer 118 (23): 5830-9, 2012. [PUBMED Abstract]
  20. Wernham AG, Shah F, Amel-Kashipaz R, et al.: Stage I mycosis fungoides: frequent association with a favourable prognosis but disease progression and disease-specific mortality may occur. Br J Dermatol 173 (5): 1295-7, 2015. [PUBMED Abstract]
  21. Desai M, Liu S, Parker S: Clinical characteristics, prognostic factors, and survival of 393 patients with mycosis fungoides and Sézary syndrome in the southeastern United States: a single-institution cohort. J Am Acad Dermatol 72 (2): 276-85, 2015. [PUBMED Abstract]
  22. Olsen EA, Rook AH, Zic J, et al.: Sézary syndrome: immunopathogenesis, literature review of therapeutic options, and recommendations for therapy by the United States Cutaneous Lymphoma Consortium (USCLC). J Am Acad Dermatol 64 (2): 352-404, 2011. [PUBMED Abstract]
  23. Kubica AW, Davis MD, Weaver AL, et al.: Sézary syndrome: a study of 176 patients at Mayo Clinic. J Am Acad Dermatol 67 (6): 1189-99, 2012. [PUBMED Abstract]
  24. Thompson AK, Killian JM, Weaver AL, et al.: Sézary syndrome without erythroderma: A review of 16 cases at Mayo Clinic. J Am Acad Dermatol 76 (4): 683-688, 2017. [PUBMED Abstract]
  25. Kim YH, Bishop K, Varghese A, et al.: Prognostic factors in erythrodermic mycosis fungoides and the Sézary syndrome. Arch Dermatol 131 (9): 1003-8, 1995. [PUBMED Abstract]
  26. Arulogun SO, Prince HM, Ng J, et al.: Long-term outcomes of patients with advanced-stage cutaneous T-cell lymphoma and large cell transformation. Blood 112 (8): 3082-7, 2008. [PUBMED Abstract]
  27. Kadin ME, Hughey LC, Wood GS: Large-cell transformation of mycosis fungoides-differential diagnosis with implications for clinical management: a consensus statement of the US Cutaneous Lymphoma Consortium. J Am Acad Dermatol 70 (2): 374-6, 2014. [PUBMED Abstract]
  28. Benner MF, Jansen PM, Vermeer MH, et al.: Prognostic factors in transformed mycosis fungoides: a retrospective analysis of 100 cases. Blood 119 (7): 1643-9, 2012. [PUBMED Abstract]
  29. Talpur R, Bassett R, Duvic M: Prevalence and treatment of Staphylococcus aureus colonization in patients with mycosis fungoides and Sézary syndrome. Br J Dermatol 159 (1): 105-12, 2008. [PUBMED Abstract]
  30. Lebas E, Arrese JE, Nikkels AF: Risk Factors for Skin Infections in Mycosis Fungoides. Dermatology 232 (6): 731-737, 2016. [PUBMED Abstract]
  31. van Santen S, Roach RE, van Doorn R, et al.: Clinical Staging and Prognostic Factors in Folliculotropic Mycosis Fungoides. JAMA Dermatol 152 (9): 992-1000, 2016. [PUBMED Abstract]

Cellular Classification of Mycosis Fungoides and Other Cutaneous T-Cell Lymphomas

The histological diagnosis of mycosis fungoides and other cutaneous T-cell lymphomas is usually difficult to determine in the initial stages of the disease and may require the review of multiple biopsies by an experienced pathologist.

A definitive diagnosis from a skin biopsy requires the presence of cutaneous T-cell lymphoma cells (convoluted lymphocytes), a band-like upper dermal infiltrate, and epidermal infiltrations with Pautrier abscesses (collections of neoplastic lymphocytes). A definitive diagnosis of Sézary syndrome may be made from a peripheral blood evaluation when skin biopsies are consistent with the diagnosis. Supportive evidence for circulating Sézary cells is provided by T-cell receptor gene analysis, identification of the atypical lymphocytes with hyperconvoluted or cerebriform nuclei, and flow cytometry with the characteristic deletion of cell surface markers such as CD7 and CD26. However, none of these is individually pathognomonic for lymphoma.[1,2]

Established criteria for defining Sézary syndrome generally require identification of (1) a circulating T-cell clone by rearrangement of the T-cell receptor, plus (2) a level of Sézary cells in the blood of at least 1,000/μL.[3,4] It is less clear if other findings (such as a CD4:CD8 ratio ≥10, or the use of percentages instead of absolute numbers of atypical lymphocytes by flow cytometry) are reliable staging data in the absence of blood Sézary cell levels of at least 1,000/μL.[5]

References
  1. Olsen EA, Rook AH, Zic J, et al.: Sézary syndrome: immunopathogenesis, literature review of therapeutic options, and recommendations for therapy by the United States Cutaneous Lymphoma Consortium (USCLC). J Am Acad Dermatol 64 (2): 352-404, 2011. [PUBMED Abstract]
  2. Fraser-Andrews EA, Russell-Jones R, Woolford AJ, et al.: Diagnostic and prognostic importance of T-cell receptor gene analysis in patients with Sézary syndrome. Cancer 92 (7): 1745-52, 2001. [PUBMED Abstract]
  3. Olsen E, Vonderheid E, Pimpinelli N, et al.: Revisions to the staging and classification of mycosis fungoides and Sezary syndrome: a proposal of the International Society for Cutaneous Lymphomas (ISCL) and the cutaneous lymphoma task force of the European Organization of Research and Treatment of Cancer (EORTC). Blood 110 (6): 1713-22, 2007. [PUBMED Abstract]
  4. Olsen EA, Whittaker S, Willemze R, et al.: Primary cutaneous lymphoma: recommendations for clinical trial design and staging update from the ISCL, USCLC, and EORTC. Blood 140 (5): 419-437, 2022. [PUBMED Abstract]
  5. Chrisman LP, Trimark PF, Pang Y, et al.: Updated cutaneous T-cell lymphoma TNMB staging criteria fail to identify patients with Sézary syndrome with low blood burden. Blood 144 (8): 914-917, 2024. [PUBMED Abstract]

Stage Information for Mycosis Fungoides and Other Cutaneous T-Cell Lymphomas

The American Joint Committee on Cancer (AJCC) has designated staging by TNM (tumor, node, metastasis) classification to define cutaneous T-cell lymphomas.[1] Peripheral blood involvement with cutaneous T-cell lymphoma cells is correlated with more advanced skin stage, lymph node and visceral involvement, and shortened survival.

Cutaneous T-cell lymphomas also have a formal staging system proposed by the International Society for Cutaneous Lymphomas and the European Organisation for Research and Treatment of Cancer.[2,3]

Table 1. Histopathological Staging of Lymph Nodes in Cutaneous T-Cell Lymphomaa
EORTC Classification Dutch System NCI-VA Classification
DL = dermatopathic lymphadenopathy; EORTC = European Organisation for Research and Treatment of Cancer; LN = lymph nodes; N = regional lymph node; NCI = National Cancer Institute; VA = U.S. Department of Veterans Affairs.
aReprinted with permission from AJCC: Primary Cutaneous Lymphomas. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp. 967–72.
N1 Grade 1: DL LN0: No atypical lymphocytes.
LN1: Occasional and isolated atypical lymphocytes (not arranged in clusters).
LN2: Many atypical lymphocytes or lymphocytes in 3-6‒cell clusters.
N2 Grade 2: DL; early involvement by mycosis fungoides (presence of cerebriform nuclei <7.5 µm [micrometer]). LN3: Aggregates of atypical lymphocytes; nodal architecture preserved.
N3 Grade 3: Partial effacement of lymph node architecture; many atypical cerebriform mononuclear cells. LN4: Partial/complete effacement of nodal architecture by atypical lymphocytes or frankly neoplastic cells.
Grade 4: Complete effacement.
Table 2. Definitions of TNM Stages IA and IBa
Stage TNM Description B Peripheral Blood Involvement Criteria
T = primary tumor; N = regional lymph node; M = distant metastasis; B = peripheral blood involvement.
aReprinted with permission from AJCC: Primary Cutaneous Lymphomas. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp. 967–72.
The explanations for superscripts b through f are at the end of Table 5.
IA T1, N0, M0 T1 = Limited patches,b papules, and/or plaquesc covering <10% of the skin surface. B0,1 B0 = Absence of significant blood involvement: ≤5% of peripheral blood lymphocytes are atypical (Sézary) cells.d
–T1a = T1a (patch only).
–T1b = T1b (plaque ± patch). –B0a = Clone negativee
–B0b = Clone positivee
N0 = No clinically abnormal peripheral lymph nodes;f biopsy not required. B1 = Low blood tumor burden: >5% of peripheral blood lymphocytes are atypical (Sézary) cells, but does not meet the criteria of B2.
M0 = No visceral organ involvement. –B1a = Clone negativee
–B1b = Clone positivee
IB T2, N0, M0 T2 = Patches, papules, or plaques covering ≥10% of the skin surface. B0,1 See B0, B1 descriptions above in this table, Stage IA.
–T2a = T2a (patch only).
–T2b = T2b (plaque ± patch).
N0 = No clinically abnormal peripheral lymph nodes;f biopsy not required.
M0 = No visceral organ involvement.
Table 3. Definitions of TNM Stages IIA and IIBa
Stage TNM Description B Peripheral Blood Involvement Criteria
T = primary tumor; N = regional lymph node; M = distant metastasis; B = peripheral blood involvement; LN = lymph nodes; NCI = National Cancer Institute.
aReprinted with permission from AJCC: Primary Cutaneous Lymphomas. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp. 967–72.
The explanations for superscripts e through g are at the end of Table 5.
IIA T1,2; N1,2; M0 See T1–2 descriptions above in Table 2, Stages IA, IB. B0,1 See B0, B1 descriptions above in Table 2, Stage IA.
N1 = Clinically abnormal peripheral lymph nodes; histopathology Dutch grade 1 or NCI LN0–2.
–N1a = Clone negative.e
–N1b = Clone positive.e
N2 = Clinically abnormal peripheral lymph nodes; histopathology Dutch grade 2 or NCI LN3.
–N2a = Clone negative.e
–N2b = Clone positive.e
M0 = No visceral organ involvement.
IIB T3, N0–2, M0 T3 = One or more tumorsg (≥1 cm in diameter). B0,1 See B0, B1 descriptions above in Table 2, Stage IA.
–T3a = Multiple lesions involving 2 noncontiguous body regions.
–T3b = Multiple lesions involving ≥3 body regions.
N0 = No clinically abnormal peripheral lymph nodes;f biopsy not required.
See N1–2 descriptions above in this table, Stage IIA
M0 = No visceral organ involvement.
Table 4. Definitions of TNM Stages III, IIIA, and IIIBa
Stage TNM Description B Peripheral Blood Involvement Criteria
T = primary tumor; N = regional lymph node; M = distant metastasis; B = peripheral blood involvement.
aReprinted with permission from AJCC: Primary Cutaneous Lymphomas. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp. 967–72.
III T4, N0–2, M0 T4 = Confluence of erythema covering ≥80% of body surface area. B0,1 See B0, B1 descriptions above in Table 2, Stage IA.
See N0–2 descriptions above in Table 3, Stages IIA, IIB.
M0 = No visceral organ involvement.
IIIA T4, N0–2, M0 T4 = Confluence of erythema covering ≥80% of body surface area. B0 See B0 description above in Table 2, Stage IA.
See N0–2 descriptions above in Table 3, Stages IIA, IIB.
M0 = No visceral organ involvement.
IIIB T4, N0–2, M0 T4 = Confluence of erythema covering ≥80% of body surface area. B1 See B1 description above in Table 2, Stage IA.
See N0–2 descriptions above in Table 3, Stages IIA, IIB.
M0 = No visceral organ involvement.
Table 5. Definitions of TNM Stages IVA1, IVA2, and IVBa
Stage TNM Description B Peripheral Blood Involvement Criteria
T = primary tumor; N = regional lymph node; M = distant metastasis; B = peripheral blood involvement; LN = lymph nodes; NCI = National Cancer Institute.
aReprinted with permission from AJCC: Primary Cutaneous Lymphomas. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp. 967–72.
bFor skin, patch indicates any size skin lesion without significant elevation or induration. Presence/absence of hypo- or hyperpigmentation, scale, crusting, and/or poikiloderma should be noted.
cFor skin, plaque indicates any size skin lesion that is elevated or indurated. Presence/absence of scale, crusting, and/or poikiloderma should be noted. Histological features such as folliculotropism, large cell transformation (>25% large cells) and CD30 positivity or negativity, as well as clinical features such as ulceration, are important to document.
dFor blood, Sézary cells are defined as lymphocytes with hyperconvoluted cerebriform nuclei. If Sézary cells cannot be used to determine tumor burden for B2, then one of the following modified ISCL criteria, along with a positive clonal rearrangement of the T-cell receptor (TCR), may be used instead: (1) expanded CD4+ or CD3+ cells with a CD4/CD8 ratio of >10, or (2) expanded CD4+ cells with abnormal immunophenotype, including loss of CD7 (>40%) or CD26 (>30%).
eA T-cell clone is defined by polymerase chain reaction or Southern blot analysis of the TCR gene.
fFor node, abnormal peripheral lymph node(s) indicates any palpable peripheral node that on physical examination is firm, irregular, clustered, fixed or ≥1.5 cm in diameter. Node groups examined on physical examination include cervical, supraclavicular, epitrochlear, axillary, and inguinal. Central nodes, which generally are not amenable to pathological assessment, currently are not considered in the nodal classification unless used to establish N3 histopathologically.
gFor skin, tumor indicates at least one 1-cm diameter solid or nodular lesion with evidence of depth and/or vertical growth. Note the total number of lesions, total volume of lesions, largest size lesion, and region of body involved. Also note whether there is histological evidence of large cell transformation. Phenotyping for CD30 is encouraged.
hFor viscera, spleen and liver may be diagnosed by imaging criteria.
IVA1 T1–4, N0–2, M0 See T1‒2 descriptions above in Table 2, Stages IA, IB. B2 B2 = High blood tumor burden: ≥1,000 mcg/L Sézary cellsd or >40% CD4+/CD7- or increased >30% CD4+/CD26- cells with positive clone.e
T3 = One or more tumorsg (≥1 cm in diameter).
–T3a = Multiple lesions involving 2 noncontiguous body regions.
–T3b = Multiple lesions involving ≥3 body regions.
T4 = Confluence of erythema covering ≥80% of body surface area.
See N0–2 descriptions above in Table 3, Stages IIA, IIB.
M0 = No visceral organ involvement.
IVA2 T1–4, N3, M0 See T1‒2 descriptions above in Table 2, Stages IA, IB and see T3–4 descriptions above in this table, Stage IVA1. B0–2 See B0, B1 descriptions above in Table 2, Stage IA and see B2 description above in this table, Stage IVA1.
N3 = Clinically abnormal peripheral lymph nodes; histopathology Dutch grades 3–4 or NCI LN4; clone positive or negative.
M0 = No visceral organ involvement.
IVB T1–4, N0–3, M1 See T1‒2 descriptions above in Table 2, Stages IA, IB and see T3–4 descriptions above in this table, Stage IVA1. B0–2 See B0, B1 descriptions above in Table 2, Stage IA and see B2 description above in this table, Stage IVA1.
See N0–2 descriptions above in Table 3, Stages IIA, IIB.
N3 = Clinically abnormal peripheral lymph nodes; histopathology Dutch grades 3–4 or NCI LN4; clone positive or negative.
M1 = Visceral involvement (must have pathology confirmation,h and organ involved should be specified).
References
  1. Primary cutaneous lymphomas. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. Springer; 2017, pp. 967–72.
  2. Olsen E, Vonderheid E, Pimpinelli N, et al.: Revisions to the staging and classification of mycosis fungoides and Sezary syndrome: a proposal of the International Society for Cutaneous Lymphomas (ISCL) and the cutaneous lymphoma task force of the European Organization of Research and Treatment of Cancer (EORTC). Blood 110 (6): 1713-22, 2007. [PUBMED Abstract]
  3. Agar NS, Wedgeworth E, Crichton S, et al.: Survival outcomes and prognostic factors in mycosis fungoides/Sézary syndrome: validation of the revised International Society for Cutaneous Lymphomas/European Organisation for Research and Treatment of Cancer staging proposal. J Clin Oncol 28 (31): 4730-9, 2010. [PUBMED Abstract]

Treatment Option Overview for Mycosis Fungoides and Other Cutaneous T-Cell Lymphomas

Anecdotal responses, some lasting for months, can be seen with aggressive antibiotic treatment of Staphylococcus aureus, with corresponding decreased expression of interleukin-2 receptors, STAT signaling, and T-cell proliferation.[1][Level of evidence C3]

These types of treatments produce remissions, but long-term remissions are uncommon. Treatment is considered palliative for most patients, although major symptomatic improvement is regularly achieved. Survival of more than 8 years is common for patients with early stages of disease. All patients with cutaneous T-cell lymphomas are candidates for clinical trials evaluating new approaches to treatment.

Table 6. Treatment Options for Mycosis Fungoides and Other Cutaneous T-Cell Lymphomas
Stage (TNM Definitions) Treatment Options
Stage I and Stage II Mycosis Fungoides Photodynamic therapy
Radiation therapy
Biological therapy
Chemotherapy
Other drug therapy
Targeted therapy
Stage III and Stage IV Mycosis Fungoides and Sézary Syndrome Photodynamic therapy
Radiation therapy
Biological therapy
Chemotherapy
Other drug therapy
Targeted therapy
Checkpoint inhibitors
Recurrent Mycosis Fungoides and Sézary Syndrome Radiation therapy
Photodynamic therapy
Chemotherapy
Other drug therapy
Biological therapy
Allogeneic stem cell transplant
Targeted therapy
Primary Cutaneous Anaplastic Large Cell Lymphoma Radiation therapy
Targeted therapy
Chemotherapy
Subcutaneous Panniculitis-Like T-Cell Lymphoma Immunosuppression
Chemotherapy
Targeted therapy
Allogeneic stem cell transplant
Primary Cutaneous Gamma Delta T-Cell Lymphoma Chemotherapy
Allogeneic stem cell transplant
Primary Cutaneous Aggressive Epidermotropic CD8-Positive T-Cell Lymphoma Chemotherapy
Allogeneic stem cell transplant
References
  1. Lindahl LM, Willerslev-Olsen A, Gjerdrum LMR, et al.: Antibiotics inhibit tumor and disease activity in cutaneous T-cell lymphoma. Blood 134 (13): 1072-1083, 2019. [PUBMED Abstract]

Treatment of Stage I and Stage II Mycosis Fungoides

Several forms of treatment can completely resolve skin lesions at stages I and II, so the choice of therapy depends on local expertise and the facilities available. With therapy, the survival of patients with stage IA disease can be expected to be the same as for age- and sex-matched controls.[1–3]

There is no curative therapy and no clear difference in overall survival (OS) among the treatment options for patients with stage I and stage II mycosis fungoides.

A randomized study of 103 patients compared combined total-skin electron-beam radiation (TSEB) plus combination chemotherapy with sequential topical therapies.[4] In the latter group, combination chemotherapy was reserved for patients with symptomatic extracutaneous disease or disease that was refractory to topical therapies. Patients with any disease stage were eligible. Although the complete response rate was higher with combined therapy, toxic effects were considerably greater, and no difference was seen in disease-free survival (DFS) or OS between the two groups.[4][Level of evidence A1]

Treatment Options for Stage I and Stage II Mycosis Fungoides

Treatment options for stages I and II mycosis fungoides include the following:[5]

  1. Photodynamic therapy.
  2. Radiation therapy.
  3. Biological therapy.
  4. Chemotherapy.
  5. Other drug therapy.
  6. Targeted therapy.

Photodynamic therapy

  1. Psoralen and ultraviolet A (PUVA) radiation therapy.[6–11]
    • Therapeutic trials with PUVA have shown an 80% to 90% complete remission rate in patients, with those in early cutaneous stages achieving the best responses. PUVA may be used in conjunction with systemic treatment.[10] Continued maintenance therapy with PUVA at more protracted intervals is generally required to prolong remission duration.[6–8,10] PUVA combined with interferon alfa-2a is associated with a high response rate.[9,10]
  2. Narrowband ultraviolet B radiation.[12,13]
    • Single-arm and retrospective comparisons confirm the efficacy of narrowband ultraviolet B with 80% to 90% complete remission rates, especially for patients with early cutaneous stages.[12,13]
    • A Cochrane systematic review and meta-analysis compared PUVA with narrowband ultraviolet B radiation in 778 patients with early-stage mycosis fungoides (stage IA, IB, and IIA). Significantly higher complete responses were seen in patients treated with PUVA (73.8% vs. 62.2%; hazard ratio, 1.68; 95% confidence interval [CI], 1.02–2.76; P = .04). There were no significant differences in adverse effects.[11][Level of evidence B3]

Radiation therapy

  1. TSEB.[14–19]
    • Electron-beam radiation therapy of appropriate energies will penetrate only to the dermis, and thus, the skin alone can be treated without systemic effects. This therapy requires a radiation therapy facility with physics support and considerable technical expertise to deliver precise dosimetry. TSEB can result in short- and long-term cutaneous toxic effects and is not widely available.
    • This therapy can provide excellent palliation, with complete response rates as high as 80%, and may be combined with systemic treatment. Based on the long-term survival of these early-stage patients, electron-beam radiation therapy is sometimes used with curative intent.[14–18] Long-term DFS can be achieved in patients with unilesional mycosis fungoides treated with local radiation therapy.[19]
  2. Local electron-beam radiation or orthovoltage radiation therapy may be used to palliate areas of bulky or symptomatic skin disease.[20,21]

Biological therapy

  1. Interferon alfa or interferon gamma alone or in combination with topical therapy.[22,23][Level of evidence C3]
    • A retrospective review of 198 patients with mycosis fungoides and Sézary syndrome compared the time-to-next-treatment (TTNT) between patients who received interferon alfa and conventional chemotherapy. Interferon alfa provided a longer TTNT of 8.7 months (95% CI, 6.0–18.0) than did chemotherapy, with a TTNT of 3.9 months (95% CI, 3.2–5.1) (P < .00001).[23][Level of evidence C3]

Chemotherapy

Chemotherapeutic agents generally demonstrate short durations of response. In a retrospective review of 198 patients with advanced-stage disease, the median TTNT was 4 months.[23] However, these comparisons may be confounded by the order in which the agents were introduced.

  1. Topical chemotherapy with mechlorethamine.[14,24,25]
    • This form of treatment may be used palliatively or to supplement therapeutic approaches directed against nodal or visceral disease. Topical application of mechlorethamine has produced regression of cutaneous lesions, with particular efficacy in early stages of disease. The overall complete remission rate is related to skin stage; 50% to 80% of TNM classification T1 patients, 25% to 75% of T2 patients, as many as 50% of T3 patients, and 20% to 40% of T4 patients have complete responses. The overall complete remission rate in 243 patients was 64% and was related to stage; as many as 35% of stage IV patients had complete responses. Treatments are usually continued for 2 to 3 years. Continuous 5-year DFS may be possible in as many as 33% of T1 patients.[14,24,25]
  2. Oral methotrexate (NCT00425555).[26]
  3. Pegylated liposomal doxorubicin.[27–29]
  4. Fludarabine, cladribine, and pentostatin are active agents for mycosis fungoides.[30–33]
  5. Single-agent chemotherapy or combination systemic chemotherapy (chlorambucil plus prednisone, mechlorethamine, cyclophosphamide, methotrexate) is often combined with treatment directed at the skin.[4,23,34,35]
  6. Pralatrexate (folate analogue).[23,36,37]

Other drug therapy

  1. Symptomatic management with topical corticosteroids. Low potency steroids can be used on the face with safety and efficacy.[38]
  2. Bexarotene, an oral or topical retinoid (NCT00255801).[39,40]
  3. Lenalidomide.[41]
  4. Vorinostat or romidepsin or other histone deacetylase inhibitors (HDACi).[23,42–44][Level of evidence C3]
    • A retrospective review of 198 patients with mycosis fungoides and Sézary syndrome compared TTNT between HDACi and conventional chemotherapy. HDACi provided a longer TTNT of 4.5 months (95% CI, 4.0–6.1) than did chemotherapy, with a TTNT of 3.9 months (95% CI, 3.2–5.1; P = .01).[23][Level of evidence C3]

Targeted therapy

  1. Brentuximab vedotin.[45,46]
    • Two phase II trials of 58 patients with variable CD30 expression showed a 50% to 70% response rate with 50% of patients still in remission after 1 year.[45,46][Level of evidence C3]

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

References
  1. Kim YH, Jensen RA, Watanabe GL, et al.: Clinical stage IA (limited patch and plaque) mycosis fungoides. A long-term outcome analysis. Arch Dermatol 132 (11): 1309-13, 1996. [PUBMED Abstract]
  2. Zackheim HS, Amin S, Kashani-Sabet M, et al.: Prognosis in cutaneous T-cell lymphoma by skin stage: long-term survival in 489 patients. J Am Acad Dermatol 40 (3): 418-25, 1999. [PUBMED Abstract]
  3. Vollmer RT: A review of survival in mycosis fungoides. Am J Clin Pathol 141 (5): 706-11, 2014. [PUBMED Abstract]
  4. Kaye FJ, Bunn PA, Steinberg SM, et al.: A randomized trial comparing combination electron-beam radiation and chemotherapy with topical therapy in the initial treatment of mycosis fungoides. N Engl J Med 321 (26): 1784-90, 1989. [PUBMED Abstract]
  5. Trautinger F, Knobler R, Willemze R, et al.: EORTC consensus recommendations for the treatment of mycosis fungoides/Sézary syndrome. Eur J Cancer 42 (8): 1014-30, 2006. [PUBMED Abstract]
  6. Herrmann JJ, Roenigk HH, Hurria A, et al.: Treatment of mycosis fungoides with photochemotherapy (PUVA): long-term follow-up. J Am Acad Dermatol 33 (2 Pt 1): 234-42, 1995. [PUBMED Abstract]
  7. Ramsay DL, Lish KM, Yalowitz CB, et al.: Ultraviolet-B phototherapy for early-stage cutaneous T-cell lymphoma. Arch Dermatol 128 (7): 931-3, 1992. [PUBMED Abstract]
  8. Querfeld C, Rosen ST, Kuzel TM, et al.: Long-term follow-up of patients with early-stage cutaneous T-cell lymphoma who achieved complete remission with psoralen plus UV-A monotherapy. Arch Dermatol 141 (3): 305-11, 2005. [PUBMED Abstract]
  9. Kuzel TM, Roenigk HH, Samuelson E, et al.: Effectiveness of interferon alfa-2a combined with phototherapy for mycosis fungoides and the Sézary syndrome. J Clin Oncol 13 (1): 257-63, 1995. [PUBMED Abstract]
  10. Olsen EA, Hodak E, Anderson T, et al.: Guidelines for phototherapy of mycosis fungoides and Sézary syndrome: A consensus statement of the United States Cutaneous Lymphoma Consortium. J Am Acad Dermatol 74 (1): 27-58, 2016. [PUBMED Abstract]
  11. Phan K, Ramachandran V, Fassihi H, et al.: Comparison of Narrowband UV-B With Psoralen-UV-A Phototherapy for Patients With Early-Stage Mycosis Fungoides: A Systematic Review and Meta-analysis. JAMA Dermatol 155 (3): 335-341, 2019. [PUBMED Abstract]
  12. Almohideb M, Walsh S, Walsh S, et al.: Bath Psoralen-ultraviolet A and Narrowband Ultraviolet B Phototherapy as Initial Therapy for Early-stage Mycosis Fungoides: A Retrospective Cohort of 267 Cases at the University of Toronto. Clin Lymphoma Myeloma Leuk 17 (9): 604-612, 2017. [PUBMED Abstract]
  13. Elcin G, Duman N, Karahan S, et al.: Long-term follow-up of early mycosis fungoides patients treated with narrowband ultraviolet B phototherapy. J Dermatolog Treat 25 (3): 268-73, 2014. [PUBMED Abstract]
  14. Chinn DM, Chow S, Kim YH, et al.: Total skin electron beam therapy with or without adjuvant topical nitrogen mustard or nitrogen mustard alone as initial treatment of T2 and T3 mycosis fungoides. Int J Radiat Oncol Biol Phys 43 (5): 951-8, 1999. [PUBMED Abstract]
  15. Quirós PA, Jones GW, Kacinski BM, et al.: Total skin electron beam therapy followed by adjuvant psoralen/ultraviolet-A light in the management of patients with T1 and T2 cutaneous T-cell lymphoma (mycosis fungoides). Int J Radiat Oncol Biol Phys 38 (5): 1027-35, 1997. [PUBMED Abstract]
  16. Ysebaert L, Truc G, Dalac S, et al.: Ultimate results of radiation therapy for T1-T2 mycosis fungoides (including reirradiation). Int J Radiat Oncol Biol Phys 58 (4): 1128-34, 2004. [PUBMED Abstract]
  17. Jones GW, Rosenthal D, Wilson LD: Total skin electron radiation for patients with erythrodermic cutaneous T-cell lymphoma (mycosis fungoides and the Sézary syndrome). Cancer 85 (9): 1985-95, 1999. [PUBMED Abstract]
  18. Navi D, Riaz N, Levin YS, et al.: The Stanford University experience with conventional-dose, total skin electron-beam therapy in the treatment of generalized patch or plaque (T2) and tumor (T3) mycosis fungoides. Arch Dermatol 147 (5): 561-7, 2011. [PUBMED Abstract]
  19. Micaily B, Miyamoto C, Kantor G, et al.: Radiotherapy for unilesional mycosis fungoides. Int J Radiat Oncol Biol Phys 42 (2): 361-4, 1998. [PUBMED Abstract]
  20. Thomas TO, Agrawal P, Guitart J, et al.: Outcome of patients treated with a single-fraction dose of palliative radiation for cutaneous T-cell lymphoma. Int J Radiat Oncol Biol Phys 85 (3): 747-53, 2013. [PUBMED Abstract]
  21. O’Malley JT, de Masson A, Lowry EL, et al.: Radiotherapy Eradicates Malignant T Cells and Is Associated with Improved Survival in Early-Stage Mycosis Fungoides. Clin Cancer Res 26 (2): 408-418, 2020. [PUBMED Abstract]
  22. Olsen EA, Bunn PA: Interferon in the treatment of cutaneous T-cell lymphoma. Hematol Oncol Clin North Am 9 (5): 1089-107, 1995. [PUBMED Abstract]
  23. Hughes CF, Khot A, McCormack C, et al.: Lack of durable disease control with chemotherapy for mycosis fungoides and Sézary syndrome: a comparative study of systemic therapy. Blood 125 (1): 71-81, 2015. [PUBMED Abstract]
  24. Lessin SR, Duvic M, Guitart J, et al.: Topical chemotherapy in cutaneous T-cell lymphoma: positive results of a randomized, controlled, multicenter trial testing the efficacy and safety of a novel mechlorethamine, 0.02%, gel in mycosis fungoides. JAMA Dermatol 149 (1): 25-32, 2013. [PUBMED Abstract]
  25. de Quatrebarbes J, Estève E, Bagot M, et al.: Treatment of early-stage mycosis fungoides with twice-weekly applications of mechlorethamine and topical corticosteroids: a prospective study. Arch Dermatol 141 (9): 1117-20, 2005. [PUBMED Abstract]
  26. Zackheim HS, Kashani-Sabet M, McMillan A: Low-dose methotrexate to treat mycosis fungoides: a retrospective study in 69 patients. J Am Acad Dermatol 49 (5): 873-8, 2003. [PUBMED Abstract]
  27. Wollina U, Dummer R, Brockmeyer NH, et al.: Multicenter study of pegylated liposomal doxorubicin in patients with cutaneous T-cell lymphoma. Cancer 98 (5): 993-1001, 2003. [PUBMED Abstract]
  28. Dummer R, Quaglino P, Becker JC, et al.: Prospective international multicenter phase II trial of intravenous pegylated liposomal doxorubicin monochemotherapy in patients with stage IIB, IVA, or IVB advanced mycosis fungoides: final results from EORTC 21012. J Clin Oncol 30 (33): 4091-7, 2012. [PUBMED Abstract]
  29. Quereux G, Marques S, Nguyen JM, et al.: Prospective multicenter study of pegylated liposomal doxorubicin treatment in patients with advanced or refractory mycosis fungoides or Sézary syndrome. Arch Dermatol 144 (6): 727-33, 2008. [PUBMED Abstract]
  30. Saven A, Carrera CJ, Carson DA, et al.: 2-Chlorodeoxyadenosine: an active agent in the treatment of cutaneous T-cell lymphoma. Blood 80 (3): 587-92, 1992. [PUBMED Abstract]
  31. Foss FM, Ihde DC, Breneman DL, et al.: Phase II study of pentostatin and intermittent high-dose recombinant interferon alfa-2a in advanced mycosis fungoides/Sézary syndrome. J Clin Oncol 10 (12): 1907-13, 1992. [PUBMED Abstract]
  32. Foss FM, Ihde DC, Linnoila IR, et al.: Phase II trial of fludarabine phosphate and interferon alfa-2a in advanced mycosis fungoides/Sézary syndrome. J Clin Oncol 12 (10): 2051-9, 1994. [PUBMED Abstract]
  33. Kurzrock R, Pilat S, Duvic M: Pentostatin therapy of T-cell lymphomas with cutaneous manifestations. J Clin Oncol 17 (10): 3117-21, 1999. [PUBMED Abstract]
  34. Rosen ST, Foss FM: Chemotherapy for mycosis fungoides and the Sézary syndrome. Hematol Oncol Clin North Am 9 (5): 1109-16, 1995. [PUBMED Abstract]
  35. Zackheim HS, Epstein EH: Low-dose methotrexate for the Sézary syndrome. J Am Acad Dermatol 21 (4 Pt 1): 757-62, 1989. [PUBMED Abstract]
  36. Horwitz SM, Kim YH, Foss F, et al.: Identification of an active, well-tolerated dose of pralatrexate in patients with relapsed or refractory cutaneous T-cell lymphoma. Blood 119 (18): 4115-22, 2012. [PUBMED Abstract]
  37. Talpur R, Thompson A, Gangar P, et al.: Pralatrexate alone or in combination with bexarotene: long-term tolerability in relapsed/refractory mycosis fungoides. Clin Lymphoma Myeloma Leuk 14 (4): 297-304, 2014. [PUBMED Abstract]
  38. Duffy R, Jennings T, Kartan S, et al.: Special Considerations in the Treatment of Mycosis Fungoides. Am J Clin Dermatol 20 (4): 571-578, 2019. [PUBMED Abstract]
  39. Duvic M, Hymes K, Heald P, et al.: Bexarotene is effective and safe for treatment of refractory advanced-stage cutaneous T-cell lymphoma: multinational phase II-III trial results. J Clin Oncol 19 (9): 2456-71, 2001. [PUBMED Abstract]
  40. Heald P, Mehlmauer M, Martin AG, et al.: Topical bexarotene therapy for patients with refractory or persistent early-stage cutaneous T-cell lymphoma: results of the phase III clinical trial. J Am Acad Dermatol 49 (5): 801-15, 2003. [PUBMED Abstract]
  41. Querfeld C, Rosen ST, Guitart J, et al.: Results of an open-label multicenter phase 2 trial of lenalidomide monotherapy in refractory mycosis fungoides and Sézary syndrome. Blood 123 (8): 1159-66, 2014. [PUBMED Abstract]
  42. Duvic M, Dummer R, Becker JC, et al.: Panobinostat activity in both bexarotene-exposed and -naïve patients with refractory cutaneous T-cell lymphoma: results of a phase II trial. Eur J Cancer 49 (2): 386-94, 2013. [PUBMED Abstract]
  43. Olsen EA, Kim YH, Kuzel TM, et al.: Phase IIb multicenter trial of vorinostat in patients with persistent, progressive, or treatment refractory cutaneous T-cell lymphoma. J Clin Oncol 25 (21): 3109-15, 2007. [PUBMED Abstract]
  44. Piekarz RL, Frye R, Turner M, et al.: Phase II multi-institutional trial of the histone deacetylase inhibitor romidepsin as monotherapy for patients with cutaneous T-cell lymphoma. J Clin Oncol 27 (32): 5410-7, 2009. [PUBMED Abstract]
  45. Kim YH, Tavallaee M, Sundram U, et al.: Phase II Investigator-Initiated Study of Brentuximab Vedotin in Mycosis Fungoides and Sézary Syndrome With Variable CD30 Expression Level: A Multi-Institution Collaborative Project. J Clin Oncol 33 (32): 3750-8, 2015. [PUBMED Abstract]
  46. Duvic M, Tetzlaff MT, Gangar P, et al.: Results of a Phase II Trial of Brentuximab Vedotin for CD30+ Cutaneous T-Cell Lymphoma and Lymphomatoid Papulosis. J Clin Oncol 33 (32): 3759-65, 2015. [PUBMED Abstract]

Treatment of Stage III and Stage IV Mycosis Fungoides and Sézary Syndrome

Mycosis Fungoides

There is no curative therapy and no clear difference in overall survival (OS) among the treatment options for patients with stage III and stage IV disease.

The use of single alkylating agents has produced objective responses in 60% of patients, with a duration of less than 6 months. One of the alkylating agents (e.g., mechlorethamine, cyclophosphamide, or chlorambucil) or the antimetabolite methotrexate is the most frequently used. Single agents have not cured any patients, and insufficient data exist to determine whether these agents prolong survival. Combination chemotherapy is not definitely superior to single agents. Even in patients with stage IV disease, treatments directed at the skin may provide significant palliation.

A randomized study of 103 patients compared combined total-skin electron-beam radiation (TSEB) plus combination chemotherapy with conservation therapy consisting of sequential topical therapies.[1] In the latter group, combination chemotherapy was reserved for patients with symptomatic extracutaneous disease or disease that was refractory to topical therapies. Patients with any disease stage were eligible. Although the complete response rate was higher with combined therapy, toxic effects were considerably greater, and no difference was seen in disease-free survival (DFS) or OS between the two groups.[1][Level of evidence A1]

Sézary Syndrome

Sézary syndrome is a rare leukemic variant of cutaneous T-cell lymphoma. It is characterized by erythroderma, circulating Sézary cells with cerebriform nuclei, lymphadenopathy, and pruritus.[2] This condition typically progresses rapidly, with only a short duration of response to most therapies. A retrospective review of 176 patients with Sézary syndrome identified the following poor prognostic factors:[3]

  • High lactate dehydrogenase.
  • Previous diagnosis of mycosis fungoides.
  • Presence of T-cell receptor gene rearrangements in skin, blood, or both.

Remissions attained by using extracorporeal photophoresis, interferon alfa, or retinoids may be followed by allogeneic stem cell transplant. In an anecdotal series of 16 patients with Sézary syndrome after allogeneic transplant, 9 were in complete remission after 4 years.[4]

Treatment Options for Stage III and Stage IV Mycosis Fungoides and Sézary Syndrome

Treatment options for stages III and IV mycosis fungoides and Sézary syndrome include the following (note that in this clinical setting, the skin is easily injured; any of the topical therapies must be administered with extreme caution):[2,5]

  1. Photodynamic therapy.
  2. Radiation therapy.
  3. Biological therapy.
  4. Chemotherapy.
  5. Other drug therapy.
  6. Targeted therapy.
  7. Checkpoint inhibitors.

Photodynamic therapy

  1. Psoralen and ultraviolet A (PUVA) radiation therapy.[6–11]
    • Therapeutic trials with PUVA have shown an 80% to 90% complete remission rate in patients, with those in early cutaneous stages achieving the best responses. PUVA may be used in conjunction with systemic treatment.[10] Continued maintenance therapy with PUVA at more protracted intervals is generally required to prolong remission duration.[6–8,10] PUVA combined with interferon alfa-2a is associated with a high response rate.[9,10]
  2. Narrowband ultraviolet B radiation.[12,13]
    • Single-arm and retrospective comparisons confirm the efficacy of narrowband ultraviolet B with 80% to 90% complete remission rates, especially for patients with early cutaneous stages.[12,13]
    • A Cochrane systematic review and meta-analysis compared PUVA with narrowband ultraviolet B radiation in 778 patients with early-stage mycosis fungoides (stage IA, IB, and IIA). Significantly higher complete responses were seen in patients treated with PUVA (73.8% vs. 62.2%; hazard ratio, 1.68; 95% confidence interval [CI], 1.02–2.76; P = .04). There were no significant differences in adverse effects.[11][Level of evidence B3]
  3. Extracorporeal photophoresis (ECP) alone [14–17] or in combination with TSEB.[18] ECP is particularly applicable for Sézary syndrome and erythrodermic mycosis fungoides.[17]
    • In a retrospective analysis of 65 patients, with a median follow-up of 48 months, use of ECP in the first to third line of treatment yielded a longer median time-to-next treatment (TTNT) than other systemic options (P < .03).[17][Level of evidence C3]

Radiation therapy

  1. TSEB.[19–24]
    • Electron-beam radiation therapy of appropriate energies will penetrate only to the dermis, and thus, the skin alone can be treated without systemic effects. This therapy requires a radiation therapy facility with physics support and considerable technical expertise to deliver precise dosimetry. TSEB can result in short- and long-term cutaneous toxic effects and is not widely available.
    • This therapy can provide excellent palliation, with complete response rates as high as 80%, and may be combined with systemic treatment. Based on the long-term survival of these early-stage patients, electron-beam radiation therapy is sometimes used with curative intent.[19–23] Long-term DFS can be achieved in patients with unilesional mycosis fungoides treated with local radiation therapy.[24]
  2. Local electron-beam radiation or orthovoltage radiation therapy may be used to palliate areas of bulky or symptomatic disease.[25,26]

Biological therapy

  1. Interferon alfa alone or in combination with other agents, such as topical therapy.[27,28]
    • A retrospective review of 198 patients with mycosis fungoides and Sézary syndrome compared the TTNT between patients who received interferon alfa and conventional chemotherapy. Interferon alfa provided a longer TTNT of 8.7 months (95% CI, 6.0–18.0) than did chemotherapy, with a TTNT of 3.9 months (95% CI, 3.2–5.1) (P < .00001).[29][Level of evidence C3]

Chemotherapy

Chemotherapeutic agents generally demonstrate short durations of response. In a retrospective review of 198 patients with advanced-stage disease, the median TTNT was 4 months.[29] However, these comparisons may be confounded by the order in which the agents were introduced.

  1. Oral methotrexate (NCT00425555).[30]
  2. Fludarabine, cladribine, and pentostatin are active agents for mycosis fungoides and Sézary syndrome.[27,29,31–33]
  3. Single-agent chemotherapy or combination systemic chemotherapy (chlorambucil plus prednisone, mechlorethamine, cyclophosphamide, methotrexate) often combined with treatment directed at the skin.[1,29,34,35]
  4. Topical chemotherapy with mechlorethamine.[36,37]
    • This form of treatment may be used palliatively or to supplement therapeutic approaches directed against nodal or visceral disease. Topical application of mechlorethamine has produced regression of cutaneous lesions, with particular efficacy in early stages of disease. The overall complete remission rate is related to skin stage; 50% to 80% of TNM classification T1 patients, 25% to 75% of T2 patients, as many as 50% of T3 patients, and 20% to 40% of T4 patients have complete responses. The overall complete remission rate in 243 patients was 64% and was related to stage; as many as 35% of stage IV patients had complete responses. Treatments are usually continued for 2 to 3 years. Continuous 5-year DFS may be possible in as many as 33% of T1 patients.[19,36,37]
  5. Pegylated liposomal doxorubicin.[38–40]
  6. Pralatrexate (folate analogue).[29,41,42]

Other drug therapy

  1. Symptomatic management with topical corticosteroids. Low potency steroids can be used on the face with safety and efficacy.[43]
  2. Lenalidomide.[44]
  3. Bexarotene, an oral or topical retinoid.[45,46]
  4. Vorinostat or romidepsin or other histone deacetylase inhibitors (HDACi).[2,47–49]
    • A retrospective review of 198 patients with mycosis fungoides and Sézary syndrome compared TTNT between HDACi and conventional chemotherapy. HDACi provided a longer TTNT of 4.5 months (95% CI, 4.0–6.1) than did chemotherapy, with a TTNT of 3.9 months (95% CI, 3.2–5.1; P = .01).[29][Level of evidence C3]

Targeted therapy

  1. Brentuximab vedotin.[50,51]
    • Two phase II trials of 58 patients with variable CD30 expression showed a 50% to 70% response rate with 50% of patients still in remission after 1 year.[50,51][Level of evidence C3]

Checkpoint inhibitors

  1. Pembrolizumab.[52]
    • Anecdotal responses have been seen in patients with advanced relapsed or refractory mycosis fungoides. In a single-arm, multicenter, phase II trial of 24 patients treated with pembrolizumab, the overall response rate was 38%.[52][Level of evidence C3]
    • There are anecdotal reports of hyperprogression of T-cell malignancies following treatment with immune checkpoint inhibitors.[53,54]

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

References
  1. Kaye FJ, Bunn PA, Steinberg SM, et al.: A randomized trial comparing combination electron-beam radiation and chemotherapy with topical therapy in the initial treatment of mycosis fungoides. N Engl J Med 321 (26): 1784-90, 1989. [PUBMED Abstract]
  2. Olsen EA, Rook AH, Zic J, et al.: Sézary syndrome: immunopathogenesis, literature review of therapeutic options, and recommendations for therapy by the United States Cutaneous Lymphoma Consortium (USCLC). J Am Acad Dermatol 64 (2): 352-404, 2011. [PUBMED Abstract]
  3. Kubica AW, Davis MD, Weaver AL, et al.: Sézary syndrome: a study of 176 patients at Mayo Clinic. J Am Acad Dermatol 67 (6): 1189-99, 2012. [PUBMED Abstract]
  4. Polansky M, Talpur R, Daulat S, et al.: Long-Term Complete Responses to Combination Therapies and Allogeneic Stem Cell Transplants in Patients With Sézary Syndrome. Clin Lymphoma Myeloma Leuk 15 (5): e83-93, 2015. [PUBMED Abstract]
  5. Trautinger F, Knobler R, Willemze R, et al.: EORTC consensus recommendations for the treatment of mycosis fungoides/Sézary syndrome. Eur J Cancer 42 (8): 1014-30, 2006. [PUBMED Abstract]
  6. Herrmann JJ, Roenigk HH, Hurria A, et al.: Treatment of mycosis fungoides with photochemotherapy (PUVA): long-term follow-up. J Am Acad Dermatol 33 (2 Pt 1): 234-42, 1995. [PUBMED Abstract]
  7. Ramsay DL, Lish KM, Yalowitz CB, et al.: Ultraviolet-B phototherapy for early-stage cutaneous T-cell lymphoma. Arch Dermatol 128 (7): 931-3, 1992. [PUBMED Abstract]
  8. Querfeld C, Rosen ST, Kuzel TM, et al.: Long-term follow-up of patients with early-stage cutaneous T-cell lymphoma who achieved complete remission with psoralen plus UV-A monotherapy. Arch Dermatol 141 (3): 305-11, 2005. [PUBMED Abstract]
  9. Kuzel TM, Roenigk HH, Samuelson E, et al.: Effectiveness of interferon alfa-2a combined with phototherapy for mycosis fungoides and the Sézary syndrome. J Clin Oncol 13 (1): 257-63, 1995. [PUBMED Abstract]
  10. Olsen EA, Hodak E, Anderson T, et al.: Guidelines for phototherapy of mycosis fungoides and Sézary syndrome: A consensus statement of the United States Cutaneous Lymphoma Consortium. J Am Acad Dermatol 74 (1): 27-58, 2016. [PUBMED Abstract]
  11. Phan K, Ramachandran V, Fassihi H, et al.: Comparison of Narrowband UV-B With Psoralen-UV-A Phototherapy for Patients With Early-Stage Mycosis Fungoides: A Systematic Review and Meta-analysis. JAMA Dermatol 155 (3): 335-341, 2019. [PUBMED Abstract]
  12. Almohideb M, Walsh S, Walsh S, et al.: Bath Psoralen-ultraviolet A and Narrowband Ultraviolet B Phototherapy as Initial Therapy for Early-stage Mycosis Fungoides: A Retrospective Cohort of 267 Cases at the University of Toronto. Clin Lymphoma Myeloma Leuk 17 (9): 604-612, 2017. [PUBMED Abstract]
  13. Elcin G, Duman N, Karahan S, et al.: Long-term follow-up of early mycosis fungoides patients treated with narrowband ultraviolet B phototherapy. J Dermatolog Treat 25 (3): 268-73, 2014. [PUBMED Abstract]
  14. Edelson R, Berger C, Gasparro F, et al.: Treatment of cutaneous T-cell lymphoma by extracorporeal photochemotherapy. Preliminary results. N Engl J Med 316 (6): 297-303, 1987. [PUBMED Abstract]
  15. Heald PW, Perez MI, McKiernan G, et al.: Extracorporeal photochemotherapy for CTCL. Prog Clin Biol Res 337: 443-7, 1990. [PUBMED Abstract]
  16. Scarisbrick JJ, Taylor P, Holtick U, et al.: U.K. consensus statement on the use of extracorporeal photopheresis for treatment of cutaneous T-cell lymphoma and chronic graft-versus-host disease. Br J Dermatol 158 (4): 659-78, 2008. [PUBMED Abstract]
  17. Gao C, McCormack C, van der Weyden C, et al.: Prolonged survival with the early use of a novel extracorporeal photopheresis regimen in patients with Sézary syndrome. Blood 134 (16): 1346-1350, 2019. [PUBMED Abstract]
  18. Palareti G, Maccaferri M, Manotti C, et al.: Fibrinogen assays: a collaborative study of six different methods. C.I.S.M.E.L. Comitato Italiano per la Standardizzazione dei Metodi in Ematologia e Laboratorio. Clin Chem 37 (5): 714-9, 1991. [PUBMED Abstract]
  19. Chinn DM, Chow S, Kim YH, et al.: Total skin electron beam therapy with or without adjuvant topical nitrogen mustard or nitrogen mustard alone as initial treatment of T2 and T3 mycosis fungoides. Int J Radiat Oncol Biol Phys 43 (5): 951-8, 1999. [PUBMED Abstract]
  20. Quirós PA, Jones GW, Kacinski BM, et al.: Total skin electron beam therapy followed by adjuvant psoralen/ultraviolet-A light in the management of patients with T1 and T2 cutaneous T-cell lymphoma (mycosis fungoides). Int J Radiat Oncol Biol Phys 38 (5): 1027-35, 1997. [PUBMED Abstract]
  21. Ysebaert L, Truc G, Dalac S, et al.: Ultimate results of radiation therapy for T1-T2 mycosis fungoides (including reirradiation). Int J Radiat Oncol Biol Phys 58 (4): 1128-34, 2004. [PUBMED Abstract]
  22. Jones GW, Rosenthal D, Wilson LD: Total skin electron radiation for patients with erythrodermic cutaneous T-cell lymphoma (mycosis fungoides and the Sézary syndrome). Cancer 85 (9): 1985-95, 1999. [PUBMED Abstract]
  23. Navi D, Riaz N, Levin YS, et al.: The Stanford University experience with conventional-dose, total skin electron-beam therapy in the treatment of generalized patch or plaque (T2) and tumor (T3) mycosis fungoides. Arch Dermatol 147 (5): 561-7, 2011. [PUBMED Abstract]
  24. Micaily B, Miyamoto C, Kantor G, et al.: Radiotherapy for unilesional mycosis fungoides. Int J Radiat Oncol Biol Phys 42 (2): 361-4, 1998. [PUBMED Abstract]
  25. Thomas TO, Agrawal P, Guitart J, et al.: Outcome of patients treated with a single-fraction dose of palliative radiation for cutaneous T-cell lymphoma. Int J Radiat Oncol Biol Phys 85 (3): 747-53, 2013. [PUBMED Abstract]
  26. O’Malley JT, de Masson A, Lowry EL, et al.: Radiotherapy Eradicates Malignant T Cells and Is Associated with Improved Survival in Early-Stage Mycosis Fungoides. Clin Cancer Res 26 (2): 408-418, 2020. [PUBMED Abstract]
  27. Foss FM, Ihde DC, Breneman DL, et al.: Phase II study of pentostatin and intermittent high-dose recombinant interferon alfa-2a in advanced mycosis fungoides/Sézary syndrome. J Clin Oncol 10 (12): 1907-13, 1992. [PUBMED Abstract]
  28. Olsen EA, Bunn PA: Interferon in the treatment of cutaneous T-cell lymphoma. Hematol Oncol Clin North Am 9 (5): 1089-107, 1995. [PUBMED Abstract]
  29. Hughes CF, Khot A, McCormack C, et al.: Lack of durable disease control with chemotherapy for mycosis fungoides and Sézary syndrome: a comparative study of systemic therapy. Blood 125 (1): 71-81, 2015. [PUBMED Abstract]
  30. Zackheim HS, Kashani-Sabet M, McMillan A: Low-dose methotrexate to treat mycosis fungoides: a retrospective study in 69 patients. J Am Acad Dermatol 49 (5): 873-8, 2003. [PUBMED Abstract]
  31. Saven A, Carrera CJ, Carson DA, et al.: 2-Chlorodeoxyadenosine: an active agent in the treatment of cutaneous T-cell lymphoma. Blood 80 (3): 587-92, 1992. [PUBMED Abstract]
  32. Foss FM, Ihde DC, Linnoila IR, et al.: Phase II trial of fludarabine phosphate and interferon alfa-2a in advanced mycosis fungoides/Sézary syndrome. J Clin Oncol 12 (10): 2051-9, 1994. [PUBMED Abstract]
  33. Kurzrock R, Pilat S, Duvic M: Pentostatin therapy of T-cell lymphomas with cutaneous manifestations. J Clin Oncol 17 (10): 3117-21, 1999. [PUBMED Abstract]
  34. Rosen ST, Foss FM: Chemotherapy for mycosis fungoides and the Sézary syndrome. Hematol Oncol Clin North Am 9 (5): 1109-16, 1995. [PUBMED Abstract]
  35. Zackheim HS, Epstein EH: Low-dose methotrexate for the Sézary syndrome. J Am Acad Dermatol 21 (4 Pt 1): 757-62, 1989. [PUBMED Abstract]
  36. Lessin SR, Duvic M, Guitart J, et al.: Topical chemotherapy in cutaneous T-cell lymphoma: positive results of a randomized, controlled, multicenter trial testing the efficacy and safety of a novel mechlorethamine, 0.02%, gel in mycosis fungoides. JAMA Dermatol 149 (1): 25-32, 2013. [PUBMED Abstract]
  37. de Quatrebarbes J, Estève E, Bagot M, et al.: Treatment of early-stage mycosis fungoides with twice-weekly applications of mechlorethamine and topical corticosteroids: a prospective study. Arch Dermatol 141 (9): 1117-20, 2005. [PUBMED Abstract]
  38. Dummer R, Quaglino P, Becker JC, et al.: Prospective international multicenter phase II trial of intravenous pegylated liposomal doxorubicin monochemotherapy in patients with stage IIB, IVA, or IVB advanced mycosis fungoides: final results from EORTC 21012. J Clin Oncol 30 (33): 4091-7, 2012. [PUBMED Abstract]
  39. Wollina U, Dummer R, Brockmeyer NH, et al.: Multicenter study of pegylated liposomal doxorubicin in patients with cutaneous T-cell lymphoma. Cancer 98 (5): 993-1001, 2003. [PUBMED Abstract]
  40. Quereux G, Marques S, Nguyen JM, et al.: Prospective multicenter study of pegylated liposomal doxorubicin treatment in patients with advanced or refractory mycosis fungoides or Sézary syndrome. Arch Dermatol 144 (6): 727-33, 2008. [PUBMED Abstract]
  41. Horwitz SM, Kim YH, Foss F, et al.: Identification of an active, well-tolerated dose of pralatrexate in patients with relapsed or refractory cutaneous T-cell lymphoma. Blood 119 (18): 4115-22, 2012. [PUBMED Abstract]
  42. Talpur R, Thompson A, Gangar P, et al.: Pralatrexate alone or in combination with bexarotene: long-term tolerability in relapsed/refractory mycosis fungoides. Clin Lymphoma Myeloma Leuk 14 (4): 297-304, 2014. [PUBMED Abstract]
  43. Duffy R, Jennings T, Kartan S, et al.: Special Considerations in the Treatment of Mycosis Fungoides. Am J Clin Dermatol 20 (4): 571-578, 2019. [PUBMED Abstract]
  44. Querfeld C, Rosen ST, Guitart J, et al.: Results of an open-label multicenter phase 2 trial of lenalidomide monotherapy in refractory mycosis fungoides and Sézary syndrome. Blood 123 (8): 1159-66, 2014. [PUBMED Abstract]
  45. Duvic M, Hymes K, Heald P, et al.: Bexarotene is effective and safe for treatment of refractory advanced-stage cutaneous T-cell lymphoma: multinational phase II-III trial results. J Clin Oncol 19 (9): 2456-71, 2001. [PUBMED Abstract]
  46. Heald P, Mehlmauer M, Martin AG, et al.: Topical bexarotene therapy for patients with refractory or persistent early-stage cutaneous T-cell lymphoma: results of the phase III clinical trial. J Am Acad Dermatol 49 (5): 801-15, 2003. [PUBMED Abstract]
  47. Duvic M, Dummer R, Becker JC, et al.: Panobinostat activity in both bexarotene-exposed and -naïve patients with refractory cutaneous T-cell lymphoma: results of a phase II trial. Eur J Cancer 49 (2): 386-94, 2013. [PUBMED Abstract]
  48. Olsen EA, Kim YH, Kuzel TM, et al.: Phase IIb multicenter trial of vorinostat in patients with persistent, progressive, or treatment refractory cutaneous T-cell lymphoma. J Clin Oncol 25 (21): 3109-15, 2007. [PUBMED Abstract]
  49. Piekarz RL, Frye R, Turner M, et al.: Phase II multi-institutional trial of the histone deacetylase inhibitor romidepsin as monotherapy for patients with cutaneous T-cell lymphoma. J Clin Oncol 27 (32): 5410-7, 2009. [PUBMED Abstract]
  50. Kim YH, Tavallaee M, Sundram U, et al.: Phase II Investigator-Initiated Study of Brentuximab Vedotin in Mycosis Fungoides and Sézary Syndrome With Variable CD30 Expression Level: A Multi-Institution Collaborative Project. J Clin Oncol 33 (32): 3750-8, 2015. [PUBMED Abstract]
  51. Duvic M, Tetzlaff MT, Gangar P, et al.: Results of a Phase II Trial of Brentuximab Vedotin for CD30+ Cutaneous T-Cell Lymphoma and Lymphomatoid Papulosis. J Clin Oncol 33 (32): 3759-65, 2015. [PUBMED Abstract]
  52. Khodadoust MS, Rook AH, Porcu P, et al.: Pembrolizumab in Relapsed and Refractory Mycosis Fungoides and Sézary Syndrome: A Multicenter Phase II Study. J Clin Oncol 38 (1): 20-28, 2020. [PUBMED Abstract]
  53. Ratner L, Waldmann TA, Janakiram M, et al.: Rapid Progression of Adult T-Cell Leukemia-Lymphoma after PD-1 Inhibitor Therapy. N Engl J Med 378 (20): 1947-1948, 2018. [PUBMED Abstract]
  54. Bennani NN, Kim HJ, Pederson LD, et al.: Nivolumab in patients with relapsed or refractory peripheral T-cell lymphoma: modest activity and cases of hyperprogression. J Immunother Cancer 10 (6): , 2022. [PUBMED Abstract]

Treatment of Recurrent Mycosis Fungoides and Sézary Syndrome

The treatment of patients with relapsed mycosis fungoides and Sézary syndrome involves the joint decisions of a dermatologist, medical oncologist, and radiation oncologist. It may be possible to re-treat localized areas of relapse in the skin with additional electron-beam radiation therapy or to repeat total-skin electron-beam radiation therapy (TSEB).[1] Photon radiation to bulky skin or nodal masses may prove beneficial. If these options are not possible, then continued topical treatment with other modalities, such as mechlorethamine or psoralen and ultraviolet A radiation (PUVA) may be warranted to relieve cutaneous symptoms.

Patients should consider clinical trials as a therapeutic option.

Treatment Options for Recurrent Mycosis Fungoides and Sézary Syndrome

Treatment options under clinical evaluation for recurrent mycosis fungoides and Sézary syndrome include the following:[2,3]

  1. Radiation therapy.
  2. Photodynamic therapy.
  3. Chemotherapy.
  4. Other drug therapy.
  5. Biological therapy.
  6. Allogeneic stem cell transplant.
  7. Targeted therapy.

Radiation therapy

  1. Additional electron-beam radiation therapy or a repeat of TSEB.
    • Electron-beam radiation therapy of appropriate energies will penetrate only to the dermis, and thus, the skin alone can be treated without systemic effects. This therapy requires a radiation therapy facility with physics support and considerable technical expertise to deliver precise dosimetry. TSEB can result in short- and long-term cutaneous toxic effects and is not widely available.
    • This therapy can provide excellent palliation, with complete response rates as high as 80%, and may be combined with systemic treatment. Based on the long-term survival of these early-stage patients, electron-beam radiation therapy is sometimes used with curative intent.[4–8] Long-term disease-free survival (DFS) can be achieved in patients with unilesional mycosis fungoides treated with local radiation therapy.[9]
  2. Photon radiation to bulky skin or nodal masses.[10]

Photodynamic therapy

  1. PUVA radiation therapy.[11–16]
    • Therapeutic trials with PUVA have shown an 80% to 90% complete remission rate in patients, with those in early cutaneous stages achieving the best responses. PUVA may be used in conjunction with systemic treatment.[15] Continued maintenance therapy with PUVA at more protracted intervals is generally required to prolong remission duration.[11–13,15] PUVA combined with interferon alfa-2a is associated with a high response rate.[14,15]
  2. Narrowband ultraviolet B radiation.[17,18]
    • Single-arm and retrospective comparisons confirm the efficacy of narrowband ultraviolet B with 80% to 90% complete remission rates, especially for patients with early cutaneous stages.[17,18]
    • A Cochrane systematic review and meta-analysis compared PUVA with narrowband ultraviolet B radiation in 778 patients with early-stage mycosis fungoides (stage IA, IB, and IIA). Significantly higher complete response rates were seen in patients treated with PUVA (73.8% vs. 62.2%; hazard ratio [HR], 1.68; 95% confidence interval [CI], 1.02–2.76; P = .04). There were no significant differences in adverse effects.[16][Level of evidence B3]
  3. Extracorporeal photophoresis (ECP) has produced tumor regression in patients who are resistant to other therapies.[19,20]
    • In a retrospective analysis of 65 patients, with a median follow-up of 48 months, use of ECP in the first to third line of treatment yielded a longer median time-to-next treatment (TTNT) than other systemic options (P < .03).[21][Level of evidence C3]

Chemotherapy

  1. Topical treatment with mechlorethamine or PUVA.
    • This form of treatment may be used palliatively or to supplement therapeutic approaches directed against nodal or visceral disease. Topical application of mechlorethamine has produced regression of cutaneous lesions, with particular efficacy in early stages of disease. The overall complete remission rate is related to skin stage; 50% to 80% of TNM classification T1 patients, 25% to 75% of T2 patients, as many as 50% of T3 patients, and 20% to 40% of T4 patients have complete responses. The overall complete remission rate in 243 patients was 64% and was related to stage; as many as 35% of stage IV patients had complete responses. Treatments are usually continued for 2 to 3 years. Continuous 5-year DFS may be possible in as many as 33% of T1 patients.[4,22,23]
  2. Pralatrexate (folate analogue).[24,25]
    • Chemotherapeutic agents generally yield short durations of response. In a retrospective review of 198 patients with advanced-stage disease, the median TTNT was 4 months.[26]
  3. Pegylated liposomal doxorubicin.[27–29]
  4. Systemic chemotherapy: chlorambucil plus prednisone, mechlorethamine, cyclophosphamide, methotrexate, and combination chemotherapy.[26,30–32]

Other drug therapy

  1. Symptomatic management with topical corticosteroids.
  2. Bexarotene, an oral or topical retinoid.[33,34]
  3. Lenalidomide.[35]
  4. Vorinostat or romidepsin or other histone deacetylase inhibitors (HDACi).[36–38]
    • A retrospective review of 198 patients with mycosis fungoides and Sézary syndrome compared the TTNT between HDACi and conventional chemotherapy. HDACi provided a longer TTNT of 4.5 months (95% CI, 4.0–6.1) than did chemotherapy, with a TTNT of 3.9 months (95% CI, 3.2–5.1; P = .01).[26][Level of evidence C3]

Biological therapy

  1. Interferon alfa alone or in combination with other agents, such as topical therapy.[39,40]
    • A retrospective review of 198 patients with mycosis fungoides and Sézary syndrome compared the TTNT between patients who received interferon alfa and conventional chemotherapy. Interferon alfa provided a longer TTNT of 8.7 months (95% CI, 6.0–18.0) than did chemotherapy, with a TTNT of 3.9 months (95% CI, 3.2–5.1) (P < .00001).[26][Level of evidence C3]

Allogeneic stem cell transplant

  1. Allogeneic stem cell transplant (SCT).[41–43,43–45]
    • Among highly selected patients, the 5-year overall survival (OS) rate ranges from 30% to 50%, with a relapse-free survival rate of 15% to 25%.[41–45]

Targeted therapy

  1. Brentuximab vedotin.[46,47]
    • Two phase II trials of 58 patients with variable CD30 expression showed a 50% to 70% response rate with 50% of patients still in remission after 1 year.[46,47][Level of evidence C3]
  2. Mogamulizumab.[48]
    1. In a prospective randomized trial, 372 previously treated patients received either mogamulizumab, a monoclonal antibody directed against C-C chemokine receptor 4, or the HDACi vorinostat.
      • With a median follow-up of 17 months, the median progression-free survival was 7.7 months for patients who received mogamulizumab and 3.1 months for patients who received vorinostat (HR, 0.53; 95% CI, 0.41−0.69; P < .0001).[48][Level of evidence B1]
      • Mogamulizumab appeared to be especially effective in patients with blood involvement, such as those with Sézary syndrome.
      • This preliminary study was not designed to detect differences in OS.

    Mogamulizumab is often avoided in patients scheduled to undergo allogeneic SCT, based on data from a Japanese study that showed an increased risk of severe graft-versus-host disease (GVHD) in patients treated with mogamulizumab beforehand.[49] The relevance of these findings in other countries and the impact of different GVHD prophylaxis regimens in these patients remains to be determined.

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

References
  1. Becker M, Hoppe RT, Knox SJ: Multiple courses of high-dose total skin electron beam therapy in the management of mycosis fungoides. Int J Radiat Oncol Biol Phys 32 (5): 1445-9, 1995. [PUBMED Abstract]
  2. Trautinger F, Knobler R, Willemze R, et al.: EORTC consensus recommendations for the treatment of mycosis fungoides/Sézary syndrome. Eur J Cancer 42 (8): 1014-30, 2006. [PUBMED Abstract]
  3. Prince HM, Duvic M, Martin A, et al.: Phase III placebo-controlled trial of denileukin diftitox for patients with cutaneous T-cell lymphoma. J Clin Oncol 28 (11): 1870-7, 2010. [PUBMED Abstract]
  4. Chinn DM, Chow S, Kim YH, et al.: Total skin electron beam therapy with or without adjuvant topical nitrogen mustard or nitrogen mustard alone as initial treatment of T2 and T3 mycosis fungoides. Int J Radiat Oncol Biol Phys 43 (5): 951-8, 1999. [PUBMED Abstract]
  5. Quirós PA, Jones GW, Kacinski BM, et al.: Total skin electron beam therapy followed by adjuvant psoralen/ultraviolet-A light in the management of patients with T1 and T2 cutaneous T-cell lymphoma (mycosis fungoides). Int J Radiat Oncol Biol Phys 38 (5): 1027-35, 1997. [PUBMED Abstract]
  6. Ysebaert L, Truc G, Dalac S, et al.: Ultimate results of radiation therapy for T1-T2 mycosis fungoides (including reirradiation). Int J Radiat Oncol Biol Phys 58 (4): 1128-34, 2004. [PUBMED Abstract]
  7. Jones GW, Rosenthal D, Wilson LD: Total skin electron radiation for patients with erythrodermic cutaneous T-cell lymphoma (mycosis fungoides and the Sézary syndrome). Cancer 85 (9): 1985-95, 1999. [PUBMED Abstract]
  8. Navi D, Riaz N, Levin YS, et al.: The Stanford University experience with conventional-dose, total skin electron-beam therapy in the treatment of generalized patch or plaque (T2) and tumor (T3) mycosis fungoides. Arch Dermatol 147 (5): 561-7, 2011. [PUBMED Abstract]
  9. Micaily B, Miyamoto C, Kantor G, et al.: Radiotherapy for unilesional mycosis fungoides. Int J Radiat Oncol Biol Phys 42 (2): 361-4, 1998. [PUBMED Abstract]
  10. Thomas TO, Agrawal P, Guitart J, et al.: Outcome of patients treated with a single-fraction dose of palliative radiation for cutaneous T-cell lymphoma. Int J Radiat Oncol Biol Phys 85 (3): 747-53, 2013. [PUBMED Abstract]
  11. Herrmann JJ, Roenigk HH, Hurria A, et al.: Treatment of mycosis fungoides with photochemotherapy (PUVA): long-term follow-up. J Am Acad Dermatol 33 (2 Pt 1): 234-42, 1995. [PUBMED Abstract]
  12. Ramsay DL, Lish KM, Yalowitz CB, et al.: Ultraviolet-B phototherapy for early-stage cutaneous T-cell lymphoma. Arch Dermatol 128 (7): 931-3, 1992. [PUBMED Abstract]
  13. Querfeld C, Rosen ST, Kuzel TM, et al.: Long-term follow-up of patients with early-stage cutaneous T-cell lymphoma who achieved complete remission with psoralen plus UV-A monotherapy. Arch Dermatol 141 (3): 305-11, 2005. [PUBMED Abstract]
  14. Kuzel TM, Roenigk HH, Samuelson E, et al.: Effectiveness of interferon alfa-2a combined with phototherapy for mycosis fungoides and the Sézary syndrome. J Clin Oncol 13 (1): 257-63, 1995. [PUBMED Abstract]
  15. Olsen EA, Hodak E, Anderson T, et al.: Guidelines for phototherapy of mycosis fungoides and Sézary syndrome: A consensus statement of the United States Cutaneous Lymphoma Consortium. J Am Acad Dermatol 74 (1): 27-58, 2016. [PUBMED Abstract]
  16. Phan K, Ramachandran V, Fassihi H, et al.: Comparison of Narrowband UV-B With Psoralen-UV-A Phototherapy for Patients With Early-Stage Mycosis Fungoides: A Systematic Review and Meta-analysis. JAMA Dermatol 155 (3): 335-341, 2019. [PUBMED Abstract]
  17. Almohideb M, Walsh S, Walsh S, et al.: Bath Psoralen-ultraviolet A and Narrowband Ultraviolet B Phototherapy as Initial Therapy for Early-stage Mycosis Fungoides: A Retrospective Cohort of 267 Cases at the University of Toronto. Clin Lymphoma Myeloma Leuk 17 (9): 604-612, 2017. [PUBMED Abstract]
  18. Elcin G, Duman N, Karahan S, et al.: Long-term follow-up of early mycosis fungoides patients treated with narrowband ultraviolet B phototherapy. J Dermatolog Treat 25 (3): 268-73, 2014. [PUBMED Abstract]
  19. Edelson R, Berger C, Gasparro F, et al.: Treatment of cutaneous T-cell lymphoma by extracorporeal photochemotherapy. Preliminary results. N Engl J Med 316 (6): 297-303, 1987. [PUBMED Abstract]
  20. Heald PW, Perez MI, McKiernan G, et al.: Extracorporeal photochemotherapy for CTCL. Prog Clin Biol Res 337: 443-7, 1990. [PUBMED Abstract]
  21. Gao C, McCormack C, van der Weyden C, et al.: Prolonged survival with the early use of a novel extracorporeal photopheresis regimen in patients with Sézary syndrome. Blood 134 (16): 1346-1350, 2019. [PUBMED Abstract]
  22. Lessin SR, Duvic M, Guitart J, et al.: Topical chemotherapy in cutaneous T-cell lymphoma: positive results of a randomized, controlled, multicenter trial testing the efficacy and safety of a novel mechlorethamine, 0.02%, gel in mycosis fungoides. JAMA Dermatol 149 (1): 25-32, 2013. [PUBMED Abstract]
  23. de Quatrebarbes J, Estève E, Bagot M, et al.: Treatment of early-stage mycosis fungoides with twice-weekly applications of mechlorethamine and topical corticosteroids: a prospective study. Arch Dermatol 141 (9): 1117-20, 2005. [PUBMED Abstract]
  24. Horwitz SM, Kim YH, Foss F, et al.: Identification of an active, well-tolerated dose of pralatrexate in patients with relapsed or refractory cutaneous T-cell lymphoma. Blood 119 (18): 4115-22, 2012. [PUBMED Abstract]
  25. Talpur R, Thompson A, Gangar P, et al.: Pralatrexate alone or in combination with bexarotene: long-term tolerability in relapsed/refractory mycosis fungoides. Clin Lymphoma Myeloma Leuk 14 (4): 297-304, 2014. [PUBMED Abstract]
  26. Hughes CF, Khot A, McCormack C, et al.: Lack of durable disease control with chemotherapy for mycosis fungoides and Sézary syndrome: a comparative study of systemic therapy. Blood 125 (1): 71-81, 2015. [PUBMED Abstract]
  27. Dummer R, Quaglino P, Becker JC, et al.: Prospective international multicenter phase II trial of intravenous pegylated liposomal doxorubicin monochemotherapy in patients with stage IIB, IVA, or IVB advanced mycosis fungoides: final results from EORTC 21012. J Clin Oncol 30 (33): 4091-7, 2012. [PUBMED Abstract]
  28. Wollina U, Dummer R, Brockmeyer NH, et al.: Multicenter study of pegylated liposomal doxorubicin in patients with cutaneous T-cell lymphoma. Cancer 98 (5): 993-1001, 2003. [PUBMED Abstract]
  29. Quereux G, Marques S, Nguyen JM, et al.: Prospective multicenter study of pegylated liposomal doxorubicin treatment in patients with advanced or refractory mycosis fungoides or Sézary syndrome. Arch Dermatol 144 (6): 727-33, 2008. [PUBMED Abstract]
  30. Kaye FJ, Bunn PA, Steinberg SM, et al.: A randomized trial comparing combination electron-beam radiation and chemotherapy with topical therapy in the initial treatment of mycosis fungoides. N Engl J Med 321 (26): 1784-90, 1989. [PUBMED Abstract]
  31. Rosen ST, Foss FM: Chemotherapy for mycosis fungoides and the Sézary syndrome. Hematol Oncol Clin North Am 9 (5): 1109-16, 1995. [PUBMED Abstract]
  32. Zackheim HS, Epstein EH: Low-dose methotrexate for the Sézary syndrome. J Am Acad Dermatol 21 (4 Pt 1): 757-62, 1989. [PUBMED Abstract]
  33. Miller VA, Benedetti FM, Rigas JR, et al.: Initial clinical trial of a selective retinoid X receptor ligand, LGD1069. J Clin Oncol 15 (2): 790-5, 1997. [PUBMED Abstract]
  34. Duvic M, Hymes K, Heald P, et al.: Bexarotene is effective and safe for treatment of refractory advanced-stage cutaneous T-cell lymphoma: multinational phase II-III trial results. J Clin Oncol 19 (9): 2456-71, 2001. [PUBMED Abstract]
  35. Querfeld C, Rosen ST, Guitart J, et al.: Results of an open-label multicenter phase 2 trial of lenalidomide monotherapy in refractory mycosis fungoides and Sézary syndrome. Blood 123 (8): 1159-66, 2014. [PUBMED Abstract]
  36. Duvic M, Dummer R, Becker JC, et al.: Panobinostat activity in both bexarotene-exposed and -naïve patients with refractory cutaneous T-cell lymphoma: results of a phase II trial. Eur J Cancer 49 (2): 386-94, 2013. [PUBMED Abstract]
  37. Olsen EA, Kim YH, Kuzel TM, et al.: Phase IIb multicenter trial of vorinostat in patients with persistent, progressive, or treatment refractory cutaneous T-cell lymphoma. J Clin Oncol 25 (21): 3109-15, 2007. [PUBMED Abstract]
  38. Piekarz RL, Frye R, Turner M, et al.: Phase II multi-institutional trial of the histone deacetylase inhibitor romidepsin as monotherapy for patients with cutaneous T-cell lymphoma. J Clin Oncol 27 (32): 5410-7, 2009. [PUBMED Abstract]
  39. Foss FM, Ihde DC, Breneman DL, et al.: Phase II study of pentostatin and intermittent high-dose recombinant interferon alfa-2a in advanced mycosis fungoides/Sézary syndrome. J Clin Oncol 10 (12): 1907-13, 1992. [PUBMED Abstract]
  40. Olsen EA, Bunn PA: Interferon in the treatment of cutaneous T-cell lymphoma. Hematol Oncol Clin North Am 9 (5): 1089-107, 1995. [PUBMED Abstract]
  41. Molina A, Zain J, Arber DA, et al.: Durable clinical, cytogenetic, and molecular remissions after allogeneic hematopoietic cell transplantation for refractory Sezary syndrome and mycosis fungoides. J Clin Oncol 23 (25): 6163-71, 2005. [PUBMED Abstract]
  42. Duvic M, Donato M, Dabaja B, et al.: Total skin electron beam and non-myeloablative allogeneic hematopoietic stem-cell transplantation in advanced mycosis fungoides and Sezary syndrome. J Clin Oncol 28 (14): 2365-72, 2010. [PUBMED Abstract]
  43. Duarte RF, Boumendil A, Onida F, et al.: Long-term outcome of allogeneic hematopoietic cell transplantation for patients with mycosis fungoides and Sézary syndrome: a European society for blood and marrow transplantation lymphoma working party extended analysis. J Clin Oncol 32 (29): 3347-8, 2014. [PUBMED Abstract]
  44. Schlaak M, Pickenhain J, Theurich S, et al.: Allogeneic stem cell transplantation versus conventional therapy for advanced primary cutaneous T-cell lymphoma. Cochrane Database Syst Rev 1: CD008908, 2012. [PUBMED Abstract]
  45. Lechowicz MJ, Lazarus HM, Carreras J, et al.: Allogeneic hematopoietic cell transplantation for mycosis fungoides and Sezary syndrome. Bone Marrow Transplant 49 (11): 1360-5, 2014. [PUBMED Abstract]
  46. Kim YH, Tavallaee M, Sundram U, et al.: Phase II Investigator-Initiated Study of Brentuximab Vedotin in Mycosis Fungoides and Sézary Syndrome With Variable CD30 Expression Level: A Multi-Institution Collaborative Project. J Clin Oncol 33 (32): 3750-8, 2015. [PUBMED Abstract]
  47. Duvic M, Tetzlaff MT, Gangar P, et al.: Results of a Phase II Trial of Brentuximab Vedotin for CD30+ Cutaneous T-Cell Lymphoma and Lymphomatoid Papulosis. J Clin Oncol 33 (32): 3759-65, 2015. [PUBMED Abstract]
  48. Kim YH, Bagot M, Pinter-Brown L, et al.: Mogamulizumab versus vorinostat in previously treated cutaneous T-cell lymphoma (MAVORIC): an international, open-label, randomised, controlled phase 3 trial. Lancet Oncol 19 (9): 1192-1204, 2018. [PUBMED Abstract]
  49. Sugio T, Kato K, Aoki T, et al.: Mogamulizumab Treatment Prior to Allogeneic Hematopoietic Stem Cell Transplantation Induces Severe Acute Graft-versus-Host Disease. Biol Blood Marrow Transplant 22 (9): 1608-1614, 2016. [PUBMED Abstract]

Treatment of Primary Cutaneous Anaplastic Large Cell Lymphoma

Primary cutaneous anaplastic large cell lymphoma presents in the skin only with no preexisting lymphoproliferative disease and no extracutaneous sites of involvement.[1–3] Patients with this type of lymphoma have disease ranging from clinically benign lymphomatoid papulosis, marked by localized nodules that may regress spontaneously, to progressive and systemic illness requiring aggressive doxorubicin-based combination chemotherapy. This spectrum has been called the primary cutaneous CD30-positive T-cell lymphoproliferative disorder.

Patients with localized disease usually undergo radiation therapy. With more disseminated involvement, watchful waiting or doxorubicin-based combination chemotherapy is used.[1–3]

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

References
  1. de Bruin PC, Beljaards RC, van Heerde P, et al.: Differences in clinical behaviour and immunophenotype between primary cutaneous and primary nodal anaplastic large cell lymphoma of T-cell or null cell phenotype. Histopathology 23 (2): 127-35, 1993. [PUBMED Abstract]
  2. Willemze R, Beljaards RC: Spectrum of primary cutaneous CD30 (Ki-1)-positive lymphoproliferative disorders. A proposal for classification and guidelines for management and treatment. J Am Acad Dermatol 28 (6): 973-80, 1993. [PUBMED Abstract]
  3. Kempf W, Pfaltz K, Vermeer MH, et al.: EORTC, ISCL, and USCLC consensus recommendations for the treatment of primary cutaneous CD30-positive lymphoproliferative disorders: lymphomatoid papulosis and primary cutaneous anaplastic large-cell lymphoma. Blood 118 (15): 4024-35, 2011. [PUBMED Abstract]

Treatment of Subcutaneous Panniculitis-Like T-Cell Lymphoma

Subcutaneous panniculitis-like T-cell lymphoma (SPTCL) is localized to subcutaneous tissue and can be associated with hemophagocytic lymphohistiocytosis (HLH).[1–4] Anecdotal reports suggest that the presence or absence of HLH is an important prognostic indicator.[5] Patients with SPTCL have cells that express alpha-beta phenotype.

Patients with gamma-delta phenotype have a more aggressive clinical course that is instead classified as primary cutaneous gamma-delta T-cell lymphoma.[6–8] For more information, see Peripheral T-Cell Non-Hodgkin Lymphoma Treatment.

The management of SPTCL depends on the clinical presentation—including the severity of symptoms, cytopenias, and the presence or absence of HLH—and the apparent disease trajectory and aggressiveness. Indolent or smoldering forms of SPTCL are often treated with immunosuppression, including oral methotrexate [9] or cyclosporine.[10] In contrast, aggressive forms are frequently treated with combination chemotherapy such as CHO(E)P (cyclophosphamide, doxorubicin, vincristine, and prednisone with or without etoposide) with variable responses per anecdotal reports.[11] The JAK2 inhibitor ruxolitinib has also been used in SPTCL with associated HLH, including anecdotal reports of responses in patients with disease that did not respond to CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) therapy.[12] In cases of particularly aggressive or relapsed disease, consolidation with allogeneic stem cell transplant has also been used.[13,14]

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

References
  1. Go RS, Wester SM: Immunophenotypic and molecular features, clinical outcomes, treatments, and prognostic factors associated with subcutaneous panniculitis-like T-cell lymphoma: a systematic analysis of 156 patients reported in the literature. Cancer 101 (6): 1404-13, 2004. [PUBMED Abstract]
  2. Marzano AV, Berti E, Paulli M, et al.: Cytophagic histiocytic panniculitis and subcutaneous panniculitis-like T-cell lymphoma: report of 7 cases. Arch Dermatol 136 (7): 889-96, 2000. [PUBMED Abstract]
  3. Hoque SR, Child FJ, Whittaker SJ, et al.: Subcutaneous panniculitis-like T-cell lymphoma: a clinicopathological, immunophenotypic and molecular analysis of six patients. Br J Dermatol 148 (3): 516-25, 2003. [PUBMED Abstract]
  4. Salhany KE, Macon WR, Choi JK, et al.: Subcutaneous panniculitis-like T-cell lymphoma: clinicopathologic, immunophenotypic, and genotypic analysis of alpha/beta and gamma/delta subtypes. Am J Surg Pathol 22 (7): 881-93, 1998. [PUBMED Abstract]
  5. Willemze R: Cutaneous lymphomas with a panniculitic presentation. Semin Diagn Pathol 34 (1): 36-43, 2017. [PUBMED Abstract]
  6. Massone C, Chott A, Metze D, et al.: Subcutaneous, blastic natural killer (NK), NK/T-cell, and other cytotoxic lymphomas of the skin: a morphologic, immunophenotypic, and molecular study of 50 patients. Am J Surg Pathol 28 (6): 719-35, 2004. [PUBMED Abstract]
  7. Arnulf B, Copie-Bergman C, Delfau-Larue MH, et al.: Nonhepatosplenic gammadelta T-cell lymphoma: a subset of cytotoxic lymphomas with mucosal or skin localization. Blood 91 (5): 1723-31, 1998. [PUBMED Abstract]
  8. Toro JR, Liewehr DJ, Pabby N, et al.: Gamma-delta T-cell phenotype is associated with significantly decreased survival in cutaneous T-cell lymphoma. Blood 101 (9): 3407-12, 2003. [PUBMED Abstract]
  9. Grinich E, Koon SM, Cascio MJ, et al.: Subcutaneous panniculitis-like T-cell lymphoma responsive to combination therapy with methotrexate and corticosteroids. Dermatol Online J 24 (9): , 2018. [PUBMED Abstract]
  10. Rojnuckarin P, Nakorn TN, Assanasen T, et al.: Cyclosporin in subcutaneous panniculitis-like T-cell lymphoma. Leuk Lymphoma 48 (3): 560-3, 2007. [PUBMED Abstract]
  11. Willemze R, Jansen PM, Cerroni L, et al.: Subcutaneous panniculitis-like T-cell lymphoma: definition, classification, and prognostic factors: an EORTC Cutaneous Lymphoma Group Study of 83 cases. Blood 111 (2): 838-45, 2008. [PUBMED Abstract]
  12. Lévy R, Fusaro M, Guerin F, et al.: Efficacy of ruxolitinib in subcutaneous panniculitis-like T-cell lymphoma and hemophagocytic lymphohistiocytosis. Blood Adv 4 (7): 1383-1387, 2020. [PUBMED Abstract]
  13. Weng W, Iragavarapu C, Weng GM, et al.: Long-term remission with allogeneic transplant in patients with refractory/relapsed cutaneous cytotoxic T-cell lymphoma. Blood Neoplasia 1 (2): 2024.
  14. Ichii M, Hatanaka K, Imakita M, et al.: Successful treatment of refractory subcutaneous panniculitis-like T-cell lymphoma with allogeneic peripheral blood stem cell transplantation from HLA-mismatched sibling donor. Leuk Lymphoma 47 (10): 2250-2, 2006. [PUBMED Abstract]

Treatment of Primary Cutaneous Gamma-Delta T-Cell Lymphoma

Primary cutaneous gamma-delta T-cell lymphoma (PCGDTCL) is a rare and extremely aggressive form of cutaneous T-cell lymphoma with a poor prognosis. These patients may manifest involvement of the epidermis, dermis, subcutaneous region, or mucosa with or without ulceration. PCGDTCL is treated similarly to the most aggressive peripheral T-cell lymphomas, with CHO(E)P (cyclophosphamide doxorubicin, vincristine, and prednisone with or without etoposide).[1–5] For patients achieving remission, there are reports of prolonged survival following consolidation with allogeneic stem cell transplant.[6]

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

References
  1. Arnulf B, Copie-Bergman C, Delfau-Larue MH, et al.: Nonhepatosplenic gammadelta T-cell lymphoma: a subset of cytotoxic lymphomas with mucosal or skin localization. Blood 91 (5): 1723-31, 1998. [PUBMED Abstract]
  2. Toro JR, Liewehr DJ, Pabby N, et al.: Gamma-delta T-cell phenotype is associated with significantly decreased survival in cutaneous T-cell lymphoma. Blood 101 (9): 3407-12, 2003. [PUBMED Abstract]
  3. Le Gouill S, Milpied N, Buzyn A, et al.: Graft-versus-lymphoma effect for aggressive T-cell lymphomas in adults: a study by the Société Francaise de Greffe de Moëlle et de Thérapie Cellulaire. J Clin Oncol 26 (14): 2264-71, 2008. [PUBMED Abstract]
  4. Pro B, Allen P, Behdad A: Hepatosplenic T-cell lymphoma: a rare but challenging entity. Blood 136 (18): 2018-2026, 2020. [PUBMED Abstract]
  5. Alberti-Violetti S, Maronese CA, Venegoni L, et al.: Primary Cutaneous Gamma-Delta T Cell Lymphomas: A Case Series and Overview of the Literature. Dermatopathology (Basel) 8 (4): 515-524, 2021. [PUBMED Abstract]
  6. Isufi I, Seropian S, Gowda L, et al.: Outcomes for allogeneic stem cell transplantation in refractory mycosis fungoides and primary cutaneous gamma Delta T cell lymphomas. Leuk Lymphoma 61 (12): 2955-2961, 2020. [PUBMED Abstract]

Treatment of Primary Cutaneous Aggressive Epidermotropic CD8-Positive T-Cell Lymphoma

Primary cutaneous aggressive epidermotropic CD8-positive T-cell lymphoma is another rare and especially aggressive form of cutaneous T-cell lymphoma. Patients typically present with ulcerative plaques or tumors, and mucosal involvement is common. Neoplastic cells are characterized by expression of CD8 and a cytotoxic phenotype.[1] Multimodal chemotherapy, such as CHO(E)P (cyclophosphamide, doxorubicin, vincristine, and prednisone with or without etoposide), is often used. Outcomes are generally poor, and prolonged remissions are extremely uncommon in the absence of allogeneic stem cell transplant.[2]

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

References
  1. Nofal A, Abdel-Mawla MY, Assaf M, et al.: Primary cutaneous aggressive epidermotropic CD8+ T-cell lymphoma: proposed diagnostic criteria and therapeutic evaluation. J Am Acad Dermatol 67 (4): 748-59, 2012. [PUBMED Abstract]
  2. Guitart J, Martinez-Escala ME, Subtil A, et al.: Primary cutaneous aggressive epidermotropic cytotoxic T-cell lymphomas: reappraisal of a provisional entity in the 2016 WHO classification of cutaneous lymphomas. Mod Pathol 30 (5): 761-772, 2017. [PUBMED Abstract]

Key References for Mycosis Fungoides and Other Cutaneous T-Cell Lymphomas

These references have been identified by members of the PDQ Adult Treatment Editorial Board as significant in the field of mycosis fungoides and other cutaneous T-cell lymphoma treatment. This list is provided to inform users of important studies that have helped shape the current understanding of and treatment options for MF/SS. Listed after each reference are the sections within this summary where the reference is cited.

Latest Updates to This Summary (02/19/2025)

The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.

Cellular Classification of Mycosis Fungoides and Other Cutaneous T-Cell Lymphomas

Added text to state that established criteria for defining Sézary syndrome generally require identification of (1) a circulating T-cell clone by rearrangement of the T-cell receptor, plus (2) a level of Sézary cells in the blood of at least 1,000/μL (cited 2007 Olsen et al. as reference 3 and 2022 Olsen et al. as reference 4). It is less clear if other findings are reliable staging data in the absence of blood Sézary cell levels of at least 1,000/μL (cited Chrisman et al. as reference 5).

This summary is written and maintained by the PDQ Adult Treatment Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ® Cancer Information for Health Professionals pages.

About This PDQ Summary

Purpose of This Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of mycosis fungoides and other cutaneous T-cell lymphomas. It is intended as a resource to inform and assist clinicians in the care of their patients. It does not provide formal guidelines or recommendations for making health care decisions.

Reviewers and Updates

This summary is reviewed regularly and updated as necessary by the PDQ Adult Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).

Board members review recently published articles each month to determine whether an article should:

  • be discussed at a meeting,
  • be cited with text, or
  • replace or update an existing article that is already cited.

Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.

The lead reviewers for Mycosis Fungoides and Other Cutaneous T-Cell Lymphomas Treatment are:

  • Eric J. Seifter, MD (Johns Hopkins University)
  • Cole H. Sterling, MD (Johns Hopkins University)

Any comments or questions about the summary content should be submitted to Cancer.gov through the NCI website’s Email Us. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.

Levels of Evidence

Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Adult Treatment Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.

Permission to Use This Summary

PDQ is a registered trademark. Although the content of PDQ documents can be used freely as text, it cannot be identified as an NCI PDQ cancer information summary unless it is presented in its entirety and is regularly updated. However, an author would be permitted to write a sentence such as “NCI’s PDQ cancer information summary about breast cancer prevention states the risks succinctly: [include excerpt from the summary].”

The preferred citation for this PDQ summary is:

PDQ® Adult Treatment Editorial Board. PDQ Mycosis Fungoides and Other Cutaneous T-Cell Lymphomas Treatment. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: /types/lymphoma/hp/mycosis-fungoides-treatment-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389288]

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Primary Central Nervous System Lymphoma Treatment (PDQ®)–Health Professional Version

Primary Central Nervous System Lymphoma Treatment (PDQ®)–Health Professional Version

General Information About Primary Central Nervous System Lymphoma

Go to Patient Version

Primary central nervous system (CNS) lymphoma is lymphoma limited to the cranial-spinal axis, including the brain, spinal cord, cerebrospinal fluid (leptomeningeal space), and vitreoretinal space (ocular space), without systemic disease (stage IE).[1] This disease has increasingly been seen among immunocompromised patients, such as those with HIV. Immunosuppression-related primary CNS lymphomas are almost always associated with the Epstein-Barr virus.

Histology

Almost all primary CNS lymphomas are diffuse large B-cell lymphomas of the activated B-cell nongerminal center subtype with additional pathogenic variants in the B-cell receptor signaling pathway, especially MYD88 and CD79B variants.[1] However, patients with immunosuppression-related disease almost never have an activated B-cell phenotype.[2]

More than 95% of patients with primary CNS lymphoma have B-cell phenoptype. However, in a retrospective series with data collected from 12 cancer centers, the 45 patients with CNS lymphoma of T-cell phenotype showed no difference in presentation or outcome.[3]

Anecdotal cases of primary CNS Hodgkin lymphoma have also been reported.[4]

Diagnostic Evaluation

Computed tomography (CT) scans are used to diagnose primary CNS lymphoma. These scans may show ring enhancement in 50% of patients with HIV, while homogenous enhancement is almost always seen in patients without HIV.[5]

Positron emission tomography (PET)–CT scans are used to exclude occult systemic disease of the chest, abdomen, and pelvis. A bone marrow biopsy may be excluded with a clear PET-CT scan.[6] All compartments of the CNS should be evaluated, even if asymptomatic, including the vitreoretinal compartment and the cerebrospinal fluid (CSF) when feasible.

In one prospective case series of 282 patients with primary CNS lymphoma, 17% of patients were found to have meningeal dissemination by cytomorphology, polymerase chain reaction of rearranged immunoglobulin heavy-chain genes, or meningeal enhancement on magnetic resonance imaging.[7]

Prognosis and Prognostic Factors

Primary CNS lymphoma is usually aggressive, and the median overall survival in published trials generally ranges from 2 to 5 years.[8,9] However, a retrospective case series of 40 patients with low-grade primary CNS lymphoma, derived from 18 cancer centers in five countries, reported a better long-term outcome (median survival, 7 years).[10][Level of evidence C3]

Poor prognostic factors for primary CNS lymphoma include:[11]

  • Age older than 60 years.
  • HIV positivity.
  • Elevated serum lactate dehydrogenase level.
  • Elevated CSF protein concentration.
  • Involvement of nonhemispheric areas of the brain (periventricular, basal ganglia, brainstem, and cerebellum).
  • Intraocular disease and concomitant brain involvement.[12] When tumor progression occurs, it is usually confined to the CNS and/or the eye.[1]

Older age and HIV positivity are the most clinically relevant poor prognostic factors. However, the prognosis for patients with HIV-associated primary CNS lymphoma has improved with the use of highly active antiretroviral therapy.[13] These patients are treated with the same paradigm as patients who do not have HIV or immunosuppression.

References
  1. Schaff LR, Grommes C: Primary central nervous system lymphoma. Blood 140 (9): 971-979, 2022. [PUBMED Abstract]
  2. Gandhi MK, Hoang T, Law SC, et al.: EBV-associated primary CNS lymphoma occurring after immunosuppression is a distinct immunobiological entity. Blood 137 (11): 1468-1477, 2021. [PUBMED Abstract]
  3. Shenkier TN, Blay JY, O’Neill BP, et al.: Primary CNS lymphoma of T-cell origin: a descriptive analysis from the international primary CNS lymphoma collaborative group. J Clin Oncol 23 (10): 2233-9, 2005. [PUBMED Abstract]
  4. Gerstner ER, Abrey LE, Schiff D, et al.: CNS Hodgkin lymphoma. Blood 112 (5): 1658-61, 2008. [PUBMED Abstract]
  5. Fine HA, Mayer RJ: Primary central nervous system lymphoma. Ann Intern Med 119 (11): 1093-104, 1993. [PUBMED Abstract]
  6. Jelicic J, Hansen DL, Carlsen SS, et al.: Is it possible to omit bone marrow biopsy in diagnostic workup in patients with newly diagnosed primary CNS lymphoma? A retrospective analysis in the PET/CT era. [Abstract] Blood 140 (Suppl 1): A-627, 1334-5, 2022.
  7. Fischer L, Martus P, Weller M, et al.: Meningeal dissemination in primary CNS lymphoma: prospective evaluation of 282 patients. Neurology 71 (14): 1102-8, 2008. [PUBMED Abstract]
  8. Grommes C, DeAngelis LM: Primary CNS Lymphoma. J Clin Oncol 35 (21): 2410-2418, 2017. [PUBMED Abstract]
  9. Fox CP, Phillips EH, Smith J, et al.: Guidelines for the diagnosis and management of primary central nervous system diffuse large B-cell lymphoma. Br J Haematol 184 (3): 348-363, 2019. [PUBMED Abstract]
  10. Jahnke K, Korfel A, O’Neill BP, et al.: International study on low-grade primary central nervous system lymphoma. Ann Neurol 59 (5): 755-62, 2006. [PUBMED Abstract]
  11. Lukas RV, Stupp R, Gondi V, et al.: Primary Central Nervous System Lymphoma-PART 1: Epidemiology, Diagnosis, Staging, and Prognosis. Oncology (Williston Park) 32 (1): 17-22, 2018. [PUBMED Abstract]
  12. Kreher S, Strehlow F, Martus P, et al.: Prognostic impact of intraocular involvement in primary CNS lymphoma: experience from the G-PCNSL-SG1 trial. Ann Hematol 94 (3): 409-14, 2015. [PUBMED Abstract]
  13. Gupta NK, Nolan A, Omuro A, et al.: Long-term survival in AIDS-related primary central nervous system lymphoma. Neuro Oncol 19 (1): 99-108, 2017. [PUBMED Abstract]

Treatment of Primary Central Nervous System Lymphoma

Treatment Options for Primary Central Nervous System (CNS) Lymphoma

Treatment options for primary CNS lymphoma include:

  1. Induction therapy.
  2. Consolidation after induction therapy.

Induction therapy

Trials using chemotherapy alone were justified because of the unsatisfactory results of using whole-brain radiation therapy (WBRT) alone [1,2] and significant neurological toxicity using high-dose methotrexate or other chemotherapeutic agents that cross the blood-brain barrier in combination with WBRT.[3–5]

Severe, delayed, neurological toxic effects were rarely seen in chemotherapy-only trials in the absence of subsequent radiation therapy. However, salvage radiation can be given for relapsed or refractory disease, sometimes at reduced dosage.[6,7]

Numerous phase I and phase II studies over two decades established the following active drugs for induction therapy or for treatment of relapsing disease. The following drugs have been used as single agents and in combinations:

  • High-dose methotrexate.[8–13] Outside of clinical trials, high-dose methotrexate is the most frequently used standard induction therapy.[14] However, it is given to inpatients, and it is too toxic for patients with a creatinine clearance under 35 cc/min or for most patients older than 75 years.
  • Lenalidomide with rituximab.[15] When high-dose chemotherapy is not feasible, this is the most frequently used combination. Lenalidomide can be initiated at low doses (e.g., 5 mg daily, 21 out of 28 days) in patients with renal insufficiency.
  • High-dose cytarabine.[12,13,16]
  • Rituximab.[16–18]
  • Thiotepa.[18,19]
  • Temozolomide.[20]
  • Ibrutinib.[21,22]
  • Procarbazine.[23]
  • Vincristine.[23]
  • Pomalidomide.[24]
  • Nivolumab.[25]

Evidence (chemotherapy with or without other therapy):

  1. The International Extranodal Lymphoma Study Group evaluated three different induction combinations in 227 patients with newly diagnosed, HIV-negative primary CNS lymphoma. Patients were randomly assigned to receive high-dose methotrexate (HD MTX) + high-dose cytarabine (HDA) (group 1), HD MTX + HDA + rituximab (R) (group 2), or HD MTX + HDA + R + thiotepa (the MATRix regimen) (group 3).[26][Level of evidence A1]
    • With a median follow-up of 88 months, the overall survival (OS) rate was 21% for group 1, 37% for group 2, and 56% for group 3.

    The groups were compared as follows:

    • Group 1 versus group 2: hazard ratio (HR), 0.64; 95% confidence interval (CI), 0.41–0.99; P = .04.
    • Group 1 versus group 3: HR, 0.42; 95% CI, 0.24–0.64; P = .00005.
    • Group 2 versus group 3: HR, 0.66; 95% CI, 0.44–0.98; P = .04.

    The OS rate favored the complete MATRix regimen in all comparisons.[26][Level of evidence A1]

    • The 113 patients who attained a complete response, partial response, or stable disease were randomly assigned to 36 Gy whole-brain radiation therapy versus autologous stem cell transplant (SCT) after thiotepa + bic-chloroethylnitrosourea + carmustine (BCNU) conditioning. No significant differences were seen in 7-year progression-free survival (PFS) or OS in regard to consolidation in this phase II trial.[26][Level of evidence B1]
    • The thiotepa + BCNU conditioning regimen was well tolerated by patients aged 60 to 70 years. It had improved tolerability compared with prior reports using the more intensive thiotepa + busulfan regimen.[26][Level of evidence D]
    • Patients who received the two-drug combination had a complete remission rate of 23% (interquartile range [IQR], 14%‒31%; HR, 0.46; 95% CI, 0.28‒0.74). Patients who received the three-drug combination had a complete remission rate of 30% (IQR, 21%‒42%; HR, 0.61; 95% CI, 0.40‒0.94). Patients who received the four-drug MATRix combination had a complete remission rate of 49% (95% CI, 38%‒60%).
    • The addition of rituximab and thiotepa to high-dose methotrexate plus cytarabine resulted in a significant improvement in complete response, PFS, and OS.[26][Level of evidence A1]
  2. In a randomized, nonblinded multicenter trial, 79 patients were assigned to receive high-dose methotrexate with or without cytarabine.[27][Level of evidence B1]
    • The 3-year PFS rate was better for patients who received the two-drug regimen (HR, 0.54; 95% CI, 0.31–0.92; P = .01).
    • There was no statistical difference in the 3-year OS rate (46% for the two-drug regimen vs. 32% for the one-drug regimen; HR, 0.65; 95% CI, 0.38–1.13; P = .07).
    • This trial was the basis for setting the combination of high-dose methotrexate and high-dose cytarabine as the control arm in the MATRix trial.
  3. In a randomized, prospective, multicenter trial, 200 patients were assigned to receive intravenous high-dose methotrexate, carmustine, teniposide, and oral prednisone with or without rituximab.[28][Level of evidence B1]
    • With a median follow-up of 32.9 months, there was no difference in the 1-year event-free survival (EFS) rate: 52% with rituximab (95% CI, 42%−61%) and 49% without rituximab (95% CI, 39%−58%; HR, 1.00; 95% CI, 0.70−1.43; P = .99).
  4. Several other combination induction regimens were created empirically and presented as phase II trials.[29][Level of evidence C3]
    • Rituximab + high-dose methotrexate + procarbazine + vincristine (R-MPV) (objective response rate, 97%; complete response, 66%)[23].
    • High-dose methotrexate + rituximab + temozolomide (HD MTX + R + TEM) (objective response rate, 80%; complete response, 66%).[20]
    • High-dose methotrexate ± rituximab (HD MTX ± R) + other chemotherapy (retrospective analysis of 885 patients) (objective response rate, 59%; complete response, 50%).[29]

Summary

High-dose methotrexate regimens delivered with rituximab and other chemotherapeutic agents is used for induction therapy. The MATRix regimen described above has become one such standard based on randomized OS benefit with a four-drug regimen versus a two-drug or a three-drug regimen.[26][Level of evidence 1A] The MATRix regimen has never been compared with some of the other combination therapies mentioned above. A meta-analysis of rituximab randomized trials found improved PFS with the addition of rituximab (HR, 0.65; 95% CI, 0.45–0.95) but no difference in OS.[30][Level of evidence B2]

Consolidation after induction chemotherapy

Consolidation therapy with or without WBRT

Evidence (consolidation therapy with or without WBRT):

  1. In a prospective, randomized, phase II trial, 87 patients (median age, 59–66 years) had induction therapy with high-dose methotrexate + high-dose cytarabine + rituximab + procarbazine + vincristine. Afterward, 37 patients had consolidation therapy with low-dose WBRT at 23.4 Gy.[31]
    • With a median follow-up of 55 months, the 2-year intention-to-treat PFS was 78% with low-dose WBRT versus 54% without low-dose WBRT (HR, 0.51; P = .015).[31][Level of evidence B1]
    • Investigator-assessed neurotoxicity was less than 15% in each arm and not significantly different. Another small phase II trial that examined low-dose WBRT at 23.4 Gy also found no increased problems seen on neuropsychological testing.[32,33]
  2. In a prospective, randomized, phase II trial of 97 newly diagnosed patients who received high-dose methotrexate combination therapy for induction, patients were randomly assigned to receive WBRT at 40 Gy versus autologous SCT.[34]
    • With a median follow-up of 8 years, deterioration of balance was significantly greater for patients who received WBRT versus patients who received autologous SCT (52% vs. 10%, P ≤ .001). Worsening neurocognition was also greater for patients who received WBRT (64% vs. 13%, P < .001).
    • The 8-year EFS rate was 67% for patients who received autologous SCT versus 39% for patients who received WBRT (HR, 0.13; P < .001). There was no significant difference in OS (69% for autologous SCT vs. 54% for WBRT).[34][Level of evidence B1]
    • The authors concluded that 40 Gy WBRT should be avoided in first-line treatment because of its neurotoxicity and inferior efficacy.
  3. In a prospective, randomized trial of 551 immunocompetent patients with newly diagnosed primary CNS lymphoma, all patients received induction chemotherapy with six cycles of high-dose methotrexate (4 g/m2) with or without ifosfamide. After chemotherapy was completed, responders were randomly assigned to receive either WBRT (45 Gy) or no treatment for complete-response patients and cytarabine for partial-response patients.[35]
    • There was no statistical difference in median OS at 32.4 months for patients who received WBRT versus at 37.1 months for those who did not receive WBRT (HR, 1.06; 95% CI, 0.80–1.40; P = .71).[35][Level of evidence A1]
    • Treatment-related neurotoxic effects were significantly worse in the WBRT arm.
  4. In a prospective, randomized trial, 410 immunocompetent patients with newly diagnosed primary CNS lymphoma were scheduled to receive high-dose methotrexate. Patients were randomly assigned to receive either WBRT or no radiation therapy.[36]
    • In the intent-to-treat population, WBRT was associated with longer PFS at 15.4 months versus 9.9 months (HR, 0.79; 95% CI, 0.64–0.98; P = .034). There was no difference in OS at 32.4 months versus 36.1 months (HR, 0.98; 95% CI, 0.79–1.26; P = .98).[36][Level of evidence B1]
    • Long-term treatment-related neurotoxic effects were not reported, and the induction chemotherapy would now be considered substandard.

Summary

The significant neurotoxicity of standard-dose WBRT [37] has reduced its role to short-duration disease control at relapse, when the expected survival is short enough that the benefit outweighs the longer-term neurological consequences. For patients unable to undergo consolidation with autologous SCT due to age, performance status, or comorbidities, low-dose WBRT (23.4 Gy) would be a consolidation option.

Consolidation therapy with or without autologous SCT

Evidence (consolidation therapy with or without autologous SCT):

  1. In a prospective, randomized trial published in abstract form, 346 patients with newly diagnosed primary CNS lymphoma (patients aged 65 years and younger and patients aged 66–70 years with a performance status of 2 or lower) underwent induction therapy with 4 cycles of rituximab, high-dose methotrexate, high-dose cytarabine, and thiotepa (IELSG43 [NCT02531841]). Eighty-six patients discontinued treatment due to toxicity or progression. Of the 260 patients who completed induction therapy, 229 patients were randomly assigned to receive either chemotherapy consolidation with rituximab, dexamethasone, etoposide, ifosfamide, and carboplatin (n = 115) or autologous SCT using BCNU and thiotepa (n = 114).[38][Level of evidence A1]
    • With a median follow-up of 44 months, the 3-year OS rate was 86% (78%–91%) for autologous SCT versus 71% (61%–78%) for chemotherapy alone (HR, 0.47; P = .01).[38][Level of evidence A1]
    • The 3-year PFS rate was 79% (71%–86%) for autologous SCT versus 53% (43%–62%) for chemotherapy alone.
    • There was no negative effect on neurocognitive function in either arm in the absence of progression.
    • This was the first randomized trial establishing a survival advantage for newly diagnosed patients receiving autologous SCT who are young enough and healthy enough to endure this aggressive approach.
  2. In a prospective, randomized, phase II trial, 97 newly diagnosed patients receiving high-dose methotrexate combination therapy for induction were randomly assigned to receive WBRT at 40 Gy or autologous SCT.[34]
    • With a median follow-up of 8 years, deterioration of balance was significantly greater for patients who received WBRT than for patients who received autologous SCT (52% vs. 10%, P ≤ .001). Worsening neurocognition was also greater for patients who received WBRT (64% vs. 13%, P < .001).
    • The 8-year EFS rate was 67% for patients who received autologous SCT versus 39% for patients who received WBRT (HR, 0.13; P < .001). There was no difference in OS (69% for autologous SCT vs. 65% for WBRT).[34][Level of evidence B1]
    • The authors concluded that 40 Gy WBRT should be avoided in first-line treatment because of its neurotoxicity and inferior efficacy.
  3. A prospective, randomized, phase II trial included newly diagnosed patients aged 75 years and younger. Patients received intensive induction therapy with high-dose methotrexate at 8 g/m2 every 2 weeks, temozolomide, rituximab, and high-dose cytarabine. Patients were randomly assigned at the start of therapy to consolidation with thiotepa + BCNU conditioning with autologous SCT or nonmyeloablative therapy with high-dose cytarabine with a 46-hour infusion of etoposide (EA).[39]
    • With a median follow-up of 3.8 years, the median PFS was 6 years (95% CI, 3.9–not reached [NR]) for autologous SCT versus 2.4 years (95% CI, 0.6–NR) for EA (P = .02).[39][Level of evidence B1]
    • PFS from the time of consolidation was not statistically different (HR, 0.58; 95% CI, 0.25–1.36; P = .21).
    • There was no statistically significant difference in the 3-year OS rate: 83% (69%–91%) for autologous SCT and 72% (57%–82%) for EA.
    • This trial showed the limitations of induction therapy, which affected the impact of consolidation therapy.
  4. Several phase II studies evaluated consolidation with intensive chemotherapy supported by autologous SCT.[19,20,23,40–43] This approach is appropriate for patients aged 80 years and under with few comorbidities, good performance status, and an adequate response to induction therapy.

Summary

Consolidation therapy with autologous SCT results in an OS advantage for newly diagnosed patients with good performance status, few comorbidities, and an adequate response to induction therapy (in this case, the MATRix regimen: high-dose methotrexate, high-dose cytarabine, rituximab, and temozolomide).[39] For patients unable to proceed to autologous SCT, consolidation with low-dose WBRT (32.4 Gy) or nonmyeloablative therapy might be considered.

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

References
  1. Pollack IF, Lunsford LD, Flickinger JC, et al.: Prognostic factors in the diagnosis and treatment of primary central nervous system lymphoma. Cancer 63 (5): 939-47, 1989. [PUBMED Abstract]
  2. Nelson DF, Martz KL, Bonner H, et al.: Non-Hodgkin’s lymphoma of the brain: can high dose, large volume radiation therapy improve survival? Report on a prospective trial by the Radiation Therapy Oncology Group (RTOG): RTOG 8315. Int J Radiat Oncol Biol Phys 23 (1): 9-17, 1992. [PUBMED Abstract]
  3. Fisher B, Seiferheld W, Schultz C, et al.: Secondary analysis of Radiation Therapy Oncology Group study (RTOG) 9310: an intergroup phase II combined modality treatment of primary central nervous system lymphoma. J Neurooncol 74 (2): 201-5, 2005. [PUBMED Abstract]
  4. Ekenel M, Iwamoto FM, Ben-Porat LS, et al.: Primary central nervous system lymphoma: the role of consolidation treatment after a complete response to high-dose methotrexate-based chemotherapy. Cancer 113 (5): 1025-31, 2008. [PUBMED Abstract]
  5. van der Meulen M, Dirven L, Habets EJJ, et al.: Cognitive functioning and health-related quality of life in patients with newly diagnosed primary CNS lymphoma: a systematic review. Lancet Oncol 19 (8): e407-e418, 2018. [PUBMED Abstract]
  6. Khimani NB, Ng AK, Chen YH, et al.: Salvage radiotherapy in patients with recurrent or refractory primary or secondary central nervous system lymphoma after methotrexate-based chemotherapy. Ann Oncol 22 (4): 979-84, 2011. [PUBMED Abstract]
  7. Shah GD, Yahalom J, Correa DD, et al.: Combined immunochemotherapy with reduced whole-brain radiotherapy for newly diagnosed primary CNS lymphoma. J Clin Oncol 25 (30): 4730-5, 2007. [PUBMED Abstract]
  8. Gavrilovic IT, Hormigo A, Yahalom J, et al.: Long-term follow-up of high-dose methotrexate-based therapy with and without whole brain irradiation for newly diagnosed primary CNS lymphoma. J Clin Oncol 24 (28): 4570-4, 2006. [PUBMED Abstract]
  9. Blay JY, Conroy T, Chevreau C, et al.: High-dose methotrexate for the treatment of primary cerebral lymphomas: analysis of survival and late neurologic toxicity in a retrospective series. J Clin Oncol 16 (3): 864-71, 1998. [PUBMED Abstract]
  10. Batchelor T, Carson K, O’Neill A, et al.: Treatment of primary CNS lymphoma with methotrexate and deferred radiotherapy: a report of NABTT 96-07. J Clin Oncol 21 (6): 1044-9, 2003. [PUBMED Abstract]
  11. Hoang-Xuan K, Taillandier L, Chinot O, et al.: Chemotherapy alone as initial treatment for primary CNS lymphoma in patients older than 60 years: a multicenter phase II study (26952) of the European Organization for Research and Treatment of Cancer Brain Tumor Group. J Clin Oncol 21 (14): 2726-31, 2003. [PUBMED Abstract]
  12. Pels H, Schmidt-Wolf IG, Glasmacher A, et al.: Primary central nervous system lymphoma: results of a pilot and phase II study of systemic and intraventricular chemotherapy with deferred radiotherapy. J Clin Oncol 21 (24): 4489-95, 2003. [PUBMED Abstract]
  13. Juergens A, Pels H, Rogowski S, et al.: Long-term survival with favorable cognitive outcome after chemotherapy in primary central nervous system lymphoma. Ann Neurol 67 (2): 182-9, 2010. [PUBMED Abstract]
  14. Schaff LR, Grommes C: Primary central nervous system lymphoma. Blood 140 (9): 971-979, 2022. [PUBMED Abstract]
  15. Ghesquieres H, Chevrier M, Laadhari M, et al.: Lenalidomide in combination with intravenous rituximab (REVRI) in relapsed/refractory primary CNS lymphoma or primary intraocular lymphoma: a multicenter prospective ‘proof of concept’ phase II study of the French Oculo-Cerebral lymphoma (LOC) Network and the Lymphoma Study Association (LYSA)†. Ann Oncol 30 (4): 621-628, 2019. [PUBMED Abstract]
  16. Chen YB, Batchelor T, Li S, et al.: Phase 2 trial of high-dose rituximab with high-dose cytarabine mobilization therapy and high-dose thiotepa, busulfan, and cyclophosphamide autologous stem cell transplantation in patients with central nervous system involvement by non-Hodgkin lymphoma. Cancer 121 (2): 226-33, 2015. [PUBMED Abstract]
  17. Mocikova H, Pytlik R, Sykorova A, et al.: Role of rituximab in treatment of patients with primary central nervous system lymphoma: a retrospective analysis of the Czech lymphoma study group registry. Leuk Lymphoma 57 (12): 2777-2783, 2016. [PUBMED Abstract]
  18. Ferreri AJ, Cwynarski K, Pulczynski E, et al.: Chemoimmunotherapy with methotrexate, cytarabine, thiotepa, and rituximab (MATRix regimen) in patients with primary CNS lymphoma: results of the first randomisation of the International Extranodal Lymphoma Study Group-32 (IELSG32) phase 2 trial. Lancet Haematol 3 (5): e217-27, 2016. [PUBMED Abstract]
  19. Schorb E, Fox CP, Fritsch K, et al.: High-dose thiotepa-based chemotherapy with autologous stem cell support in elderly patients with primary central nervous system lymphoma: a European retrospective study. Bone Marrow Transplant 52 (8): 1113-1119, 2017. [PUBMED Abstract]
  20. Rubenstein JL, Hsi ED, Johnson JL, et al.: Intensive chemotherapy and immunotherapy in patients with newly diagnosed primary CNS lymphoma: CALGB 50202 (Alliance 50202). J Clin Oncol 31 (25): 3061-8, 2013. [PUBMED Abstract]
  21. Illerhaus G, Schorb E, Kasenda B: Novel agents for primary central nervous system lymphoma: evidence and perspectives. Blood 132 (7): 681-688, 2018. [PUBMED Abstract]
  22. Grommes C, Tang SS, Wolfe J, et al.: Phase 1b trial of an ibrutinib-based combination therapy in recurrent/refractory CNS lymphoma. Blood 133 (5): 436-445, 2019. [PUBMED Abstract]
  23. Omuro A, Correa DD, DeAngelis LM, et al.: R-MPV followed by high-dose chemotherapy with TBC and autologous stem-cell transplant for newly diagnosed primary CNS lymphoma. Blood 125 (9): 1403-10, 2015. [PUBMED Abstract]
  24. Tun HW, Johnston PB, DeAngelis LM, et al.: Phase 1 study of pomalidomide and dexamethasone for relapsed/refractory primary CNS or vitreoretinal lymphoma. Blood 132 (21): 2240-2248, 2018. [PUBMED Abstract]
  25. Nayak L, Iwamoto FM, LaCasce A, et al.: PD-1 blockade with nivolumab in relapsed/refractory primary central nervous system and testicular lymphoma. Blood 129 (23): 3071-3073, 2017. [PUBMED Abstract]
  26. Ferreri AJM, Cwynarski K, Pulczynski E, et al.: Long-term efficacy, safety and neurotolerability of MATRix regimen followed by autologous transplant in primary CNS lymphoma: 7-year results of the IELSG32 randomized trial. Leukemia 36 (7): 1870-1878, 2022. [PUBMED Abstract]
  27. Ferreri AJ, Reni M, Foppoli M, et al.: High-dose cytarabine plus high-dose methotrexate versus high-dose methotrexate alone in patients with primary CNS lymphoma: a randomised phase 2 trial. Lancet 374 (9700): 1512-20, 2009. [PUBMED Abstract]
  28. Bromberg JEC, Issa S, Bakunina K, et al.: Rituximab in patients with primary CNS lymphoma (HOVON 105/ALLG NHL 24): a randomised, open-label, phase 3 intergroup study. Lancet Oncol 20 (2): 216-228, 2019. [PUBMED Abstract]
  29. Houillier C, Soussain C, Ghesquières H, et al.: Management and outcome of primary CNS lymphoma in the modern era: An LOC network study. Neurology 94 (10): e1027-e1039, 2020. [PUBMED Abstract]
  30. Schmitt AM, Herbrand AK, Fox CP, et al.: Rituximab in primary central nervous system lymphoma-A systematic review and meta-analysis. Hematol Oncol 37 (5): 548-557, 2019. [PUBMED Abstract]
  31. Omuro AM, DeAngelis LM, Karrison T, et al.: Randomized phase II study of rituximab, methotrexate (MTX), procarbazine, vincristine, and cytarabine (R-MPV-A) with and without low-dose whole-brain radiotherapy (LD-WBRT) for newly diagnosed primary CNS lymphoma (PCNSL). [Abstract] J Clin Oncol 38 (Suppl 15): A-2501, 2020.
  32. Morris PG, Correa DD, Yahalom J, et al.: Rituximab, methotrexate, procarbazine, and vincristine followed by consolidation reduced-dose whole-brain radiotherapy and cytarabine in newly diagnosed primary CNS lymphoma: final results and long-term outcome. J Clin Oncol 31 (31): 3971-9, 2013. [PUBMED Abstract]
  33. Lesueur P, Damaj G, Hoang-Xuan K, et al.: Reduced-dose WBRT as consolidation treatment for patients with primary CNS lymphoma: an LOC network study. Blood Adv 6 (16): 4807-4815, 2022. [PUBMED Abstract]
  34. Houillier C, Dureau S, Taillandier L, et al.: Radiotherapy or Autologous Stem-Cell Transplantation for Primary CNS Lymphoma in Patients Age 60 Years and Younger: Long-Term Results of the Randomized Phase II PRECIS Study. J Clin Oncol 40 (32): 3692-3698, 2022. [PUBMED Abstract]
  35. Thiel E, Korfel A, Martus P, et al.: High-dose methotrexate with or without whole brain radiotherapy for primary CNS lymphoma (G-PCNSL-SG-1): a phase 3, randomised, non-inferiority trial. Lancet Oncol 11 (11): 1036-47, 2010. [PUBMED Abstract]
  36. Korfel A, Thiel E, Martus P, et al.: Randomized phase III study of whole-brain radiotherapy for primary CNS lymphoma. Neurology 84 (12): 1242-8, 2015. [PUBMED Abstract]
  37. Correa DD: Neurocognitive functions in primary CNS lymphoma. Neuro Oncol 23 (8): 1220-1221, 2021. [PUBMED Abstract]
  38. Illerhaus G, Ferreri AJ, Binder M, et al.: Effects on Survival of Non-Myeloablative Chemoimmunotherapy Compared to High-Dose Chemotherapy Followed By Autologous Stem Cell Transplantation (HDC-ASCT) As Consolidation Therapy in Patients with Primary CNS Lymphoma – Results of an International Randomized Phase III Trial (MATRix/IELSG43). [Abstract] Blood 140 (Suppl 2): A-LBA-3, 2022.
  39. Batchelor T, Giri S, Ruppert A, et al.: Myeloablative versus non-myeloablative consolidative chemotherapy for newly diagnosed primary central nervous system lymphoma: Results of CALGB 51101 (Alliance). [Abstract] J Clin Oncol 39 (Suppl 15): A-7506, 2021.
  40. Illerhaus G, Kasenda B, Ihorst G, et al.: High-dose chemotherapy with autologous haemopoietic stem cell transplantation for newly diagnosed primary CNS lymphoma: a prospective, single-arm, phase 2 trial. Lancet Haematol 3 (8): e388-97, 2016. [PUBMED Abstract]
  41. Kasenda B, Schorb E, Fritsch K, et al.: Prognosis after high-dose chemotherapy followed by autologous stem-cell transplantation as first-line treatment in primary CNS lymphoma–a long-term follow-up study. Ann Oncol 23 (10): 2670-5, 2012. [PUBMED Abstract]
  42. Ferreri AJ, Illerhaus G: The role of autologous stem cell transplantation in primary central nervous system lymphoma. Blood 127 (13): 1642-9, 2016. [PUBMED Abstract]
  43. DeFilipp Z, Li S, El-Jawahri A, et al.: High-dose chemotherapy with thiotepa, busulfan, and cyclophosphamide and autologous stem cell transplantation for patients with primary central nervous system lymphoma in first complete remission. Cancer 123 (16): 3073-3079, 2017. [PUBMED Abstract]

Treatment of Recurrent Primary Central Nervous System Lymphoma

Treatment Options for Recurrent Primary Central Nervous System (CNS) Lymphoma

The prognosis for patients with recurrent CNS lymphoma is poor, with a median survival of 6 to 12 months, but up to 43 to 50 months if autologous stem cell transplant (SCT) consolidation is performed (if not applied previously).[1] This finding implies that deferred autologous SCT until first relapse may still result in longer-term survival. The prognosis is worse for patients 60 years and older, who account for more than 50% of cases.[2]

Treatment options for recurrent primary CNS lymphoma include:

  1. Reinduction therapy followed by SCT.

Reinduction therapy followed by SCT

Patients with recurrence after high-dose methotrexate-based combination chemotherapy may try autologous SCT consolidation after reinduction of remission with single-agent or combination therapy from the following options:[3]

  1. Rituximab + lenalidomide.[4]
  2. Rituximab + lenalidomide + ibrutinib.[5]
  3. Rituximab.[6]
  4. Ibrutinib.[7]
  5. Temozolomide.
  6. Chimeric antigen receptor (CAR) T cells.
  7. DA-TEDDI-R: temozolomide, etoposide, liposomal doxorubicin, dexamethasone, ibrutinib, and rituximab (under clinical evaluation).

Patients deemed ineligible for transplant can receive palliative care with these agents.

Evidence (reinduction therapy):

  1. A phase I/II clinical trial evaluated CD19-directed CAR T-cell therapy using tisagenlecleucel in patients with relapsed primary CNS lymphoma.[8][Level of evidence C3]
    • One-half of the patients (6 of 12) had a complete response.
    • Three patients maintained a complete response at 9 months, 12 months, and 23 months at the time of data cutoff.
    • Five patients had low-grade immune cell–assisted neurotoxicity.
    • One patient had grade 3 neurotoxicity.

    CAR T-cell therapy provides an option for patients with relapsed primary CNS lymphoma.[8]

  2. The DA-TEDDI-R regimen incorporates temozolomide, etoposide, liposomal doxorubicin, dexamethasone, ibrutinib, and rituximab.[7][Level of evidence C3]
    • Among 18 patients who received this regimen (five previously untreated), the complete remission rate was 86%, but high rates (39%) of invasive aspergillosis were reported.

    Further studies of this regimen are under way (NCT03964090 and NCT02203526). Dexamethasone should be avoided with ibrutinib single agent or combination therapy due to the risk of serious fungal infections. This approach requires access to intravenous antifungal agents not available outside of a clinical trial. By eliminating dexamethasone and ibrutinib, the other drugs may be used together with less risk of fungal infections.

  3. In a phase II study, patients with relapsed or refractory primary CNS lymphoma were treated with rituximab plus lenalidomide.[4][Level of evidence C3]
    • An overall response rate of 36% was reported.

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

References
  1. Schenone L, Houillier C, Tanguy ML, et al.: Intensive chemotherapy followed by autologous stem cell transplantation in primary central nervous system lymphomas (PCNSLs). Therapeutic outcomes in real life-experience of the French Network. Bone Marrow Transplant 57 (6): 966-974, 2022. [PUBMED Abstract]
  2. Jahnke K, Thiel E, Martus P, et al.: Relapse of primary central nervous system lymphoma: clinical features, outcome and prognostic factors. J Neurooncol 80 (2): 159-65, 2006. [PUBMED Abstract]
  3. Han CH, Batchelor TT: Diagnosis and management of primary central nervous system lymphoma. Cancer 123 (22): 4314-4324, 2017. [PUBMED Abstract]
  4. Ghesquieres H, Chevrier M, Laadhari M, et al.: Lenalidomide in combination with intravenous rituximab (REVRI) in relapsed/refractory primary CNS lymphoma or primary intraocular lymphoma: a multicenter prospective ‘proof of concept’ phase II study of the French Oculo-Cerebral lymphoma (LOC) Network and the Lymphoma Study Association (LYSA)†. Ann Oncol 30 (4): 621-628, 2019. [PUBMED Abstract]
  5. Houillier C, Chabrot CM, Moles-Moreau MP, et al.: Rituximab-Lenalidomide-Ibrutinib Combination for Relapsed/Refractory Primary CNS Lymphoma: A Case Series of the LOC Network. Neurology 97 (13): 628-631, 2021. [PUBMED Abstract]
  6. Schmitt AM, Herbrand AK, Fox CP, et al.: Rituximab in primary central nervous system lymphoma-A systematic review and meta-analysis. Hematol Oncol 37 (5): 548-557, 2019. [PUBMED Abstract]
  7. Lionakis MS, Dunleavy K, Roschewski M, et al.: Inhibition of B Cell Receptor Signaling by Ibrutinib in Primary CNS Lymphoma. Cancer Cell 31 (6): 833-843.e5, 2017. [PUBMED Abstract]
  8. Frigault MJ, Dietrich J, Gallagher K, et al.: Safety and efficacy of tisagenlecleucel in primary CNS lymphoma: a phase 1/2 clinical trial. Blood 139 (15): 2306-2315, 2022. [PUBMED Abstract]

Treatment of Intraocular Lymphoma

Retrospective reviews of selected patients with primary intraocular lymphoma and no evidence of disseminated central nervous system (CNS) disease showed that localized therapy with intraocular methotrexate or ocular radiation therapy or systemic therapy with rituximab were effective in clearing lymphoma cells from the eye. However, most patients had subsequent CNS relapse.[1,2][Level of evidence C3] Anecdotal series reported lower relapse rates when high-dose methotrexate was added, but prospective multicenter trials with even retrospective controls do not exist.[1,2][Level of evidence D]

Relapsing disease in the rest of the CNS is treated with the same options listed for primary CNS lymphoma in the brain. In a phase III randomized study of whole-brain radiation therapy, patients with intraocular disease and concomitant brain involvement had a worse prognosis than those with brain involvement alone (19 patients with both, 391 patients with brain involvement only).[3]

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

References
  1. Grimm SA, Pulido JS, Jahnke K, et al.: Primary intraocular lymphoma: an International Primary Central Nervous System Lymphoma Collaborative Group Report. Ann Oncol 18 (11): 1851-5, 2007. [PUBMED Abstract]
  2. Soussain C, Malaise D, Cassoux N: Primary vitreoretinal lymphoma: a diagnostic and management challenge. Blood 138 (17): 1519-1534, 2021. [PUBMED Abstract]
  3. Korfel A, Thiel E, Martus P, et al.: Randomized phase III study of whole-brain radiotherapy for primary CNS lymphoma. Neurology 84 (12): 1242-8, 2015. [PUBMED Abstract]

Key References for Primary Central Nervous System Lymphoma Treatment

These references have been identified by members of the PDQ Adult Treatment Editorial Board as significant in the field of primary central nervous system (CNS) lymphoma treatment. This list is provided to inform users of important studies that have helped shape the current understanding of and treatment options for primary CNS lymphoma. Listed after each reference are the sections within this summary where the reference is cited.

Latest Updates to This Summary (05/13/2025)

The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.

Editorial changes were made to this summary.

This summary is written and maintained by the PDQ Adult Treatment Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ® Cancer Information for Health Professionals pages.

About This PDQ Summary

Purpose of This Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of primary CNS lymphoma. It is intended as a resource to inform and assist clinicians in the care of their patients. It does not provide formal guidelines or recommendations for making health care decisions.

Reviewers and Updates

This summary is reviewed regularly and updated as necessary by the PDQ Adult Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).

Board members review recently published articles each month to determine whether an article should:

  • be discussed at a meeting,
  • be cited with text, or
  • replace or update an existing article that is already cited.

Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.

The lead reviewer for Primary Central Nervous System Lymphoma Treatment is:

  • Eric J. Seifter, MD (Johns Hopkins University)

Any comments or questions about the summary content should be submitted to Cancer.gov through the NCI website’s Email Us. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.

Levels of Evidence

Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Adult Treatment Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.

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The preferred citation for this PDQ summary is:

PDQ® Adult Treatment Editorial Board. PDQ Primary Central Nervous System Lymphoma Treatment. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: /types/lymphoma/hp/primary-cns-lymphoma-treatment-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389331]

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Based on the strength of the available evidence, treatment options may be described as either “standard” or “under clinical evaluation.” These classifications should not be used as a basis for insurance reimbursement determinations. More information on insurance coverage is available on Cancer.gov on the Managing Cancer Care page.

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