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AIDS-Related Lymphoma Treatment (PDQ®)–Health Professional Version

AIDS-Related Lymphoma Treatment (PDQ®)–Health Professional Version

General Information About AIDS-Related Lymphoma

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Background and Definitions

AIDS was first described in 1981, and the first definitions included certain opportunistic infections, Kaposi sarcoma, and central nervous system (CNS) lymphomas. In 1984, a multicenter study described the clinical spectrum of non-Hodgkin lymphomas (NHLs) in the populations at risk of AIDS.[1] The incidence of NHL has increased in a course almost parallel to that of the AIDS epidemic and accounts for 2% to 3% of newly diagnosed AIDS cases.[2] Since the introduction of highly active antiretroviral therapy (HAART) in the mid-1990s, the incidence of lymphomas has decreased, and outcomes have improved.[3] Higher CD4-positive T-lymphocyte (CD4) counts in the HAART era have been associated with a shift in histological diagnoses. The shift is away from primary effusion lymphoma and primary CNS lymphoma, which occur with the lowest CD4 counts, and toward histologies that occur at higher CD4 counts, such as Burkitt lymphoma and Hodgkin lymphoma (HL).[4–6] In contrast to less-frequent incidences of all the lymphoproliferative disorders in the HAART era, the incidence rate of anal cancer has not changed.[7]

Histology

Pathologically, AIDS-related lymphomas comprise a narrow spectrum of histological types consisting almost exclusively of B-cell tumors of aggressive type. These include:

  • Diffuse large B-cell lymphoma (including B-cell immunoblastic lymphoma).
  • Small noncleaved lymphoma, either Burkitt or Burkitt-like.

The HIV-associated lymphomas can be categorized as:

  • Aggressive B-cell lymphoma (see above).
  • Primary CNS lymphoma (PCNSL).
  • Primary effusion lymphoma.
  • Plasmablastic multicentric Castleman disease.
  • HL.

HIV-associated Hodgkin lymphoma

Multiple reviews of HL occurring in patients at risk of AIDS have been done;[8,9] however, HL is still not part of the Centers for Disease Control and Prevention (CDC) definition of AIDS because no clear demonstration of its increased incidence in conjunction with HIV has been shown, as is the case for aggressive NHL. The CDC, in conjunction with the San Francisco Department of Public Health, has reported a cohort study in which HIV-infected men had an excess risk that was attributable to the HIV infection in 19.3 cases of HL per 100,000 person-years and 224.9 cases of NHL per 100,000 person-years. Although this report found an excess incidence of HL in HIV-infected homosexual men, additional epidemiologic studies will be needed before the CDC will reconsider HL as an HIV-associated malignancy.[10]

HIV-associated HL presents in an aggressive fashion, often with extranodal or bone marrow involvement.[8,9,11] A distinctive feature of HIV-associated HL is the lesser frequency of mediastinal adenopathy compared with non–HIV-associated HL. Most patients in these series had either mixed cellularity or lymphocyte-depleted HL, expression of Epstein-Barr virus (EBV)-associated proteins in Reed-Sternberg cells, B symptoms, and a median CD4 lymphocyte count of 300/dL or lower.[12] In a retrospective multicenter review of 62 patients, those receiving HAART with chemotherapy had a 74% 2-year overall survival (OS) rate versus a 30% OS rate for those not receiving HAART (P < .001).[13][Level of evidence C1] Among 201 patients with classical HL and HIV positivity, the 2- to 5-year OS rate of 88% to 90% after treatment with ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine), or similar regimens, and HAART, was not significantly different from the OS rate of HIV-negative patients with newly diagnosed HL in two uncontrolled comparisons.[14,15][Level of evidence C3] These studies confirm that patients with HL who were treated with standard regimens and HAART have outcomes that are similar to those of the uninfected population.[16] Furthermore, immune function recovers over the course of 6 to 9 months after completion of chemotherapy.[15]

Primary effusion lymphoma

Primary effusion lymphoma has been associated with Kaposi sarcoma (KS)-associated herpesvirus (KSHV)/human herpes virus type 8 (HHV8).[17,18] Primary effusion lymphoma presents as a liquid phase spreading along serous membranes in the absence of masses or adenopathy.[17] In addition to HHV8, many cases are also associated with EBV. Extension of lymphoma from the effusion to underlying tissue may occur. A series of 20 patients, including 19 treated with modified infusional etoposide, vincristine, and doxorubicin plus cyclophosphamide and prednisone (modEPOCH), had a 3-year cancer-specific survival rate of 47% and a median OS of 22 months.[19][Level of evidence C3]

Multicentric Castleman disease

The plasmablastic type of multicentric Castleman disease is also associated with a coinfection of KSHV/HHV8 and HIV.[20] Patients typically present with fever, night sweats, weight loss, lymphadenopathy, and hepatosplenomegaly. Patients may progress to primary effusion lymphoma or to plasmablastic or anaplastic large cell lymphoma. Anecdotal responses to the anti-CD20 monoclonal antibody rituximab alone (along with HAART), have been reported.[21–24][Level of evidence C3] For a prospective cohort of 84 patients treated with rituximab for HIV and HHV8 multicentric Castleman disease, the 5-year rate of relapse-free survival was 82% (95% confidence interval [CI], 72%–92%), and all patients responded again to rituximab at relapse.[24][Level of evidence C2]

Incidence and Prevention

An international database of 48,000 HIV-seropositive individuals from the United States, Europe, and Australia found a 42% decline in the incidence of NHLs from 1997 to 1999 compared with the same incidences in 1992 to 1996, both for PCNSL and for systemic lymphoma.[25] The introduction of HAART is the proposed explanation for this decline.[26] The diagnosis of AIDS precedes the onset of NHL in approximately 50% of the patients; however, in the other half of the patients, the diagnosis of AIDS is made at the time of the diagnosis of NHL and HIV positivity.[3] The geographic distribution of these lymphomas is also similar to the geographic spread of AIDS. Unlike KS, which has a predilection for homosexual men and appears to be on the decline in incidence, all risk groups appear to have an excess number of NHLs; these risk groups include intravenous drug users and children of HIV-positive individuals.

Clinical Presentation

In general, the clinical setting and response to treatment of patients with AIDS-related lymphoma is very different from that of the non-HIV patients with lymphoma. The HIV-infected individual with aggressive lymphoma usually presents with advanced-stage disease that is frequently extranodal.[27]

Common extranodal sites include:

  • Bone marrow.
  • Liver.
  • Meninges.
  • Gastrointestinal tract.

Very unusual sites are also characteristic and include:

  • Anus.
  • Heart.
  • Bile duct.
  • Gingiva.
  • Muscles.

The clinical course is more aggressive, and the disease is both more extensive and less responsive to chemotherapy. Immunodeficiency and cytopenias, common in these patients at the time of initial presentation, are exacerbated by the administration of chemotherapy. Treatment of the malignancy increases the risk of opportunistic infections, which further compromise the delivery of adequate treatment.

Prognosis and Survival

Prognoses of patients with AIDS-related lymphoma have been associated with:[28]

  • Stage (i.e., extent of disease, extranodal involvement, lactate dehydrogenase level, and bone marrow involvement).
  • Age.
  • Severity of the underlying immunodeficiency (measured by CD4 lymphocyte count in peripheral blood).
  • Performance status.
  • Prior AIDS diagnosis (i.e., history of opportunistic infection or KS).

Patients with AIDS-related PCNSL appear to have more severe underlying HIV-related disease than do patients with systemic lymphoma. In one report, this severity was evidenced by patients with PCNSL who had a higher incidence of previously diagnosed AIDS (73% vs. 37%), lower median number of CD4 lymphocytes (30/dL vs. 189/dL), and a worse median survival time (2.5 months vs. 6.0 months).[29] This report also showed that patients with poor risk factors—defined as Karnofsky Performance Status score lower than 70%, history of previously diagnosed AIDS, and bone marrow involvement—had a median survival time of 4.0 months compared with patients in a good prognosis group who had none of these risk factors, and who had a median survival time of 11.3 months.

In another report (NIAID-ACTG-142), prognostic factors were evaluated in a group of 192 patients with newly diagnosed AIDS-related lymphoma who were randomly assigned to receive either low-dose methotrexate, bleomycin, doxorubicin, cyclophosphamide, vincristine, and dexamethasone (m-BACOD) or standard-dose m-BACOD with granulocyte-macrophage colony-stimulating factor.[30] No differences existed between these two treatments in terms of efficacy for disease-free survival, median survival, or risk ratio for death.[30][Level of evidence A1] On multivariate analysis, factors associated with decreased survival included age older than 35 years, history of intravenous drug use, stage III or stage IV disease, and CD4 counts lower than 100 cells/mm3. The International Prognostic Index may also be predictive for survival.[31–33] In a multicenter cohort study of 203 patients, in a multivariable Cox model, response to HAART was independently associated with prolonged survival (relative hazard, 0.32; 95% CI, 0.16–0.62).[34][Level of evidence C2]

References
  1. Ziegler JL, Beckstead JA, Volberding PA, et al.: Non-Hodgkin’s lymphoma in 90 homosexual men. Relation to generalized lymphadenopathy and the acquired immunodeficiency syndrome. N Engl J Med 311 (9): 565-70, 1984. [PUBMED Abstract]
  2. Rabkin CS, Yellin F: Cancer incidence in a population with a high prevalence of infection with human immunodeficiency virus type 1. J Natl Cancer Inst 86 (22): 1711-6, 1994. [PUBMED Abstract]
  3. Noy A: Optimizing treatment of HIV-associated lymphoma. Blood 134 (17): 1385-1394, 2019. [PUBMED Abstract]
  4. Little RF, Wilson WH: Update on the Pathogenesis, Diagnosis, and Therapy of AIDS-related Lymphoma. Curr Infect Dis Rep 5 (2): 176-184, 2003. [PUBMED Abstract]
  5. Carbone A, Gloghini A: AIDS-related lymphomas: from pathogenesis to pathology. Br J Haematol 130 (5): 662-70, 2005. [PUBMED Abstract]
  6. Gopal S, Patel MR, Yanik EL, et al.: Temporal trends in presentation and survival for HIV-associated lymphoma in the antiretroviral therapy era. J Natl Cancer Inst 105 (16): 1221-9, 2013. [PUBMED Abstract]
  7. Piketty C, Selinger-Leneman H, Bouvier AM, et al.: Incidence of HIV-related anal cancer remains increased despite long-term combined antiretroviral treatment: results from the french hospital database on HIV. J Clin Oncol 30 (35): 4360-6, 2012. [PUBMED Abstract]
  8. Spina M, Vaccher E, Nasti G, et al.: Human immunodeficiency virus-associated Hodgkin’s disease. Semin Oncol 27 (4): 480-8, 2000. [PUBMED Abstract]
  9. Thompson LD, Fisher SI, Chu WS, et al.: HIV-associated Hodgkin lymphoma: a clinicopathologic and immunophenotypic study of 45 cases. Am J Clin Pathol 121 (5): 727-38, 2004. [PUBMED Abstract]
  10. Hessol NA, Katz MH, Liu JY, et al.: Increased incidence of Hodgkin disease in homosexual men with HIV infection. Ann Intern Med 117 (4): 309-11, 1992. [PUBMED Abstract]
  11. Re A, Casari S, Cattaneo C, et al.: Hodgkin disease developing in patients infected by human immunodeficiency virus results in clinical features and a prognosis similar to those in patients with human immunodeficiency virus-related non-Hodgkin lymphoma. Cancer 92 (11): 2739-45, 2001. [PUBMED Abstract]
  12. Dolcetti R, Boiocchi M, Gloghini A, et al.: Pathogenetic and histogenetic features of HIV-associated Hodgkin’s disease. Eur J Cancer 37 (10): 1276-87, 2001. [PUBMED Abstract]
  13. Hentrich M, Maretta L, Chow KU, et al.: Highly active antiretroviral therapy (HAART) improves survival in HIV-associated Hodgkin’s disease: results of a multicenter study. Ann Oncol 17 (6): 914-9, 2006. [PUBMED Abstract]
  14. Montoto S, Shaw K, Okosun J, et al.: HIV status does not influence outcome in patients with classical Hodgkin lymphoma treated with chemotherapy using doxorubicin, bleomycin, vinblastine, and dacarbazine in the highly active antiretroviral therapy era. J Clin Oncol 30 (33): 4111-6, 2012. [PUBMED Abstract]
  15. Hentrich M, Berger M, Wyen C, et al.: Stage-adapted treatment of HIV-associated Hodgkin lymphoma: results of a prospective multicenter study. J Clin Oncol 30 (33): 4117-23, 2012. [PUBMED Abstract]
  16. Kaplan LD: Management of HIV-associated Hodgkin lymphoma: how far we have come. J Clin Oncol 30 (33): 4056-8, 2012. [PUBMED Abstract]
  17. Simonelli C, Spina M, Cinelli R, et al.: Clinical features and outcome of primary effusion lymphoma in HIV-infected patients: a single-institution study. J Clin Oncol 21 (21): 3948-54, 2003. [PUBMED Abstract]
  18. Nador RG, Cesarman E, Chadburn A, et al.: Primary effusion lymphoma: a distinct clinicopathologic entity associated with the Kaposi’s sarcoma-associated herpes virus. Blood 88 (2): 645-56, 1996. [PUBMED Abstract]
  19. Lurain K, Polizzotto MN, Aleman K, et al.: Viral, immunologic, and clinical features of primary effusion lymphoma. Blood 133 (16): 1753-1761, 2019. [PUBMED Abstract]
  20. Bower M, Newsom-Davis T, Naresh K, et al.: Clinical Features and Outcome in HIV-Associated Multicentric Castleman’s Disease. J Clin Oncol 29 (18): 2481-6, 2011. [PUBMED Abstract]
  21. Goedert JJ: Multicentric Castleman disease: viral and cellular targets for intervention. Blood 102 (8): 2710-11, 2003.
  22. Uldrick TS, Polizzotto MN, Aleman K, et al.: Rituximab plus liposomal doxorubicin in HIV-infected patients with KSHV-associated multicentric Castleman disease. Blood 124 (24): 3544-52, 2014. [PUBMED Abstract]
  23. Marcelin AG, Aaron L, Mateus C, et al.: Rituximab therapy for HIV-associated Castleman disease. Blood 102 (8): 2786-8, 2003. [PUBMED Abstract]
  24. Pria AD, Pinato D, Roe J, et al.: Relapse of HHV8-positive multicentric Castleman disease following rituximab-based therapy in HIV-positive patients. Blood 129 (15): 2143-2147, 2017. [PUBMED Abstract]
  25. International Collaboration on HIV and Cancer: Highly active antiretroviral therapy and incidence of cancer in human immunodeficiency virus-infected adults. J Natl Cancer Inst 92 (22): 1823-30, 2000. [PUBMED Abstract]
  26. Stebbing J, Gazzard B, Mandalia S, et al.: Antiretroviral treatment regimens and immune parameters in the prevention of systemic AIDS-related non-Hodgkin’s lymphoma. J Clin Oncol 22 (11): 2177-83, 2004. [PUBMED Abstract]
  27. Sparano JA: Clinical aspects and management of AIDS-related lymphoma. Eur J Cancer 37 (10): 1296-305, 2001. [PUBMED Abstract]
  28. Bower M, Gazzard B, Mandalia S, et al.: A prognostic index for systemic AIDS-related non-Hodgkin lymphoma treated in the era of highly active antiretroviral therapy. Ann Intern Med 143 (4): 265-73, 2005. [PUBMED Abstract]
  29. Levine AM, Sullivan-Halley J, Pike MC, et al.: Human immunodeficiency virus-related lymphoma. Prognostic factors predictive of survival. Cancer 68 (11): 2466-72, 1991. [PUBMED Abstract]
  30. Kaplan LD, Straus DJ, Testa MA, et al.: Low-dose compared with standard-dose m-BACOD chemotherapy for non-Hodgkin’s lymphoma associated with human immunodeficiency virus infection. National Institute of Allergy and Infectious Diseases AIDS Clinical Trials Group. N Engl J Med 336 (23): 1641-8, 1997. [PUBMED Abstract]
  31. Navarro JT, Ribera JM, Oriol A, et al.: International prognostic index is the best prognostic factor for survival in patients with AIDS-related non-Hodgkin’s lymphoma treated with CHOP. A multivariate study of 46 patients. Haematologica 83 (6): 508-13, 1998. [PUBMED Abstract]
  32. Rossi G, Donisi A, Casari S, et al.: The International Prognostic Index can be used as a guide to treatment decisions regarding patients with human immunodeficiency virus-related systemic non-Hodgkin lymphoma. Cancer 86 (11): 2391-7, 1999. [PUBMED Abstract]
  33. Straus DJ, Huang J, Testa MA, et al.: Prognostic factors in the treatment of human immunodeficiency virus-associated non-Hodgkin’s lymphoma: analysis of AIDS Clinical Trials Group protocol 142–low-dose versus standard-dose m-BACOD plus granulocyte-macrophage colony-stimulating factor. National Institute of Allergy and Infectious Diseases. J Clin Oncol 16 (11): 3601-6, 1998. [PUBMED Abstract]
  34. Hoffmann C, Wolf E, Fätkenheuer G, et al.: Response to highly active antiretroviral therapy strongly predicts outcome in patients with AIDS-related lymphoma. AIDS 17 (10): 1521-9, 2003. [PUBMED Abstract]

Cellular Classification of AIDS-Related Lymphoma

Pathologically, AIDS-related lymphomas comprise a narrow spectrum of histological types consisting almost exclusively of B-cell tumors of aggressive type. These include:

  • Diffuse large B-cell lymphoma (B-cell immunoblastic lymphoma).
  • Small noncleaved lymphoma, either Burkitt or Burkitt-like.

AIDS-related lymphomas, though usually of B-cell origin as demonstrated by immunoglobulin heavy-chain gene rearrangement studies, have also been shown to be oligoclonal, polyclonal, and monoclonal in origin. Although HIV does not appear to have a direct etiologic role, HIV infection does lead to an altered immunologic milieu. HIV generally infects T lymphocytes with the loss of regulation function that leads to hypergammaglobulinemia and polyclonal B-cell hyperplasia. B cells are not the targets of HIV infection. Instead, Epstein-Barr virus (EBV) is thought to be at least a cofactor in the etiology of some of these lymphomas. The EBV genome has been detected in most patients with AIDS-related lymphomas; molecular analysis suggests that the cells were infected before clonal proliferation began.[1] The rare primary effusion lymphoma consistently harbors human herpes virus type 8 and frequently contains EBV.[2] HIV-related T-cell lymphomas have also been identified and appear to be associated with EBV infection.[3]

References
  1. Thorley-Lawson DA, Gross A: Persistence of the Epstein-Barr virus and the origins of associated lymphomas. N Engl J Med 350 (13): 1328-37, 2004. [PUBMED Abstract]
  2. Simonelli C, Spina M, Cinelli R, et al.: Clinical features and outcome of primary effusion lymphoma in HIV-infected patients: a single-institution study. J Clin Oncol 21 (21): 3948-54, 2003. [PUBMED Abstract]
  3. Thomas JA, Cotter F, Hanby AM, et al.: Epstein-Barr virus-related oral T-cell lymphoma associated with human immunodeficiency virus immunosuppression. Blood 81 (12): 3350-6, 1993. [PUBMED Abstract]

Stage Information for AIDS-Related Lymphoma

Although stage is important in selecting the treatment of patients with non-Hodgkin lymphoma (NHL) who do not have AIDS, most patients with AIDS-related lymphomas have far-advanced disease.

Staging Subclassification System

Lugano classification

The American Joint Committee on Cancer (AJCC) has adopted the Lugano classification to evaluate and stage lymphoma.[1] The Lugano classification system replaces the Ann Arbor classification system, which was adopted in 1971 at the Ann Arbor Conference,[2] with some modifications 18 years later from the Cotswolds meeting.[3,4]

Table 1. 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 lungs (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 2. Notation for Identification of Sites
N = nodes H = liver L = lung M = marrow
S = spleen P = pleura O = bone D = skin

Current practice assigns a clinical stage (CS) based on the findings of the clinical evaluation and a pathological stage (PS) based on the findings made as a result of invasive procedures beyond the initial biopsy.

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

A number of 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:

  • Age.
  • Performance status (PS).
  • Tumor size.
  • Lactate dehydrogenase (LDH) values.
  • The number of extranodal sites.
References
  1. 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.
  2. 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]
  3. 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]
  4. 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]

Treatment Option Overview for AIDS-Related Lymphoma

The treatment of patients with AIDS-related lymphomas presents the challenge of integrating therapy appropriate for the stage and histological subset of malignant lymphoma with the limitations imposed by HIV infection.[1] In addition to antitumor therapy, essential components of an optimal non-Hodgkin lymphoma treatment strategy include:[2,3]

  • Highly active antiretroviral therapy.
  • Prophylaxis for opportunistic infections.
  • Rapid recognition and treatment of intercurrent infections.

Patients with HIV positivity and underlying immunodeficiency have poor bone marrow reserve, which compromises the potential for drug dose intensity. Intercurrent opportunistic infection is a risk that may also lead to a decrease in drug delivery. Furthermore, chemotherapy itself compromises the immune system and increases the likelihood of opportunistic infection.

References
  1. Levine AM: Acquired immunodeficiency syndrome-related lymphoma: clinical aspects. Semin Oncol 27 (4): 442-53, 2000. [PUBMED Abstract]
  2. Tirelli U, Bernardi D: Impact of HAART on the clinical management of AIDS-related cancers. Eur J Cancer 37 (10): 1320-4, 2001. [PUBMED Abstract]
  3. Noy A: Optimizing treatment of HIV-associated lymphoma. Blood 134 (17): 1385-1394, 2019. [PUBMED Abstract]

Treatment of AIDS-Related Peripheral/Systemic Lymphoma

The treatment of AIDS-related lymphomas involves overcoming several problems. These are all aggressive lymphomas, which by definition are diffuse large cell/immunoblastic lymphoma or small noncleaved cell lymphoma (Burkitt lymphoma). These lymphomas frequently involve the bone marrow and central nervous system (CNS) and, therefore, are usually in an advanced stage. In addition, the immunodeficiency of AIDS and the leukopenia that is commonly seen with HIV infection makes the use of immunosuppressive chemotherapy challenging.

The introduction of highly active antiretroviral therapy (HAART) has led to a marked reduction in opportunistic infections, prolonged survival with HIV infection, and a median overall survival (OS) for patients with AIDS-related lymphoma that is comparable with the outcome in the nonimmunosuppressed population.[1–7][Level of evidence C3] The use of HAART has also allowed standard-dose and even intensive chemotherapy regimens to be given with reasonable safety to patients with AIDS-related lymphomas, which is comparable with the outcome in patients without HIV.[1–10]

Several prospective nonrandomized trials and pooled individual data from 19 prospective trials that included 1,546 patients show that the addition of rituximab to combination chemotherapy improves the complete response rate, progression-free survival, and OS.[3–6][Level of evidence C3] Several other prospective nonrandomized trials and the pooled individual data from the same 1,546 patients also show that infusional EPOCH (infusional etoposide, infusional vincristine, infusional doxorubicin, cyclophosphamide, and prednisone) produced better outcomes than did CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) (hazard ratioOS, 0.33; P = .03).[3,6,7][Level of evidence C3] Concurrent use of HAART with the infusional EPOCH regimen is controversial; one group advocated for HAART after completion of chemotherapy,[7] while others allowed concurrent therapy.[6]

For patients with Burkitt lymphoma, dose-modified regimens such as R-CODOX (cyclophosphamide, doxorubicin, vincristine, methotrexate, cytarabine and rituximab)-M/IVAC (ifosfamide, etoposide, and high-dose cytarabine) or R-EPOCH (etoposide, prednisone, vincristine, and doxorubicin in combination with rituximab) have shown good results with concurrent or sequential HAART.[7,11,12]

Patients at risk of subsequent CNS involvement include those with bone marrow involvement or those with EBV identified in the primary tumor or in the cerebrospinal fluid (i.e., by polymerase chain reaction).[13,14] Intrathecal chemotherapy is usually considered for patients who are at higher risk of CNS involvement.

Highly selected patients with resistant or relapsed lymphoma after first-line chemotherapy and with continued responsiveness to HAART underwent second-line chemotherapy followed by high-dose therapy and autologous peripheral stem cell transplant. Long-term survivors have been reported anecdotally for these highly selected patients who relapsed.[15–18][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. Mounier N, Spina M, Gabarre J, et al.: AIDS-related non-Hodgkin lymphoma: final analysis of 485 patients treated with risk-adapted intensive chemotherapy. Blood 107 (10): 3832-40, 2006. [PUBMED Abstract]
  2. Weiss R, Mitrou P, Arasteh K, et al.: Acquired immunodeficiency syndrome-related lymphoma: simultaneous treatment with combined cyclophosphamide, doxorubicin, vincristine, and prednisone chemotherapy and highly active antiretroviral therapy is safe and improves survival–results of the German Multicenter Trial. Cancer 106 (7): 1560-8, 2006. [PUBMED Abstract]
  3. Barta SK, Xue X, Wang D, et al.: Treatment factors affecting outcomes in HIV-associated non-Hodgkin lymphomas: a pooled analysis of 1546 patients. Blood 122 (19): 3251-62, 2013. [PUBMED Abstract]
  4. Wyen C, Jensen B, Hentrich M, et al.: Treatment of AIDS-related lymphomas: rituximab is beneficial even in severely immunosuppressed patients. AIDS 26 (4): 457-64, 2012. [PUBMED Abstract]
  5. Levine AM, Noy A, Lee JY, et al.: Pegylated liposomal doxorubicin, rituximab, cyclophosphamide, vincristine, and prednisone in AIDS-related lymphoma: AIDS Malignancy Consortium Study 047. J Clin Oncol 31 (1): 58-64, 2013. [PUBMED Abstract]
  6. Sparano JA, Lee JY, Kaplan LD, et al.: Rituximab plus concurrent infusional EPOCH chemotherapy is highly effective in HIV-associated B-cell non-Hodgkin lymphoma. Blood 115 (15): 3008-16, 2010. [PUBMED Abstract]
  7. Dunleavy K, Little RF, Pittaluga S, et al.: The role of tumor histogenesis, FDG-PET, and short-course EPOCH with dose-dense rituximab (SC-EPOCH-RR) in HIV-associated diffuse large B-cell lymphoma. Blood 115 (15): 3017-24, 2010. [PUBMED Abstract]
  8. Ratner L, Lee J, Tang S, et al.: Chemotherapy for human immunodeficiency virus-associated non-Hodgkin’s lymphoma in combination with highly active antiretroviral therapy. J Clin Oncol 19 (8): 2171-8, 2001. [PUBMED Abstract]
  9. Wang ES, Straus DJ, Teruya-Feldstein J, et al.: Intensive chemotherapy with cyclophosphamide, doxorubicin, high-dose methotrexate/ifosfamide, etoposide, and high-dose cytarabine (CODOX-M/IVAC) for human immunodeficiency virus-associated Burkitt lymphoma. Cancer 98 (6): 1196-205, 2003. [PUBMED Abstract]
  10. Cortes J, Thomas D, Rios A, et al.: Hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone and highly active antiretroviral therapy for patients with acquired immunodeficiency syndrome-related Burkitt lymphoma/leukemia. Cancer 94 (5): 1492-9, 2002. [PUBMED Abstract]
  11. Noy A: Optimizing treatment of HIV-associated lymphoma. Blood 134 (17): 1385-1394, 2019. [PUBMED Abstract]
  12. Noy A, Kaplan L, Lee J: Feasibility and toxicity of a modified dose intensive R-CODOX-M/IVAC for HIV-associated Burkitt and atypical Burkitt lymphoma (BL): preliminary results of a prospective multicenter phase II trial of the AIDS Malignancy Consortium (AMC). [Abstract] Blood 114 (22): A-3673, 2009.
  13. Cingolani A, Gastaldi R, Fassone L, et al.: Epstein-Barr virus infection is predictive of CNS involvement in systemic AIDS-related non-Hodgkin’s lymphomas. J Clin Oncol 18 (19): 3325-30, 2000. [PUBMED Abstract]
  14. Scadden DT: Epstein-Barr virus, the CNS, and AIDS-related lymphomas: as close as flame to smoke. J Clin Oncol 18 (19): 3323-4, 2000. [PUBMED Abstract]
  15. Re A, Michieli M, Casari S, et al.: High-dose therapy and autologous peripheral blood stem cell transplantation as salvage treatment for AIDS-related lymphoma: long-term results of the Italian Cooperative Group on AIDS and Tumors (GICAT) study with analysis of prognostic factors. Blood 114 (7): 1306-13, 2009. [PUBMED Abstract]
  16. Krishnan A, Molina A, Zaia J, et al.: Durable remissions with autologous stem cell transplantation for high-risk HIV-associated lymphomas. Blood 105 (2): 874-8, 2005. [PUBMED Abstract]
  17. Costello RT, Zerazhi H, Charbonnier A, et al.: Intensive sequential chemotherapy with hematopoietic growth factor support for non-Hodgkin lymphoma in patients infected with the human immunodeficiency virus. Cancer 100 (4): 667-76, 2004. [PUBMED Abstract]
  18. Balsalobre P, Díez-Martín JL, Re A, et al.: Autologous stem-cell transplantation in patients with HIV-related lymphoma. J Clin Oncol 27 (13): 2192-8, 2009. [PUBMED Abstract]

Treatment of AIDS-Related Primary Central Nervous System Lymphoma

As with other AIDS-related lymphomas, primary central nervous system (CNS) lymphoma (PCNSL) is an aggressive B-cell neoplasm, either diffuse large B-cell or diffuse immunoblastic non-Hodgkin lymphoma (a subtype of diffuse large B-cell lymphoma). AIDS-related PCNSL has been reported to have a 100% association with Epstein-Barr virus (EBV).[1] These patients usually have evidence of low CD4-positive T lymphocyte counts, high HIV viral load, severe debilitation, and focal neurological symptoms such as seizures, changes in mental status, and paralysis.

Computed tomographic scans show contrast-enhancing mass lesions that may not always be distinguished from other CNS diseases, such as toxoplasmosis, that occur in patients with AIDS.[2] Magnetic resonance imaging studies using gadolinium contrast may be a more useful initial diagnostic tool in differentiating lymphoma from cerebral toxoplasmosis or progressive multifocal leukoencephalopathy. Lymphoma tends to present with large lesions, which are enhanced by gadolinium. In cerebral toxoplasmosis, ring enhancement is very common, lesions tend to be smaller, and multiple lesions are seen.[3–5] Use of positron emission scanning has demonstrated an improved ability to distinguish PCNSL from toxoplasmosis.[6,7] PCNSL has an increased uptake while toxoplasmosis lesions are metabolically inactive. Antibodies against toxoplasmosis may also be very useful because most cerebral toxoplasmosis occurs as a consequence of reactivity of a previous infection. If the immunoglobulin G titer is less than 1:4, the disease is unlikely to be toxoplasmotic. A lumbar puncture may be useful to detect as many as 23% of patients with malignant cells in their cerebrospinal fluid (CSF). Evaluating the CSF for EBV DNA may be a useful lymphoma-specific tool because EBV is present in all patients with PCNSL. Despite the many evaluations, however, most patients with PCNSL require a pathological diagnosis.[8–10] Diagnosis is made by biopsy. Sometimes, a biopsy is attempted only after failure of antibiotics for toxoplasmosis, which will produce clinical and radiographic improvement within 1 to 3 weeks in patients with cerebral toxoplasmosis.[11]

Radiation therapy alone has usually been used in this group of patients. With doses in the range of 35 Gy to 40 Gy, median duration of survival has been only 72 to 119 days.[2,12,13] Survival is longer in younger patients with better performance status and the absence of opportunistic infection.[14] In the highly active antiretroviral therapy (HAART) era, a median survival of 18 months has been seen with radiation therapy alone.[15] An anecdotal report using HAART and high-dose methotrexate for patients with AIDS-related PCNSL showed a median survival that had not been reached with a median follow-up of 27 months.[16] Most patients respond to treatment by showing partial improvement in neurological symptoms. Autopsies have revealed that these patients die of opportunistic infections as well as tumor progression. Treatment of these patients is also complicated by other AIDS-related CNS infections, including subacute AIDS encephalitis, cytomegalovirus encephalitis, and toxoplasmosis encephalitis. Spontaneous remissions have been reported after HAART.[17]

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. MacMahon EM, Glass JD, Hayward SD, et al.: Epstein-Barr virus in AIDS-related primary central nervous system lymphoma. Lancet 338 (8773): 969-73, 1991. [PUBMED Abstract]
  2. Goldstein JD, Dickson DW, Moser FG, et al.: Primary central nervous system lymphoma in acquired immune deficiency syndrome. A clinical and pathologic study with results of treatment with radiation. Cancer 67 (11): 2756-65, 1991. [PUBMED Abstract]
  3. Nyberg DA, Federle MP: AIDS-related Kaposi sarcoma and lymphomas. Semin Roentgenol 22 (1): 54-65, 1987. [PUBMED Abstract]
  4. Fine HA, Mayer RJ: Primary central nervous system lymphoma. Ann Intern Med 119 (11): 1093-104, 1993. [PUBMED Abstract]
  5. Ciricillo SF, Rosenblum ML: Use of CT and MR imaging to distinguish intracranial lesions and to define the need for biopsy in AIDS patients. J Neurosurg 73 (5): 720-4, 1990. [PUBMED Abstract]
  6. Hoffman JM, Waskin HA, Schifter T, et al.: FDG-PET in differentiating lymphoma from nonmalignant central nervous system lesions in patients with AIDS. J Nucl Med 34 (4): 567-75, 1993. [PUBMED Abstract]
  7. Pierce MA, Johnson MD, Maciunas RJ, et al.: Evaluating contrast-enhancing brain lesions in patients with AIDS by using positron emission tomography. Ann Intern Med 123 (8): 594-8, 1995. [PUBMED Abstract]
  8. Cinque P, Brytting M, Vago L, et al.: Epstein-Barr virus DNA in cerebrospinal fluid from patients with AIDS-related primary lymphoma of the central nervous system. Lancet 342 (8868): 398-401, 1993. [PUBMED Abstract]
  9. Cingolani A, De Luca A, Larocca LM, et al.: Minimally invasive diagnosis of acquired immunodeficiency syndrome-related primary central nervous system lymphoma. J Natl Cancer Inst 90 (5): 364-9, 1998. [PUBMED Abstract]
  10. Yarchoan R, Jaffe ES, Little R: Diagnosing central nervous system lymphoma in the setting of AIDS: a step forward. J Natl Cancer Inst 90 (5): 346-7, 1998. [PUBMED Abstract]
  11. Mathews C, Barba D, Fullerton SC: Early biopsy versus empiric treatment with delayed biopsy of non-responders in suspected HIV-associated cerebral toxoplasmosis: a decision analysis. AIDS 9 (11): 1243-50, 1995. [PUBMED Abstract]
  12. Baumgartner JE, Rachlin JR, Beckstead JH, et al.: Primary central nervous system lymphomas: natural history and response to radiation therapy in 55 patients with acquired immunodeficiency syndrome. J Neurosurg 73 (2): 206-11, 1990. [PUBMED Abstract]
  13. Remick SC, Diamond C, Migliozzi JA, et al.: Primary central nervous system lymphoma in patients with and without the acquired immune deficiency syndrome. A retrospective analysis and review of the literature. Medicine (Baltimore) 69 (6): 345-60, 1990. [PUBMED Abstract]
  14. Corn BW, Donahue BR, Rosenstock JG, et al.: Performance status and age as independent predictors of survival among AIDS patients with primary CNS lymphoma: a multivariate analysis of a multi-institutional experience. Cancer J Sci Am 3 (1): 52-6, 1997 Jan-Feb. [PUBMED Abstract]
  15. Hoffmann C, Tabrizian S, Wolf E, et al.: Survival of AIDS patients with primary central nervous system lymphoma is dramatically improved by HAART-induced immune recovery. AIDS 15 (16): 2119-27, 2001. [PUBMED Abstract]
  16. 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]
  17. McGowan JP, Shah S: Long-term remission of AIDS-related primary central nervous system lymphoma associated with highly active antiretroviral therapy. AIDS 12 (8): 952-4, 1998. [PUBMED Abstract]

Latest Updates to This Summary (09/18/2024)

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 AIDS-related 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 AIDS-Related Lymphoma Treatment are:

  • Eric J. Seifter, MD (Johns Hopkins University)
  • Minh Tam Truong, MD (Boston University Medical Center)

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 AIDS-Related Lymphoma Treatment. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: /types/lymphoma/hp/aids-related-treatment-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389186]

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.

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 Email Us.

Non-Hodgkin Lymphoma Treatment During Pregnancy (PDQ®)–Health Professional Version

Non-Hodgkin Lymphoma Treatment During Pregnancy (PDQ®)–Health Professional Version

General Information About Non-Hodgkin Lymphoma Treatment During Pregnancy

Non-Hodgkin lymphoma (NHL) is more common in older patients, with a median age at diagnosis of 68 years.[1] Hodgkin lymphoma is most common in early adulthood and in patients older than 65 years.[2] This age distribution may explain why there are fewer reports of NHL in pregnant patients.[3]

References
  1. Surveillance, Epidemiology, and End Results Program: SEER Cancer Stat Facts: Non-Hodgkin Lymphoma. Bethesda, Md: National Cancer Institute, DCCPS, Surveillance Research Program. Available online. Last accessed December 16, 2024.
  2. Surveillance, Epidemiology, and End Results Program: SEER Cancer Stat Facts: Hodgkin Lymphoma. Bethesda, Md: National Cancer Institute. Available online. Last accessed December 16, 2024.
  3. Ward FT, Weiss RB: Lymphoma and pregnancy. Semin Oncol 16 (5): 397-409, 1989. [PUBMED Abstract]

Stage Information for Non-Hodgkin Lymphoma During Pregnancy

To avoid exposure to ionizing radiation, magnetic resonance imaging is the preferred tool for staging evaluation.[1] For more information, see the Stage Information for Indolent B-Cell Non-Hodgkin Lymphoma section in Indolent B-Cell Non-Hodgkin Lymphoma Treatment.

References
  1. Nicklas AH, Baker ME: Imaging strategies in the pregnant cancer patient. Semin Oncol 27 (6): 623-32, 2000. [PUBMED Abstract]

Treatment Option Overview for Non-Hodgkin Lymphoma During Pregnancy

Table 1. Treatment Options for Non-Hodgkin Lymphoma (NHL) During Pregnancy
Stage Treatment Options
Indolent NHL During Pregnancy Delay treatment until after delivery
Aggressive NHL During Pregnancy Immediate therapy
Early delivery, when feasible
Termination of pregnancy

Treatment of Indolent Non-Hodgkin Lymphoma During Pregnancy

Treatment may be delayed for women with an indolent non-Hodgkin lymphoma.

Treatment of Aggressive Non-Hodgkin Lymphoma During Pregnancy

Immediate Therapy

According to anecdotal case series, most non-Hodgkin lymphomas (NHLs) in pregnant patients are aggressive, and delay of therapy until after delivery appears to have poor outcomes.[1–4] Consequently, some investigators favor immediate therapy, even during pregnancy.[4] In a review of 121 patient case reports from 74 papers, one-half of the patients had very aggressive lymphomas, such as Burkitt lymphoma, and one-half of the patients had involvement of the breast, ovaries, uterus, or placenta.[5] One-half of the patients received therapy antepartum, and the 6-month survival rate was 53%, with a live-birth rate of 83%.[5][Level of evidence C3]

A multicenter retrospective analysis of 50 patients described pregnancy termination in 3 patients, deferral of therapy to postpartum in 15 patients (median 30 weeks gestation), and antenatal therapy in the remaining 32 patients (median 21 weeks gestation, all done after the first trimester).[6] With a median follow-up of 41 months, the 3-year progression-free survival rate was 53%, and the overall survival rate was 82%, using R-CHOP (rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, and prednisone) or modifications of this regimen.[6][Level of evidence C3]

Early Delivery, When Feasible

For some women, early delivery, when feasible, may minimize or avoid fetal exposure to chemotherapy or radiation therapy.

Termination of Pregnancy

Termination of pregnancy in the first trimester may allow immediate therapy for women with aggressive NHL.

Effects of Treatment on Children

Evidence (treatment effect on children exposed in utero):

  • With follow-up ranging from several months to 11 years, children who were exposed to high-dose doxorubicin-containing combination chemotherapy in utero (especially during the second and third trimester) had normal growth and no evidence of congenital malformations.[4,7–9] For most of the chemotherapeutic agents used for the treatment of NHL, there are no data regarding long-term effects on children exposed in utero.
  • In one anecdotal case, a newborn exposed to a rituximab-containing regimen in utero was born with no circulating B lymphocytes. The newborn was otherwise healthy and recovered the circulating B lymphocytes by age 6 months with no unusual or persisting intercurrent infections.[10]
References
  1. Ward FT, Weiss RB: Lymphoma and pregnancy. Semin Oncol 16 (5): 397-409, 1989. [PUBMED Abstract]
  2. Steiner-Salz D, Yahalom J, Samuelov A, et al.: Non-Hodgkin’s lymphoma associated with pregnancy. A report of six cases, with a review of the literature. Cancer 56 (8): 2087-91, 1985. [PUBMED Abstract]
  3. Spitzer M, Citron M, Ilardi CF, et al.: Non-Hodgkin’s lymphoma during pregnancy. Gynecol Oncol 43 (3): 309-12, 1991. [PUBMED Abstract]
  4. Gelb AB, van de Rijn M, Warnke RA, et al.: Pregnancy-associated lymphomas. A clinicopathologic study. Cancer 78 (2): 304-10, 1996. [PUBMED Abstract]
  5. Horowitz NA, Benyamini N, Wohlfart K, et al.: Reproductive organ involvement in non-Hodgkin lymphoma during pregnancy: a systematic review. Lancet Oncol 14 (7): e275-82, 2013. [PUBMED Abstract]
  6. Evens AM, Advani R, Press OW, et al.: Lymphoma occurring during pregnancy: antenatal therapy, complications, and maternal survival in a multicenter analysis. J Clin Oncol 31 (32): 4132-9, 2013. [PUBMED Abstract]
  7. Avilés A, Díaz-Maqueo JC, Torras V, et al.: Non-Hodgkin’s lymphomas and pregnancy: presentation of 16 cases. Gynecol Oncol 37 (3): 335-7, 1990. [PUBMED Abstract]
  8. Moore DT, Taslimi MM: Multi-agent chemotherapy in a case of non-Hodgkin’s lymphoma in second trimester of pregnancy. J Tenn Med Assoc 84 (9): 435-6, 1991. [PUBMED Abstract]
  9. Nantel S, Parboosingh J, Poon MC: Treatment of an aggressive non-Hodgkin’s lymphoma during pregnancy with MACOP-B chemotherapy. Med Pediatr Oncol 18 (2): 143-5, 1990. [PUBMED Abstract]
  10. Mandal PK, Dolai TK, Bagchi B, et al.: B cell suppression in newborn following treatment of pregnant diffuse large B-cell lymphoma patient with rituximab containing regimen. Indian J Pediatr 81 (10): 1092-4, 2014. [PUBMED Abstract]

Latest Updates to This Summary (02/18/2025)

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 non-Hodgkin lymphoma during pregnancy. 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 Non-Hodgkin Lymphoma Treatment During Pregnancy 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 Non-Hodgkin Lymphoma Treatment During Pregnancy. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: /types/lymphoma/hp/non-hodgkin-lymphoma-treatment-during-pregnancy-pdq. Accessed <MM/DD/YYYY>. [PMID: 37437081]

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.

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 Email Us.

Hodgkin Lymphoma Treatment During Pregnancy (PDQ®)–Health Professional Version

Hodgkin Lymphoma Treatment During Pregnancy (PDQ®)–Health Professional Version

General Information About Hodgkin Lymphoma Treatment During Pregnancy

Hodgkin lymphoma (HL) primarily affects young women, some of whom may be pregnant. When treating a pregnant woman, an oncologist will provide therapy that minimizes risk to the fetus. Treatment choice must be individualized, taking the following into consideration:

  • The mother’s wishes.
  • The severity and aggressiveness of the HL.
  • The trimester of the pregnancy.

Stage Information for Hodgkin Lymphoma During Pregnancy

To avoid exposing a pregnant woman to ionizing radiation, magnetic resonance imaging is the preferred method for staging evaluation.[1] The presenting stage, clinical behavior, prognosis, and histological subtypes of Hodgkin lymphoma (HL) in pregnant women do not differ from those in nonpregnant women during their childbearing years.[2] For more information, see the Stage Information for HL section in Hodgkin Lymphoma Treatment.

References
  1. Nicklas AH, Baker ME: Imaging strategies in the pregnant cancer patient. Semin Oncol 27 (6): 623-32, 2000. [PUBMED Abstract]
  2. Gelb AB, van de Rijn M, Warnke RA, et al.: Pregnancy-associated lymphomas. A clinicopathologic study. Cancer 78 (2): 304-10, 1996. [PUBMED Abstract]

Treatment Options for Hodgkin Lymphoma During Pregnancy

Treatment options for Hodgkin lymphoma (HL) during pregnancy include:

  1. Watchful waiting.
  2. Radiation therapy.
  3. Chemotherapy.

In one study, the 20-year survival rate of pregnant women with HL did not differ from the 20-year survival rate of nonpregnant women who were matched for similar stage of disease, age at diagnosis, and calendar year of treatment.[1]

The long-term effects on children after chemotherapy exposure in utero are unknown.[1–5]

Based on anecdotal series, there is no evidence that a pregnancy after completion of therapy increases the relapse rate for patients in remission.[6,7]

Therapy During the First Trimester

HL that is diagnosed in the first trimester of pregnancy does not constitute an absolute indication for therapeutic abortion. Treatment options for each patient must take into account disease stage, rapidity of growth of the lymphoma, and the patient’s wishes.[8]

Watchful waiting

If the HL presents in early stage above the diaphragm and is growing slowly, patients can be observed carefully, with plans to induce delivery early and proceed with definitive therapy.[9]

Radiation therapy

Alternatively, these patients can receive radiation therapy with proper shielding.[10–13] Investigators at the MD Anderson Cancer Center reported no congenital abnormalities in 16 babies delivered after the mothers had received supradiaphragmatic radiation while the uterus was shielded with five half-value layers of lead.[14] Because of theoretical risks of the fetus developing future malignancies from even minimal scattered radiation doses outside the radiation field, postponing radiation therapy—if possible, until after delivery—should be considered.[15]

Chemotherapy

Evidence (chemotherapy during the first trimester):

  1. Chemotherapy that is administered during the first trimester has been associated with congenital abnormalities in as many as 33% of infants.[2,16] Consequently, some women may opt to continue the pregnancy and agree to radiation therapy or chemotherapy if immediate treatment is required after the first trimester.
  2. A multicenter retrospective analysis of 40 patients described pregnancy termination in 3 patients, deferral of therapy to the postpartum period in 13 patients (median 30-week gestation), and antenatal therapy given to the remaining 24 patients (median 21-week gestation, all done after the first trimester).[17]
    • With a median follow-up of 41 months, the 3-year progression-free survival (PFS) rate was 85%, and the overall survival (OS) rate was 97%, often with the use of ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine).[17][Level of evidence C3]
  3. A retrospective analysis of 39 patients from the MD Anderson Cancer Center described pregnancy termination in 3 patients, deferral of therapy to the postpartum period in 12 patients, and antenatal therapy given to 24 patients.[18]
    • Two women had a miscarriage after receiving doxorubicin-based chemotherapy during the first trimester.
    • With a median follow-up of 68 months from diagnosis, the 5-year PFS rate was 75%, and the OS rate was 82%. These rates did not differ between the antenatal and postpartum timing of therapy.[18][Level of evidence C3]

Therapy Later in Pregnancy

Watchful waiting

In the second half of pregnancy, patients can be observed carefully, and therapy can be postponed until induction of delivery at 32 to 36 weeks.[4,5,16]

Radiation therapy

As an alternative, a short course of radiation therapy can be used before delivery in cases of respiratory compromise caused by a rapidly enlarging mediastinal mass.

Chemotherapy

If chemotherapy is mandatory before delivery—such as for patients with symptomatic advanced-stage disease—vinblastine alone, given intravenously at 6 mg/m² every 2 weeks until induction of delivery, may be considered because it has not been associated with fetal abnormalities in the second half of pregnancy.[4,5] Combination chemotherapy with ABVD appears to be safe in the second half of pregnancy.[3] If chemotherapy is required after the first trimester, many clinicians prefer the combination of drugs over single-agent drugs or radiation therapy. Steroids are used both for their antitumor effect and for hastening fetal pulmonary maturity.

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. Lishner M, Zemlickis D, Degendorfer P, et al.: Maternal and foetal outcome following Hodgkin’s disease in pregnancy. Br J Cancer 65 (1): 114-7, 1992. [PUBMED Abstract]
  2. Thomas PR, Biochem D, Peckham MJ: The investigation and management of Hodgkin’s disease in the pregnant patient. Cancer 38 (3): 1443-51, 1976. [PUBMED Abstract]
  3. Avilés A, Díaz-Maqueo JC, Talavera A, et al.: Growth and development of children of mothers treated with chemotherapy during pregnancy: current status of 43 children. Am J Hematol 36 (4): 243-8, 1991. [PUBMED Abstract]
  4. Jacobs C, Donaldson SS, Rosenberg SA, et al.: Management of the pregnant patient with Hodgkin’s disease. Ann Intern Med 95 (6): 669-75, 1981. [PUBMED Abstract]
  5. Nisce LZ, Tome MA, He S, et al.: Management of coexisting Hodgkin’s disease and pregnancy. Am J Clin Oncol 9 (2): 146-51, 1986. [PUBMED Abstract]
  6. Weibull CE, Eloranta S, Smedby KE, et al.: Pregnancy and the Risk of Relapse in Patients Diagnosed With Hodgkin Lymphoma. J Clin Oncol 34 (4): 337-44, 2016. [PUBMED Abstract]
  7. Gaudio F, Nardelli C, Masciandaro P, et al.: Pregnancy rate and outcome of pregnancies in long-term survivors of Hodgkin’s lymphoma. Ann Hematol 98 (8): 1947-1952, 2019. [PUBMED Abstract]
  8. Koren G, Weiner L, Lishner M, et al.: Cancer in pregnancy: identification of unanswered questions on maternal and fetal risks. Obstet Gynecol Surv 45 (8): 509-14, 1990. [PUBMED Abstract]
  9. Anselmo AP, Cavalieri E, Enrici RM, et al.: Hodgkin’s disease during pregnancy: diagnostic and therapeutic management. Fetal Diagn Ther 14 (2): 102-5, 1999 Mar-Apr. [PUBMED Abstract]
  10. Mazonakis M, Varveris H, Fasoulaki M, et al.: Radiotherapy of Hodgkin’s disease in early pregnancy: embryo dose measurements. Radiother Oncol 66 (3): 333-9, 2003. [PUBMED Abstract]
  11. Greskovich JF, Macklis RM: Radiation therapy in pregnancy: risk calculation and risk minimization. Semin Oncol 27 (6): 633-45, 2000. [PUBMED Abstract]
  12. Fisher PM, Hancock BW: Hodgkin’s disease in the pregnant patient. Br J Hosp Med 56 (10): 529-32, 1996 Nov 20-Dec 10. [PUBMED Abstract]
  13. Friedman E, Jones GW: Fetal outcome after maternal radiation treatment of supradiaphragmatic Hodgkin’s disease. CMAJ 149 (9): 1281-3, 1993. [PUBMED Abstract]
  14. Woo SY, Fuller LM, Cundiff JH, et al.: Radiotherapy during pregnancy for clinical stages IA-IIA Hodgkin’s disease. Int J Radiat Oncol Biol Phys 23 (2): 407-12, 1992. [PUBMED Abstract]
  15. Lishner M: Cancer in pregnancy. Ann Oncol 14 (Suppl 3): iii31-6, 2003. [PUBMED Abstract]
  16. Cardonick E, Iacobucci A: Use of chemotherapy during human pregnancy. Lancet Oncol 5 (5): 283-91, 2004. [PUBMED Abstract]
  17. Evens AM, Advani R, Press OW, et al.: Lymphoma occurring during pregnancy: antenatal therapy, complications, and maternal survival in a multicenter analysis. J Clin Oncol 31 (32): 4132-9, 2013. [PUBMED Abstract]
  18. Pinnix CC, Osborne EM, Chihara D, et al.: Maternal and Fetal Outcomes After Therapy for Hodgkin or Non-Hodgkin Lymphoma Diagnosed During Pregnancy. JAMA Oncol 2 (8): 1065-9, 2016. [PUBMED Abstract]

Latest Updates to This Summary (01/13/2025)

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.

This is a new 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 Hodgkin lymphoma during pregnancy. 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 Hodgkin Lymphoma Treatment During Pregnancy 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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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 Hodgkin Lymphoma Treatment During Pregnancy. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: /types/lymphoma/hp/hodgkin-lymphoma-treatment-during-pregnancy-pdq. Accessed <MM/DD/YYYY>.

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Peripheral T-Cell Non-Hodgkin Lymphoma Treatment (PDQ®)–Health Professional Version

Peripheral T-Cell Non-Hodgkin Lymphoma Treatment (PDQ®)–Health Professional Version

General Information About Peripheral T-Cell Non-Hodgkin Lymphoma

The non-Hodgkin lymphoma (NHL) T-cell lymphomas are a heterogeneous group of T-cell lymphoproliferative malignancies, which account for less than 15% of NHLs.[1] About 85% of NHL cases are B-cell lymphomas. For more information, see Indolent B-Cell Non-Hodgkin Lymphoma Treatment and Aggressive B-Cell Non-Hodgkin Lymphoma Treatment.

T-cell lymphoma can be divided into cutaneous T-cell lymphoma (CTCL), peripheral T-cell lymphoma (PTCL), and T-cell lymphoblastic lymphoma/acute lymphocytic leukemia (T-LBL/ALL).

T-LBL/ALL arises from very early T cells, often involves the thymus, and is more common in young adults. The lymphoma form is often treated similarly to the leukemia form. For more information, see Acute Lymphoblastic Leukemia Treatment.

CTCL starts in the skin and includes mycosis fungoides, Sézary syndrome, primary cutaneous anaplastic large cell lymphoma, and others. For more information, see Mycosis Fungoides and Other Cutaneous T-Cell Lymphomas Treatment.

PTCL originates from mature T cells. It usually arises from lymphoid tissues but can spread to other organs. Subsets of PTCL include anaplastic large cell lymphoma (ALCL), angioimmunoblastic T-cell lymphoma (AITL), extranodal natural killer/T-cell lymphoma (ENK/TCL), PTCL not otherwise specified (PTCL-NOS), enteropathy-associated T-cell lymphoma (EATL), hepatosplenic T-cell lymphoma (HSTCL), adult T-cell leukemia/lymphoma (ATL), T-cell prolymphocytic leukemia (T-PLL), and others.

Incidence and Mortality

T-cell lymphomas make up less than 15% of NHL cases. Most T-cell lymphoma subtypes are associated with worse outcomes than those of B-cell lymphomas.[1]

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

Prognosis in PTCL varies depending on subtype, stage, and other factors. In general, PTCL is associated with a poor prognosis, with a 5-year survival rate of approximately 30% to 40%.[2,3] While outcomes are better for patients with ALK-positive ALCL, with a median 5-year overall survival (OS) closer to 70% to 80%,[2–4] other subsets are associated with worse survival, such as ALK-negative ALCL, AITL, PTCL-NOS, HSTCL, EATL, and ENK/TCL.[5,6]

Unlike B-cell NHLs, which include both indolent and aggressive forms, most PTCLs are considered aggressive.[7] As with most other aggressive lymphomas, PTCLs are often curable with systemic therapy, though effective treatment options are more limited, particularly in the relapsed or refractory setting.[8,9]

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 be included in these studies.

In addition to screening for HIV among patients with aggressive lymphomas, active hepatitis B or hepatitis C can be assessed before treatment with chemotherapy.[10,11] Patients with detectable hepatitis B virus (HBV) benefit from prophylaxis with entecavir.[12,13] 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. Prophylactic nucleoside therapy lowered HBV reactivation from 10.8% to 2.1% in a retrospective study of 326 patients.[14] Prophylaxis for herpes zoster with acyclovir or valacyclovir and prophylaxis for pneumocystis with trimethoprim/sulfamethoxazole or dapsone are usually given to patients receiving combination chemotherapy.

References
  1. American Cancer Society: Types of T-cell lymphoma. American Cancer Society, 2018. Available online. Last accessed May 13, 2025.
  2. Vose J, Armitage J, Weisenburger D, et al.: International peripheral T-cell and natural killer/T-cell lymphoma study: pathology findings and clinical outcomes. J Clin Oncol 26 (25): 4124-30, 2008. [PUBMED Abstract]
  3. Ellin F, Landström J, Jerkeman M, et al.: Real-world data on prognostic factors and treatment in peripheral T-cell lymphomas: a study from the Swedish Lymphoma Registry. Blood 124 (10): 1570-7, 2014. [PUBMED Abstract]
  4. Sibon D, Fournier M, Brière J, et al.: Long-term outcome of adults with systemic anaplastic large-cell lymphoma treated within the Groupe d’Etude des Lymphomes de l’Adulte trials. J Clin Oncol 30 (32): 3939-46, 2012. [PUBMED Abstract]
  5. Petrich AM, Helenowski IB, Bryan LJ, et al.: Factors predicting survival in peripheral T-cell lymphoma in the USA: a population-based analysis of 8802 patients in the modern era. Br J Haematol 168 (5): 708-18, 2015. [PUBMED Abstract]
  6. Foss FM, Horwitz SM, Civallero M, et al.: Incidence and outcomes of rare T cell lymphomas from the T Cell Project: hepatosplenic, enteropathy associated and peripheral gamma delta T cell lymphomas. Am J Hematol 95 (2): 151-155, 2020. [PUBMED Abstract]
  7. Armitage JO: The aggressive peripheral T-cell lymphomas: 2017. Am J Hematol 92 (7): 706-715, 2017. [PUBMED Abstract]
  8. Bellei M, Foss FM, Shustov AR, et al.: The outcome of peripheral T-cell lymphoma patients failing first-line therapy: a report from the prospective, International T-Cell Project. Haematologica 103 (7): 1191-1197, 2018. [PUBMED Abstract]
  9. Lansigan F, Horwitz SM, Pinter-Brown LC, et al.: Outcomes for Relapsed and Refractory Peripheral T-Cell Lymphoma Patients after Front-Line Therapy from the COMPLETE Registry. Acta Haematol 143 (1): 40-50, 2020. [PUBMED Abstract]
  10. 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]
  11. 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]
  12. 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]
  13. 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]
  14. 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]

Late Effects of Treatment of Peripheral T-Cell Non-Hodgkin Lymphoma

Late effects of treatment of non-Hodgkin lymphoma (NHL) have been observed. Impaired fertility may occur after exposure to alkylating agents.[1] For as many as three decades after diagnosis, patients are at a significantly elevated risk of developing second primary cancers, especially the following:[2–5]

  • 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.[1,6]

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.[3,7–14] Most of these patients show clonal hematopoiesis even before the transplant, suggesting that the hematologic injury usually occurs during induction or reinduction chemotherapy.[9,15,16] 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.[17]

A study of young women who received autologous BMT reported successful pregnancies with children born free of congenital abnormalities.[18] Late-occurring venous thromboembolism can occur after allogeneic or autologous BMT.[19]

Some patients have osteopenia or osteoporosis at the start of therapy; bone density may worsen after therapy for lymphoma.[20]

References
  1. 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]
  2. 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]
  3. 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]
  4. 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]
  5. 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]
  6. 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]
  7. 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]
  8. 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]
  9. 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]
  10. 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]
  11. 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]
  12. 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]
  13. 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]
  14. 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]
  15. 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]
  16. 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]
  17. 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]
  18. 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]
  19. 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]
  20. 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]

Cellular Classification of Peripheral T-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]

Current Classification Systems

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.[3,4]

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:

Subtypes of Peripheral T-Cell Non-Hodgkin Lymphoma

Peripheral T-cell non-Hodgkin lymphoma includes the following subtypes, among others:

  • Anaplastic large cell lymphoma.
  • 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).
  • Peripheral T-cell lymphoma, not otherwise specified.
  • Extranodal NK/T-cell lymphoma.
  • Enteropathy-associated and monomorphic epitheliotropic intestinal T-cell lymphoma.
  • Hepatosplenic T-cell lymphoma.
  • Indolent T-cell lymphoma of the gastrointestinal tract.
  • Adult T-cell leukemia/lymphoma.
  • T-cell prolymphocytic leukemia.
  • Cutaneous T-cell lymphoma (including mycosis fungoides and Sézary syndrome, subcutaneous panniculitis-like T-cell lymphoma, primary cutaneous anaplastic large cell lymphoma, primary cutaneous gamma-delta T-cell lymphoma, and others). For more information, see Mycosis Fungoides and Other Cutaneous T-Cell Lymphomas Treatment.
  • T-cell granular lymphocytic leukemia. For more information, see Chronic Lymphocytic Leukemia Treatment.
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. 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]
  4. Society for Hematopathology Program: Society for Hematopathology Program. Am J Surg Pathol 21 (1): 114-121, 1997.

Stage Information for Peripheral T-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.

Staging Subclassification System

Lugano classification

The American Joint Committee on Cancer (AJCC) has adopted the Lugano classification to evaluate and stage lymphoma.[10] The Lugano classification system replaces the Ann Arbor classification system, which was adopted in 1971 at the Ann Arbor Conference,[11] with some modifications 18 years later from the Cotswolds meeting.[12,13]

Table 1. 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 2. 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:[14]

  • 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%.
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. 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.
  11. 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]
  12. 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]
  13. 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]
  14. 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]

Treatment of Anaplastic Large Cell Lymphoma

Anaplastic large cell lymphoma (ALCL) is a peripheral T-cell lymphoma associated with the CD30 antigen. The translocation of chromosomes 2 and 5 creates a unique fusion protein with a nucleophosmin–anaplastic lymphoma kinase (ALK).[1,2] Patients whose lymphomas express ALK by immunohistochemistry are usually younger and may have systemic symptoms, extranodal disease, and advanced-stage disease. However, they have a more favorable survival rate than patients with ALK-negative disease.[3,4] ALK-negative ALCL has been further characterized by DUSP22 chromosomal rearrangements and the presence of TP63 pathogenic variants. While DUSP22 rearrangements are associated with improved prognosis, TP63 pathogenic variants are associated with poorer outcomes.[5]

Treatment Options for Anaplastic Large Cell Lymphoma

  • A prospective randomized trial included 452 patients with CD30-positive T-cell lymphoma (CD30 expression >10%). Of these patients, 70% had ALCL (22% with ALK-positive disease and 48% with ALK-negative disease). The trial compared the previously used standard regimen, CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone), with brentuximab vedotin (an anti-CD30 monoclonal antibody conjugated to a cytotoxic agent) combined with cyclophosphamide, doxorubicin, and prednisone (A+CHP regimen).[6]
    • With a median follow-up of 47.6 months, the 5-year overall survival (OS) rates were 70.1% (95% confidence interval [CI], 63.3%–75.9%) for patients who received A+CHP and 61.0% (95% CI, 54.0%–67.3%) for patients who received CHOP (hazard ratio [HR], 0.72; 95% CI, 0.53–0.99).[7][Level of evidence A1]
    • The 5-year progression-free survival (PFS) rates were 51.4% (95% CI, 42.8%–59.4%) for patients who received A+CHP and 43.0% (95% CI, 35.8%–50.0%) for patients who received CHOP (HR, 0.70; 95% CI, 0.53–0.91).
    • This established A+CHP as a new option for patients with ALCL or other CD30-positive T-cell lymphomas, such as angioimmunoblastic T-cell lymphoma and peripheral T-cell lymphoma, not otherwise specified.
  • For patients with relapsed disease, anecdotal responses have been reported for brentuximab vedotin,[8–11] belinostat,[12] romidepsin,[13] and pralatrexate.[14][Level of evidence C3]
  • In a phase II study (NCT00866047), 66% of 58 patients attained a complete response with brentuximab vedotin.[11]
    • At a median follow-up of 58 months, the 5-year PFS rate was 57% (95% CI, 41%–74%), and the 5-year OS rate was 79% (95% CI, 65%–92%). Of the patients achieving a complete response, 42% underwent hematopoietic stem cell transplant (SCT).[11][Level of evidence C3]
  • In a retrospective review, 39 patients with relapsed disease had a 3-year PFS rate of 50% after autologous or allogeneic SCT.[15][Level of evidence C2]
  • A retrospective review of 84 patients with ALK-negative ALCL suggested a survival benefit with autologous SCT. This hypothesis requires confirmation in a randomized prospective trial.[16][Level of evidence C3]
  • A retrospective study included 182 patients with relapsed or refractory ALCL (23% ALK-positive, 21% ALK-negative, and 56% ALK-unknown) who underwent allogeneic SCT.[17]
    • The 5-year PFS rate was 41% (95% CI, 34%–49%), and the 5-year OS rate was 41% (95% CI, 49%–64%).[17][Level of evidence C3]
    • On multivariate analysis, African American race (HR, 2.7; 95% CI, 1.6–4.8; P < .001) and refractory disease at time of allogeneic SCT (HR, 3.2; 95% CI, 1.6–6.2; P < .001) were predictive factors for inferior OS.
    • Despite ALK positivity being a favorable prognostic factor, outcomes after allogeneic SCT in this study did not vary significantly according to ALK status.

ALCL in children is usually characterized by systemic and cutaneous disease and has high response rates and good OS with doxorubicin-based combination chemotherapy.[18] The ALK inhibitor crizotinib has been combined with chemotherapy for previously untreated pediatric patients, and crizotinib has been used to control disease in multiply relapsed pediatric patients.[19,20] Crizotinib is associated with a high risk (around 25%) of thromboembolism, especially pulmonary embolism, and prophylaxis is recommended. There are no reports supporting the use of crizotinib in adults.

Breast Implant–Associated Anaplastic Large Cell Lymphoma

Patients with breast implant–associated ALCL may do well without chemotherapy after capsulectomy and implant removal if the disease is confined to the fibrous capsule, and no associated mass or lymphadenopathy is present.[21–24] Most patients with breast implant–associated ALCL have a characteristic deletion at 20Q13.13 that may help to diagnostically distinguish it from cutaneous or systemic ALCL.[25]

Primary cutaneous ALCL is a distinct entity that is typically ALK-negative and has a very indolent/low-grade clinical course. Breast implant–associated ALCL almost always occurs with implants that have a textured surface (so-called macrotextured implants) that helps adhere to the breast. Warnings, suspensions, and bans of macrotextured implants have occurred worldwide. The risk of breast implant–associated ALCL is approximately 1 in 12,000 people, but this risk may rise with further follow-up.[26]

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. Bai RY, Ouyang T, Miething C, et al.: Nucleophosmin-anaplastic lymphoma kinase associated with anaplastic large-cell lymphoma activates the phosphatidylinositol 3-kinase/Akt antiapoptotic signaling pathway. Blood 96 (13): 4319-27, 2000. [PUBMED Abstract]
  2. Hapgood G, Savage KJ: The biology and management of systemic anaplastic large cell lymphoma. Blood 126 (1): 17-25, 2015. [PUBMED Abstract]
  3. Gascoyne RD, Aoun P, Wu D, et al.: Prognostic significance of anaplastic lymphoma kinase (ALK) protein expression in adults with anaplastic large cell lymphoma. Blood 93 (11): 3913-21, 1999. [PUBMED Abstract]
  4. Sibon D, Fournier M, Brière J, et al.: Long-term outcome of adults with systemic anaplastic large-cell lymphoma treated within the Groupe d’Etude des Lymphomes de l’Adulte trials. J Clin Oncol 30 (32): 3939-46, 2012. [PUBMED Abstract]
  5. Onaindia A, de Villambrosía SG, Prieto-Torres L, et al.: DUSP22-rearranged anaplastic lymphomas are characterized by specific morphological features and a lack of cytotoxic and JAK/STAT surrogate markers. Haematologica 104 (4): e158-e162, 2019. [PUBMED Abstract]
  6. Horwitz S, O’Connor OA, Pro B, et al.: Brentuximab vedotin with chemotherapy for CD30-positive peripheral T-cell lymphoma (ECHELON-2): a global, double-blind, randomised, phase 3 trial. Lancet 393 (10168): 229-240, 2019. [PUBMED Abstract]
  7. Horwitz S, O’Connor OA, Pro B, et al.: The ECHELON-2 Trial: 5-year results of a randomized, phase III study of brentuximab vedotin with chemotherapy for CD30-positive peripheral T-cell lymphoma. Ann Oncol 33 (3): 288-298, 2022. [PUBMED Abstract]
  8. Younes A, Bartlett NL, Leonard JP, et al.: Brentuximab vedotin (SGN-35) for relapsed CD30-positive lymphomas. N Engl J Med 363 (19): 1812-21, 2010. [PUBMED Abstract]
  9. Pro B, Advani R, Brice P, et al.: Brentuximab vedotin (SGN-35) in patients with relapsed or refractory systemic anaplastic large-cell lymphoma: results of a phase II study. J Clin Oncol 30 (18): 2190-6, 2012. [PUBMED Abstract]
  10. Prince HM, Kim YH, Horwitz SM, et al.: Brentuximab vedotin or physician’s choice in CD30-positive cutaneous T-cell lymphoma (ALCANZA): an international, open-label, randomised, phase 3, multicentre trial. Lancet 390 (10094): 555-566, 2017. [PUBMED Abstract]
  11. Pro B, Advani R, Brice P, et al.: Five-year results of brentuximab vedotin in patients with relapsed or refractory systemic anaplastic large cell lymphoma. Blood 130 (25): 2709-2717, 2017. [PUBMED Abstract]
  12. O’Connor OA, Horwitz S, Masszi T, et al.: Belinostat in Patients With Relapsed or Refractory Peripheral T-Cell Lymphoma: Results of the Pivotal Phase II BELIEF (CLN-19) Study. J Clin Oncol 33 (23): 2492-9, 2015. [PUBMED Abstract]
  13. Coiffier B, Pro B, Prince HM, et al.: Results from a pivotal, open-label, phase II study of romidepsin in relapsed or refractory peripheral T-cell lymphoma after prior systemic therapy. J Clin Oncol 30 (6): 631-6, 2012. [PUBMED Abstract]
  14. O’Connor OA, Horwitz S, Hamlin P, et al.: Phase II-I-II study of two different doses and schedules of pralatrexate, a high-affinity substrate for the reduced folate carrier, in patients with relapsed or refractory lymphoma reveals marked activity in T-cell malignancies. J Clin Oncol 27 (26): 4357-64, 2009. [PUBMED Abstract]
  15. Smith SM, Burns LJ, van Besien K, et al.: Hematopoietic cell transplantation for systemic mature T-cell non-Hodgkin lymphoma. J Clin Oncol 31 (25): 3100-9, 2013. [PUBMED Abstract]
  16. Brink M, Meeuwes FO, van der Poel MWM, et al.: Impact of etoposide and ASCT on survival among patients aged <65 years with stage II to IV PTCL: a population-based cohort study. Blood 140 (9): 1009-1019, 2022. [PUBMED Abstract]
  17. Furqan F, Ahn KW, Chen Y, et al.: Allogeneic haematopoietic cell transplant in patients with relapsed/refractory anaplastic large cell lymphoma. Br J Haematol 200 (1): 54-63, 2023. [PUBMED Abstract]
  18. Seidemann K, Tiemann M, Schrappe M, et al.: Short-pulse B-non-Hodgkin lymphoma-type chemotherapy is efficacious treatment for pediatric anaplastic large cell lymphoma: a report of the Berlin-Frankfurt-Münster Group Trial NHL-BFM 90. Blood 97 (12): 3699-706, 2001. [PUBMED Abstract]
  19. Lowe EJ, Reilly AF, Lim MS, et al.: Crizotinib in Combination With Chemotherapy for Pediatric Patients With ALK+ Anaplastic Large-Cell Lymphoma: The Results of Children’s Oncology Group Trial ANHL12P1. J Clin Oncol 41 (11): 2043-2053, 2023. [PUBMED Abstract]
  20. Mossé YP, Voss SD, Lim MS, et al.: Targeting ALK With Crizotinib in Pediatric Anaplastic Large Cell Lymphoma and Inflammatory Myofibroblastic Tumor: A Children’s Oncology Group Study. J Clin Oncol 35 (28): 3215-3221, 2017. [PUBMED Abstract]
  21. Miranda RN, Aladily TN, Prince HM, et al.: Breast implant-associated anaplastic large-cell lymphoma: long-term follow-up of 60 patients. J Clin Oncol 32 (2): 114-20, 2014. [PUBMED Abstract]
  22. Clemens MW, Medeiros LJ, Butler CE, et al.: Complete Surgical Excision Is Essential for the Management of Patients With Breast Implant-Associated Anaplastic Large-Cell Lymphoma. J Clin Oncol 34 (2): 160-8, 2016. [PUBMED Abstract]
  23. Mehta-Shah N, Clemens MW, Horwitz SM: How I treat breast implant-associated anaplastic large cell lymphoma. Blood 132 (18): 1889-1898, 2018. [PUBMED Abstract]
  24. Jaffe ES, Ashar BS, Clemens MW, et al.: Best Practices Guideline for the Pathologic Diagnosis of Breast Implant-Associated Anaplastic Large-Cell Lymphoma. J Clin Oncol 38 (10): 1102-1111, 2020. [PUBMED Abstract]
  25. Los-de Vries GT, de Boer M, van Dijk E, et al.: Chromosome 20 loss is characteristic of breast implant-associated anaplastic large cell lymphoma. Blood 136 (25): 2927-2932, 2020. [PUBMED Abstract]
  26. Kinslow CJ, Kim A, Sanchez GI, et al.: Incidence of Anaplastic Large-Cell Lymphoma of the Breast in the US, 2000 to 2018. JAMA Oncol 8 (9): 1354-1356, 2022. [PUBMED Abstract]

Treatment of Nodal Lymphomas of T Follicular Helper Cell Origin

The 2016 World Health Organization (WHO) classification recognized nodal lymphomas of T follicular helper (TFH) cell origin as a distinct subset of peripheral T-cell lymphoma (PTCL). Unified by a CD4+ TFH cell origin, this subset includes:[1]

  • Angioimmunoblastic T-cell lymphoma (AITL or ATCL).
  • Follicular peripheral T-cell lymphoma (F-PTCL).
  • Nodal peripheral T-cell lymphoma with follicular helper phenotype (nodal PTCL with TFH phenotype).

AITL is the most common of these entities and is the second-most common subtype of PTCL.[2–5] Patients often present with profound lymphadenopathy, fever, night sweats, weight loss, skin rash, a positive Coombs test, and polyclonal hypergammaglobulinemia.[6] Opportunistic infections are frequent because of an underlying immune deficiency. B-cell Epstein-Barr virus genomes are detected in most affected patients.[7] For more information about weight loss, see Nutrition in Cancer Care and for more information about skin rash, see Pruritus.

The remaining subtypes of nodal lymphomas of TFH cell origin, including F-PTCL and nodal PTCL with TFH phenotype, are derived from the same cell of origin. However, unlike AITL, these subtypes are not associated with hypervascularity on nodal biopsy and often lack the hyperinflammatory symptoms characteristic of AITL.[1]

Treatment Options for Nodal Lymphomas of T Follicular Helper Cell Origin

Doxorubicin-based combination chemotherapy, such as the CHO(E)P regimen (cyclophosphamide, doxorubicin, vincristine, etoposide, and prednisone), is commonly used for patients with AITL and other nodal lymphomas of TFH cell origin.[2,5] For CD30-positive cases, brentuximab vedotin combined with cyclophosphamide, doxorubicin, and prednisone is the proposed standard of care.[8][Level of evidence C3] Patients with AITL were included in a clinical trial involving mostly patients with anaplastic large cell lymphoma. A benefit for this smaller AITL subgroup cannot be established.[8,9][Level of evidence C3] For more information, see the Treatment of Anaplastic Large Cell Lymphoma section.

The International Peripheral T-Cell Lymphoma Project involving 22 international centers identified 243 patients with AITL. The 5-year overall survival rate was 33%, and the failure-free survival rate was 18%.[10] Myeloablative chemotherapy and radiation therapy with autologous or allogeneic peripheral stem cell support has been described in anecdotal reports.[11–16][Level of evidence C3] Anecdotal responses have been reported for patients who received cyclosporine,[17] pralatrexate,[18] bendamustine,[19] belinostat,[20] the histone deacetylase inhibitor romidepsin, hypomethylating agents (HMAs),[21,22] and brentuximab vedotin (even if there is little or no CD30 expression on the lymphoma).[23,24][Level of evidence C3] Occasional spontaneous remissions and protracted responses to steroids only have been reported. Given increased frequency of pathogenic variants in genes that regulate epigenetic modification—such as TET2, IDH2, and DNMT3A—there is increased interest in therapies targeting these aberrations with HMAs and histone deacetylase inhibitors with anecdotal reports of improved efficacy compared with other subsets of PTCL.[21,22,25][Level of evidence C3] Further studies are needed to better characterize the efficacy of this approach.[21,22,25]

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. Yoon SE, Cho J, Kim YJ, et al.: Comprehensive analysis of clinical, pathological, and genomic characteristics of follicular helper T-cell derived lymphomas. Exp Hematol Oncol 10 (1): 33, 2021. [PUBMED Abstract]
  2. Siegert W, Agthe A, Griesser H, et al.: Treatment of angioimmunoblastic lymphadenopathy (AILD)-type T-cell lymphoma using prednisone with or without the COPBLAM/IMVP-16 regimen. A multicenter study. Kiel Lymphoma Study Group. Ann Intern Med 117 (5): 364-70, 1992. [PUBMED Abstract]
  3. Jaffe ES: Angioimmunoblastic T-cell lymphoma: new insights, but the clinical challenge remains. Ann Oncol 6 (7): 631-2, 1995. [PUBMED Abstract]
  4. Siegert W, Nerl C, Agthe A, et al.: Angioimmunoblastic lymphadenopathy (AILD)-type T-cell lymphoma: prognostic impact of clinical observations and laboratory findings at presentation. The Kiel Lymphoma Study Group. Ann Oncol 6 (7): 659-64, 1995. [PUBMED Abstract]
  5. Lunning MA, Vose JM: Angioimmunoblastic T-cell lymphoma: the many-faced lymphoma. Blood 129 (9): 1095-1102, 2017. [PUBMED Abstract]
  6. Rizvi MA, Evens AM, Tallman MS, et al.: T-cell non-Hodgkin lymphoma. Blood 107 (4): 1255-64, 2006. [PUBMED Abstract]
  7. Bräuninger A, Spieker T, Willenbrock K, et al.: Survival and clonal expansion of mutating “forbidden” (immunoglobulin receptor-deficient) epstein-barr virus-infected b cells in angioimmunoblastic t cell lymphoma. J Exp Med 194 (7): 927-40, 2001. [PUBMED Abstract]
  8. Horwitz S, O’Connor OA, Pro B, et al.: Brentuximab vedotin with chemotherapy for CD30-positive peripheral T-cell lymphoma (ECHELON-2): a global, double-blind, randomised, phase 3 trial. Lancet 393 (10168): 229-240, 2019. [PUBMED Abstract]
  9. Horwitz S, O’Connor OA, Pro B, et al.: The ECHELON-2 Trial: 5-year results of a randomized, phase III study of brentuximab vedotin with chemotherapy for CD30-positive peripheral T-cell lymphoma. Ann Oncol 33 (3): 288-298, 2022. [PUBMED Abstract]
  10. Federico M, Rudiger T, Bellei M, et al.: Clinicopathologic characteristics of angioimmunoblastic T-cell lymphoma: analysis of the international peripheral T-cell lymphoma project. J Clin Oncol 31 (2): 240-6, 2013. [PUBMED Abstract]
  11. Reimer P, Rüdiger T, Geissinger E, et al.: Autologous stem-cell transplantation as first-line therapy in peripheral T-cell lymphomas: results of a prospective multicenter study. J Clin Oncol 27 (1): 106-13, 2009. [PUBMED Abstract]
  12. 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]
  13. Kyriakou C, Canals C, Finke J, et al.: Allogeneic stem cell transplantation is able to induce long-term remissions in angioimmunoblastic T-cell lymphoma: a retrospective study from the lymphoma working party of the European group for blood and marrow transplantation. J Clin Oncol 27 (24): 3951-8, 2009. [PUBMED Abstract]
  14. Park SI, Horwitz SM, Foss FM, et al.: The role of autologous stem cell transplantation in patients with nodal peripheral T-cell lymphomas in first complete remission: Report from COMPLETE, a prospective, multicenter cohort study. Cancer 125 (9): 1507-1517, 2019. [PUBMED Abstract]
  15. Brink M, Meeuwes FO, van der Poel MWM, et al.: Impact of etoposide and ASCT on survival among patients aged <65 years with stage II to IV PTCL: a population-based cohort study. Blood 140 (9): 1009-1019, 2022. [PUBMED Abstract]
  16. Los-de Vries GT, de Boer M, van Dijk E, et al.: Chromosome 20 loss is characteristic of breast implant-associated anaplastic large cell lymphoma. Blood 136 (25): 2927-2932, 2020. [PUBMED Abstract]
  17. Advani R, Horwitz S, Zelenetz A, et al.: Angioimmunoblastic T cell lymphoma: treatment experience with cyclosporine. Leuk Lymphoma 48 (3): 521-5, 2007. [PUBMED Abstract]
  18. Amengual JE, Lichtenstein R, Lue J, et al.: A phase 1 study of romidepsin and pralatrexate reveals marked activity in relapsed and refractory T-cell lymphoma. Blood 131 (4): 397-407, 2018. [PUBMED Abstract]
  19. Damaj G, Gressin R, Bouabdallah K, et al.: Results from a prospective, open-label, phase II trial of bendamustine in refractory or relapsed T-cell lymphomas: the BENTLY trial. J Clin Oncol 31 (1): 104-10, 2013. [PUBMED Abstract]
  20. O’Connor OA, Horwitz S, Masszi T, et al.: Belinostat in Patients With Relapsed or Refractory Peripheral T-Cell Lymphoma: Results of the Pivotal Phase II BELIEF (CLN-19) Study. J Clin Oncol 33 (23): 2492-9, 2015. [PUBMED Abstract]
  21. Wong J, Gruber E, Maher B, et al.: Integrated clinical and genomic evaluation of guadecitabine (SGI-110) in peripheral T-cell lymphoma. Leukemia 36 (6): 1654-1665, 2022. [PUBMED Abstract]
  22. Lemonnier F, Dupuis J, Sujobert P, et al.: Treatment with 5-azacytidine induces a sustained response in patients with angioimmunoblastic T-cell lymphoma. Blood 132 (21): 2305-2309, 2018. [PUBMED Abstract]
  23. Coiffier B, Pro B, Prince HM, et al.: Results from a pivotal, open-label, phase II study of romidepsin in relapsed or refractory peripheral T-cell lymphoma after prior systemic therapy. J Clin Oncol 30 (6): 631-6, 2012. [PUBMED Abstract]
  24. Fanale MA, Horwitz SM, Forero-Torres A, et al.: Five-year outcomes for frontline brentuximab vedotin with CHP for CD30-expressing peripheral T-cell lymphomas. Blood 131 (19): 2120-2124, 2018. [PUBMED Abstract]
  25. Pro B, Horwitz SM, Prince HM, et al.: Romidepsin induces durable responses in patients with relapsed or refractory angioimmunoblastic T-cell lymphoma. Hematol Oncol 35 (4): 914-917, 2017. [PUBMED Abstract]

Treatment of Peripheral T-Cell Lymphoma, Not Otherwise Specified

Patients with peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS) have diffuse large cell or diffuse mixed lymphoma that expresses a cell surface phenotype of a postthymic (or peripheral) T-cell expressing either CD4 or, less often, CD8.[1] PTCL-NOS encompasses a group of heterogeneous nodal T-cell lymphomas that will require future delineation.[2,3] Gene expression profiling studies have identified two distinct subtypes of PTCL-NOS based on the transcription factors GATA3 and TBX21. Early investigation and anecdotal reports suggest these subtypes may carry important prognostic implications and could predict response to certain therapies.[4] Additional studies are needed for further characterization of their clinical relevance.

Prognosis

Most investigators report worse response and survival rates for patients with PTCL-NOS than for patients with comparably staged B-cell aggressive lymphomas.[3,5] Most patients present with multiple adverse prognostic factors (i.e., older age, stage IV, multiple extranodal sites, and elevated lactate dehydrogenase), and these patients have low (<20%) failure-free survival and overall survival (OS) rates at 5 years.[3,5] As with other lymphomas (e.g., diffuse large B-cell lymphoma [DLBCL] or follicular lymphoma), event-free survival (EFS) at 24 months predicts a 5-year OS rate of 78%.[6]

Treatment Options for Peripheral T-Cell Lymphoma, Not Otherwise Specified

Therapy involves doxorubicin-based combination chemotherapy such as cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) or CHO(E)P (cyclophosphamide, doxorubicin, vincristine, etoposide, and prednisone). Doses are the same as those used for DLBCL.[7] For CD30-positive cases, brentuximab vedotin combined with cyclophosphamide, doxorubicin, and prednisone is the proposed standard of care.[8][Level of evidence C3] Patients with PTCL-NOS were included in the clinical trial involving mostly patients with anaplastic large cell lymphoma. A benefit for this smaller PTCL-NOS subgroup cannot be established.[8,9][Level of evidence C3] For more information, see the Treatment of Anaplastic Large Cell Lymphoma section.

For patients with early-stage disease, anecdotal retrospective series disagree on the value of consolidative radiation therapy after combination chemotherapy.[10][Level of evidence C3] Consolidation therapy using high-dose chemotherapy with autologous or allogeneic hematopoietic stem cell transplant (SCT) has been given to patients with advanced-stage PTCL after induction therapy in multiple phase II or retrospective trials. Evidence for this approach is anecdotal.[11–18][Level of evidence C3]

Evidence (CHOP, CHO[E]P, or other options for relapsing disease):

  1. A randomized prospective trial included 104 patients younger than 61 years with stage II, III, or IV PTCL (excluding ALK-positive anaplastic large cell lymphoma). Patients received either autologous SCT or allogeneic SCT as consolidation therapy after induction with CHO(E)P followed by DHAP (dexamethasone, cytarabine, and cisplatin).[19][Level of evidence C3]
    • With a median follow-up of 42 months, the 3-year EFS rate was 43% for patients who received allogeneic SCT and 38% for patients who received autologous SCT.
    • The 3-year OS rate was 57% for patients who received allogeneic SCT and 70% for patients who received autologous SCT (P = nonsignificant).
    • None of the 21 responding patients who proceeded to allogeneic SCT relapsed, and 36% of patients who proceeded to autologous SCT relapsed.
    • Eight of 26 patients (31%) who received allogeneic SCT died of graft-versus-host disease, and none of the 41 patients who received autologous SCT died of toxicity.
    • The benefit of graft-versus-lymphoma effect was negated by increased transplant-related mortality.
  2. In a prospective trial of 109 evaluable patients with relapsing disease, treatment with pralatrexate resulted in a 30% response rate and a median 10-month duration of response.[20,21][Level of evidence C3]
  3. Similar response rates were seen in 130 evaluable patients with relapsing disease who received romidepsin in a prospective trial.[21][Level of evidence C3]
  4. Anecdotal responses have been seen with a combination of pralatrexate and romidepsin,[22] single-agent bendamustine,[23] belinostat,[24] and brentuximab vedotin (even if there is little or no CD30 expression on the lymphoma).[25][Level of evidence C3]

    Incorporation of these new agents with CHOP chemotherapy is under clinical evaluation.[3,8]

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. Rüdiger T, Weisenburger DD, Anderson JR, et al.: Peripheral T-cell lymphoma (excluding anaplastic large-cell lymphoma): results from the Non-Hodgkin’s Lymphoma Classification Project. Ann Oncol 13 (1): 140-9, 2002. [PUBMED Abstract]
  2. Rizvi MA, Evens AM, Tallman MS, et al.: T-cell non-Hodgkin lymphoma. Blood 107 (4): 1255-64, 2006. [PUBMED Abstract]
  3. Weisenburger DD, Savage KJ, Harris NL, et al.: Peripheral T-cell lymphoma, not otherwise specified: a report of 340 cases from the International Peripheral T-cell Lymphoma Project. Blood 117 (12): 3402-8, 2011. [PUBMED Abstract]
  4. Amador C, Greiner TC, Heavican TB, et al.: Reproducing the molecular subclassification of peripheral T-cell lymphoma-NOS by immunohistochemistry. Blood 134 (24): 2159-2170, 2019. [PUBMED Abstract]
  5. Sonnen R, Schmidt WP, Müller-Hermelink HK, et al.: The International Prognostic Index determines the outcome of patients with nodal mature T-cell lymphomas. Br J Haematol 129 (3): 366-72, 2005. [PUBMED Abstract]
  6. Maurer MJ, Ellin F, Srour L, et al.: International Assessment of Event-Free Survival at 24 Months and Subsequent Survival in Peripheral T-Cell Lymphoma. J Clin Oncol 35 (36): 4019-4026, 2017. [PUBMED Abstract]
  7. Carson KR, Horwitz SM, Pinter-Brown LC, et al.: A prospective cohort study of patients with peripheral T-cell lymphoma in the United States. Cancer 123 (7): 1174-1183, 2017. [PUBMED Abstract]
  8. Horwitz S, O’Connor OA, Pro B, et al.: Brentuximab vedotin with chemotherapy for CD30-positive peripheral T-cell lymphoma (ECHELON-2): a global, double-blind, randomised, phase 3 trial. Lancet 393 (10168): 229-240, 2019. [PUBMED Abstract]
  9. Horwitz S, O’Connor OA, Pro B, et al.: The ECHELON-2 Trial: 5-year results of a randomized, phase III study of brentuximab vedotin with chemotherapy for CD30-positive peripheral T-cell lymphoma. Ann Oncol 33 (3): 288-298, 2022. [PUBMED Abstract]
  10. Briski R, Feldman AL, Bailey NG, et al.: Survival in patients with limited-stage peripheral T-cell lymphomas. Leuk Lymphoma 56 (6): 1665-70, 2015. [PUBMED Abstract]
  11. Rodriguez J, Munsell M, Yazji S, et al.: Impact of high-dose chemotherapy on peripheral T-cell lymphomas. J Clin Oncol 19 (17): 3766-70, 2001. [PUBMED Abstract]
  12. Reimer P, Rüdiger T, Geissinger E, et al.: Autologous stem-cell transplantation as first-line therapy in peripheral T-cell lymphomas: results of a prospective multicenter study. J Clin Oncol 27 (1): 106-13, 2009. [PUBMED Abstract]
  13. 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]
  14. d’Amore F, Relander T, Lauritzsen GF, et al.: Up-front autologous stem-cell transplantation in peripheral T-cell lymphoma: NLG-T-01. J Clin Oncol 30 (25): 3093-9, 2012. [PUBMED Abstract]
  15. Schmitz N, Lenz G, Stelljes M: Allogeneic hematopoietic stem cell transplantation for T-cell lymphomas. Blood 132 (3): 245-253, 2018. [PUBMED Abstract]
  16. Park SI, Horwitz SM, Foss FM, et al.: The role of autologous stem cell transplantation in patients with nodal peripheral T-cell lymphomas in first complete remission: Report from COMPLETE, a prospective, multicenter cohort study. Cancer 125 (9): 1507-1517, 2019. [PUBMED Abstract]
  17. Brink M, Meeuwes FO, van der Poel MWM, et al.: Impact of etoposide and ASCT on survival among patients aged <65 years with stage II to IV PTCL: a population-based cohort study. Blood 140 (9): 1009-1019, 2022. [PUBMED Abstract]
  18. Los-de Vries GT, de Boer M, van Dijk E, et al.: Chromosome 20 loss is characteristic of breast implant-associated anaplastic large cell lymphoma. Blood 136 (25): 2927-2932, 2020. [PUBMED Abstract]
  19. Schmitz N, Truemper L, Bouabdallah K, et al.: A randomized phase 3 trial of autologous vs allogeneic transplantation as part of first-line therapy in poor-risk peripheral T-NHL. Blood 137 (19): 2646-2656, 2021. [PUBMED Abstract]
  20. O’Connor OA, Pro B, Pinter-Brown L, et al.: Pralatrexate in patients with relapsed or refractory peripheral T-cell lymphoma: results from the pivotal PROPEL study. J Clin Oncol 29 (9): 1182-9, 2011. [PUBMED Abstract]
  21. Coiffier B, Pro B, Prince HM, et al.: Results from a pivotal, open-label, phase II study of romidepsin in relapsed or refractory peripheral T-cell lymphoma after prior systemic therapy. J Clin Oncol 30 (6): 631-6, 2012. [PUBMED Abstract]
  22. Amengual JE, Lichtenstein R, Lue J, et al.: A phase 1 study of romidepsin and pralatrexate reveals marked activity in relapsed and refractory T-cell lymphoma. Blood 131 (4): 397-407, 2018. [PUBMED Abstract]
  23. Damaj G, Gressin R, Bouabdallah K, et al.: Results from a prospective, open-label, phase II trial of bendamustine in refractory or relapsed T-cell lymphomas: the BENTLY trial. J Clin Oncol 31 (1): 104-10, 2013. [PUBMED Abstract]
  24. O’Connor OA, Horwitz S, Masszi T, et al.: Belinostat in Patients With Relapsed or Refractory Peripheral T-Cell Lymphoma: Results of the Pivotal Phase II BELIEF (CLN-19) Study. J Clin Oncol 33 (23): 2492-9, 2015. [PUBMED Abstract]
  25. Fanale MA, Horwitz SM, Forero-Torres A, et al.: Five-year outcomes for frontline brentuximab vedotin with CHP for CD30-expressing peripheral T-cell lymphomas. Blood 131 (19): 2120-2124, 2018. [PUBMED Abstract]

Treatment of Extranodal Natural Killer/T-Cell Lymphoma

Extranodal natural killer (NK)/T-cell lymphoma, nasal type, is an aggressive lymphoma marked by extensive necrosis and angioinvasion, most often presenting in extranodal sites, in particular the nasal or paranasal sinus region.[1] Other extranodal sites include the palate, trachea, skin, and gastrointestinal tract. Hemophagocytic syndrome may also occur; historically, these tumors were considered part of lethal midline granuloma.[2] Tumor cells are typically NK cells with immunophenotyping showing CD3 and CD56 expression. In nearly all cases, Epstein-Barr virus (EBV) is detectable in the tumor cells. Aggressive NK cell leukemia (ANKL) is a separate but related diagnosis, which was previously recognized as a subset of large granular lymphocyte (LGL) leukemia, and is characterized by mature NK cell neoplastic involvement of the blood or marrow involvement with a particularly aggressive course and poor prognosis.[3] A benign NK-cell enteropathy (EBV negative) on endoscopic biopsy can be distinguished from NK/T-cell lymphoma.[3] Extranodal NK-cell lymphoma (ENKL), nasal type is rare in Western countries and more commonly seen in Asia, where it represents 3% to 8% of all lymphoma cases. Most cases present with nasal involvement and localized disease. Both extranasal and advanced-stage (stages III–IV) disease are associated with poor prognosis.[4,5]

Treatment Options for Extranodal Natural Killer/T-Cell Lymphoma

The management of localized ENKL with nasal involvement involves combined modality therapy with chemotherapy and radiation therapy for those fit for chemotherapy or radiation therapy alone for those unfit for chemotherapy. The management of nonlocalized nasal ENKL and all cases of extranasal ENKL involves combination chemotherapy with or without radiation therapy.[6] Because ENKL frequently expresses P-glycoprotein which confers multidrug resistance and reduces the efficacy of traditional anthracycline-based regimens, asparaginase is typically incorporated into the chemotherapy regimens.[7,8] Various asparaginase-based combination chemotherapy regimens have been used.

Evidence (asparaginase-based combination chemotherapy):

  1. A phase II study included 28 patients with newly diagnosed stage IV or relapsed or refractory ENKL. Patients received steroids, methotrexate, ifosfamide, [L-]asparaginase, and etoposide (SMILE).[9]
    • The overall response rate after two cycles was 79% (95% confidence interval [CI], 65%–89%), and the complete response rate was 45%. The 1-year overall survival (OS) rate was 55% (95% CI, 38%–69%).
    • Grade 4 neutropenia was observed in 92% of patients, and grade 3 or 4 infections were seen in 61% of patients.[9]
    • A modification to the SMILE regimen (mSMILE) incorporating pegylated asparaginase has demonstrated reduced toxicity.[10]

    Despite no head-to-head studies, this regimen is used more often in clinical practice, in patients with advanced-stage disease, or in combination with radiation therapy for patients with localized disease. Other asparaginase-based regimens which have been studied include gemcitabine, oxaliplatin, and pegaspargase (P-GEMOX);[10] gemcitabine, etoposide, pegaspargase, and dexamethasone (GELAD);[11] and dexamethasone, cisplatin, gemcitabine, and pegaspargase (DDGP).[12]For patients who may not tolerate or who have reactions to asparaginase, a nonasparaginase regimen may be given with concurrent radiation therapy.[13][Level of evidence C3]

  2. A retrospective study (NCT02733458) included 35 patients with newly diagnosed stage III to IV, relapsed, or refractory ENKL. Patients received P-GEMOX.[10]
    • The overall response rate was 80.0%, and the complete response rate was 51.4%. The 3-year progression-free survival (PFS) rate was 38.6%, and the 3-year OS rate was 64.7%.[10][Level of evidence C3]
  3. A prospective multicenter study (NCT02733458) included 52 patients with newly diagnosed stage IE/IIE ENKL who received two cycles of GELAD followed by intensity-modulated radiotherapy (50–56 Gy in 25–58 fractions) and two additional courses of GELAD.[11]
    • With a median follow-up of 32 months, the estimated 4-year OS rate was 94.2% (95% CI, 83.2%–93.1%), and the 4-year PFS rate was 90.4% (95% CI, 78.4%–95.9%).[11][Level of evidence C3]
    • The overall response rate was 94.2%, and the complete response rate was 92.3%.
  4. A retrospective study included 80 patients with newly diagnosed (n = 48), refractory (n = 23), or first-relapse (n = 9) ENKL. Patients received DDGP.[12]
    • The overall response rate was 91.3% (95% CI, 85.0%–96.3%), and the complete response rate was 60.0% (95% CI, 48.8%–71.3%). The 2-year PFS rate was 81.4% (95% CI, 76.3%–86.5%), and the 2-year OS rate was 87.1% (95% CI, 83.4%–91.4%).[12][Level of evidence C3]
  5. A phase I/II study of 27 patients with newly diagnosed stage IE or contiguous IIE disease studied the nonasparaginase-based regimen DeVIC (dexamethasone, etoposide, ifosfamide, and carboplatin). Patients received three cycles of DeVIC at the recommended phase II dosing and concurrent radiotherapy dosed at 50 Gy.[13]
    • With a median follow-up of 32 months, the 2-year OS rate was 78% (95% CI, 57%–89%). The overall response rate was 81%, and the complete response rate was 77%.[13][Level of evidence C3]
    • The most common grade 3 or higher nonhematologic toxicity was mucositis related to radiation, which occurred in 30% of patients.

Radiation therapy is an essential component of treatment for localized ENKL, nasal type, whether given as a monotherapy or as part of combined modality therapy.

Evidence (radiation therapy with or without chemotherapy):

  1. A retrospective review included 1,273 patients with early-stage disease. Patients were stratified into a low-risk group and high-risk group using stage, age, lactate dehydrogenase level, performance status, and primary tumor invasion.
    • Low-risk patients fared best with radiation therapy alone,[14] while high-risk patients fared best with a strategy of radiation therapy combined with chemotherapy.[15–17][Level of evidence C3]
  2. A retrospective review included 303 previously untreated patients from an international consortium who received nonanthracycline chemotherapy.[18]
    • The OS rates were identical (72%−74% at 5 years) for patients with early-stage disease who received either concurrent chemotherapy and radiation therapy or chemotherapy followed by radiation therapy.[18][Level of evidence C3]

Higher doses of radiation therapy administered at more than 50 Gy are associated with improved outcomes according to anecdotal reports.[17] The highly aggressive course, with poor response and short survival with standard therapies, especially for patients with advanced-stage disease or extranasal presentation, has led some investigators to recommend autologous or allogeneic peripheral stem cell transplant consolidation.[19–24][Level of evidence C3]

For patients with relapsed or refractory disease, therapies targeting programmed death 1 (PD-1) and programmed death-ligand 1 (PD-L1) have demonstrated promising results.

Evidence (immunotherapy):

  1. In a phase II trial, the anti–PD-L1 antibody avelumab was given to 21 patients with relapsed or refractory disease.[25]
    • The complete response rate was 24%, and the overall response rate was 38%. The responses correlated with tumor PD-L1 expression.[25][Level of evidence C3]
  2. Treatment with pembrolizumab, an anti–PD-1 antibody, resulted in similar responses in patients with relapsed or refractory disease.[26][Level of evidence C3]
  3. A single-arm multicenter phase II study (GEMSTONE-201 [NCT03595657]) included 80 patients with relapsed or refractory ENKL. Patients received the anti–PD-L1 monoclonal antibody sugemalimab.
    • The objective response rate was 44.9% (95% CI, 33.6%–56.6%), and the complete response rate was 35.9%. The 12-month duration of response rate was 82.5% (95% CI, 62.0%–92.6%).[27][Level of evidence B3]

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. Tse E, Kwong YL: How I treat NK/T-cell lymphomas. Blood 121 (25): 4997-5005, 2013. [PUBMED Abstract]
  2. Rizvi MA, Evens AM, Tallman MS, et al.: T-cell non-Hodgkin lymphoma. Blood 107 (4): 1255-64, 2006. [PUBMED Abstract]
  3. Tang YT, Wang D, Luo H, et al.: Aggressive NK-cell leukemia: clinical subtypes, molecular features, and treatment outcomes. Blood Cancer J 7 (12): 660, 2017. [PUBMED Abstract]
  4. Suzuki R, Suzumiya J, Yamaguchi M, et al.: Prognostic factors for mature natural killer (NK) cell neoplasms: aggressive NK cell leukemia and extranodal NK cell lymphoma, nasal type. Ann Oncol 21 (5): 1032-40, 2010. [PUBMED Abstract]
  5. Qi SN, Li YX, Specht L, et al.: Modern Radiation Therapy for Extranodal Nasal-Type NK/T-cell Lymphoma: Risk-Adapted Therapy, Target Volume, and Dose Guidelines from the International Lymphoma Radiation Oncology Group. Int J Radiat Oncol Biol Phys 110 (4): 1064-1081, 2021. [PUBMED Abstract]
  6. Obama K, Tara M, Niina K: L-asparaginase-Based induction therapy for advanced extranodal NK/T-cell lymphoma. Int J Hematol 78 (3): 248-50, 2003. [PUBMED Abstract]
  7. Ando M, Sugimoto K, Kitoh T, et al.: Selective apoptosis of natural killer-cell tumours by l-asparaginase. Br J Haematol 130 (6): 860-8, 2005. [PUBMED Abstract]
  8. Yamaguchi M, Kwong YL, Kim WS, et al.: Phase II study of SMILE chemotherapy for newly diagnosed stage IV, relapsed, or refractory extranodal natural killer (NK)/T-cell lymphoma, nasal type: the NK-Cell Tumor Study Group study. J Clin Oncol 29 (33): 4410-6, 2011. [PUBMED Abstract]
  9. Ghione P, Qi S, Imber BS, et al.: Modified SMILE (mSMILE) and intensity-modulated radiotherapy (IMRT) for extranodal NK-T lymphoma nasal type in a single-center population. Leuk Lymphoma 61 (14): 3331-3341, 2020. [PUBMED Abstract]
  10. Wang JH, Wang L, Liu CC, et al.: Efficacy of combined gemcitabine, oxaliplatin and pegaspargase (P-gemox regimen) in patients with newly diagnosed advanced-stage or relapsed/refractory extranodal NK/T-cell lymphoma. Oncotarget 7 (20): 29092-101, 2016. [PUBMED Abstract]
  11. Zhu Y, Tian S, Xu L, et al.: GELAD chemotherapy with sandwiched radiotherapy for patients with newly diagnosed stage IE/IIE natural killer/T-cell lymphoma: a prospective multicentre study. Br J Haematol 196 (4): 939-946, 2022. [PUBMED Abstract]
  12. Zhang L, Li S, Jia S, et al.: The DDGP (cisplatin, dexamethasone, gemcitabine, and pegaspargase) regimen for treatment of extranodal natural killer (NK)/T-cell lymphoma, nasal type. Oncotarget 7 (36): 58396-58404, 2016. [PUBMED Abstract]
  13. Yamaguchi M, Tobinai K, Oguchi M, et al.: Phase I/II study of concurrent chemoradiotherapy for localized nasal natural killer/T-cell lymphoma: Japan Clinical Oncology Group Study JCOG0211. J Clin Oncol 27 (33): 5594-600, 2009. [PUBMED Abstract]
  14. Yang Y, Cao JZ, Lan SM, et al.: Association of Improved Locoregional Control With Prolonged Survival in Early-Stage Extranodal Nasal-Type Natural Killer/T-Cell Lymphoma. JAMA Oncol 3 (1): 83-91, 2017. [PUBMED Abstract]
  15. Yang Y, Zhu Y, Cao JZ, et al.: Risk-adapted therapy for early-stage extranodal nasal-type NK/T-cell lymphoma: analysis from a multicenter study. Blood 126 (12): 1424-32; quiz 1517, 2015. [PUBMED Abstract]
  16. Yamaguchi M, Suzuki R, Oguchi M, et al.: Treatments and Outcomes of Patients With Extranodal Natural Killer/T-Cell Lymphoma Diagnosed Between 2000 and 2013: A Cooperative Study in Japan. J Clin Oncol 35 (1): 32-39, 2017. [PUBMED Abstract]
  17. Vargo JA, Patel A, Glaser SM, et al.: The impact of the omission or inadequate dosing of radiotherapy in extranodal natural killer T-cell lymphoma, nasal type, in the United States. Cancer 123 (16): 3176-3185, 2017. [PUBMED Abstract]
  18. Kwong YL, Kim SJ, Tse E, et al.: Sequential chemotherapy/radiotherapy was comparable with concurrent chemoradiotherapy for stage I/II NK/T-cell lymphoma. Ann Oncol 29 (1): 256-263, 2018. [PUBMED Abstract]
  19. Liang R, Todd D, Chan TK, et al.: Treatment outcome and prognostic factors for primary nasal lymphoma. J Clin Oncol 13 (3): 666-70, 1995. [PUBMED Abstract]
  20. Cheung MM, Chan JK, Lau WH, et al.: Primary non-Hodgkin’s lymphoma of the nose and nasopharynx: clinical features, tumor immunophenotype, and treatment outcome in 113 patients. J Clin Oncol 16 (1): 70-7, 1998. [PUBMED Abstract]
  21. Hausdorff J, Davis E, Long G, et al.: Non-Hodgkin’s lymphoma of the paranasal sinuses: clinical and pathological features, and response to combined-modality therapy. Cancer J Sci Am 3 (5): 303-11, 1997 Sep-Oct. [PUBMED Abstract]
  22. 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]
  23. Au WY, Weisenburger DD, Intragumtornchai T, et al.: Clinical differences between nasal and extranasal natural killer/T-cell lymphoma: a study of 136 cases from the International Peripheral T-Cell Lymphoma Project. Blood 113 (17): 3931-7, 2009. [PUBMED Abstract]
  24. Yamaguchi M, Suzuki R, Oguchi M: Advances in the treatment of extranodal NK/T-cell lymphoma, nasal type. Blood 131 (23): 2528-2540, 2018. [PUBMED Abstract]
  25. Kim SJ, Lim JQ, Laurensia Y, et al.: Avelumab for the treatment of relapsed or refractory extranodal NK/T-cell lymphoma: an open-label phase 2 study. Blood 136 (24): 2754-2763, 2020. [PUBMED Abstract]
  26. Kwong YL, Chan TSY, Tan D, et al.: PD1 blockade with pembrolizumab is highly effective in relapsed or refractory NK/T-cell lymphoma failing l-asparaginase. Blood 129 (17): 2437-2442, 2017. [PUBMED Abstract]
  27. Huang H, Tao R, Hao S, et al.: Sugemalimab Monotherapy for Patients With Relapsed or Refractory Extranodal Natural Killer/T-Cell Lymphoma (GEMSTONE-201): Results From a Single-Arm, Multicenter, Phase II Study. J Clin Oncol 41 (16): 3032-3041, 2023. [PUBMED Abstract]

Treatment of Enteropathy-Associated and Monomorphic Epitheliotropic Intestinal T-Cell Lymphomas

Enteropathy-associated T-cell lymphoma (EATL) and monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL) are rare subsets of peripheral T-cell lymphoma (PTCL) which together account for less than 5% of PTCL. EATL (sometimes referred to as type 1 EATL) is a complication of celiac disease and is more common in Europe. MEITL (sometimes referred to as type 2 EATL) is not associated with celiac disease and is more common in Asia. SETD2 pathogenic variants and, to a lesser extent, STAT5B pathogenic variants are seen in most cases of EATL and MEITL.[1,2] Because a gluten-free diet prevents the development of lymphoma in patients with celiac disease, patients diagnosed in childhood rarely develop EATL. The diagnosis of celiac disease is usually made by finding villous atrophy in the resected intestine. Surgery is often required for diagnosis and to avoid perforation during therapy.[3]

Treatment Options for Enteropathy-Associated and Monomorphic Epitheliotropic Intestinal T-Cell Lymphomas

Recommended management includes CHO(E)P (cyclophosphamide, doxorubicin, vincristine, etoposide, and prednisone), but relapse is common and outcomes are generally poor.[4–6] Complications of treatment include gastrointestinal bleeding, small bowel perforation, and enterocolic fistulae. Patients often require parenteral nutrition. For more information on parenteral nutrition, see Nutrition in Cancer Care. Multifocal intestinal perforations and visceral abdominal involvement are seen at the time of relapse. Consolidation with either high-dose chemotherapy with autologous stem cell rescue or allogeneic stem cell transplant is often used in first or later remission.[4,7,8][Level of evidence C3] Evidence for this approach is anecdotal.

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. Veloza L, Cavalieri D, Missiaglia E, et al.: Monomorphic epitheliotropic intestinal T-cell lymphoma comprises morphologic and genomic heterogeneity impacting outcome. Haematologica 108 (1): 181-195, 2023. [PUBMED Abstract]
  2. Moffitt AB, Ondrejka SL, McKinney M, et al.: Enteropathy-associated T cell lymphoma subtypes are characterized by loss of function of SETD2. J Exp Med 214 (5): 1371-1386, 2017. [PUBMED Abstract]
  3. Egan LJ, Walsh SV, Stevens FM, et al.: Celiac-associated lymphoma. A single institution experience of 30 cases in the combination chemotherapy era. J Clin Gastroenterol 21 (2): 123-9, 1995. [PUBMED Abstract]
  4. Gale J, Simmonds PD, Mead GM, et al.: Enteropathy-type intestinal T-cell lymphoma: clinical features and treatment of 31 patients in a single center. J Clin Oncol 18 (4): 795-803, 2000. [PUBMED Abstract]
  5. Daum S, Ullrich R, Heise W, et al.: Intestinal non-Hodgkin’s lymphoma: a multicenter prospective clinical study from the German Study Group on Intestinal non-Hodgkin’s Lymphoma. J Clin Oncol 21 (14): 2740-6, 2003. [PUBMED Abstract]
  6. Di Sabatino A, Biagi F, Gobbi PG, et al.: How I treat enteropathy-associated T-cell lymphoma. Blood 119 (11): 2458-68, 2012. [PUBMED Abstract]
  7. 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]
  8. Sieniawski M, Angamuthu N, Boyd K, et al.: Evaluation of enteropathy-associated T-cell lymphoma comparing standard therapies with a novel regimen including autologous stem cell transplantation. Blood 115 (18): 3664-70, 2010. [PUBMED Abstract]

Treatment of Indolent T-Cell Lymphoma of the Gastrointestinal Tract

In contrast to the more aggressive forms of T-cell lymphoma with intestinal involvement, indolent T-cell lymphoma of the gastrointestinal tract (iTCL-GI) often presents more indolently. iTCL-GI can be difficult to distinguish from inflammatory bowel disease or other autoimmune disorders with gastrointestinal involvement.[1,2]

iTCL-GI is often diagnosed when multiple biopsies from different sites show matching clones by T-cell receptor gene rearrangement testing. While the immunophenotype can vary (iTCL-GI is frequently CD4+ but can also be CD8+ or CD4-/CD8-), Ki-67 is typically very low at 5% to 10%. Unlike some other intestinal lymphomas, Epstein-Barr encoding region staining for Epstein-Barr virus is usually negative. Although initial reports of this rare entity suggested a low likelihood of transformation to a more aggressive process, transformation to peripheral T-cell lymphoma, not otherwise specific and other aggressive forms has since been documented.[3]

Treatment Options for Indolent T-Cell Lymphoma of the Gastrointestinal Tract

Response to multiagent chemotherapy is limited, and many patients can be managed with watchful waiting alone. Limited studies suggest that alterations in the JAK/STAT pathway or genes involved in epigenetic modification could serve as potential therapeutic targets.[4]

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. Margolskee E, Jobanputra V, Lewis SK, et al.: Indolent small intestinal CD4+ T-cell lymphoma is a distinct entity with unique biologic and clinical features. PLoS One 8 (7): e68343, 2013. [PUBMED Abstract]
  2. Perry AM, Warnke RA, Hu Q, et al.: Indolent T-cell lymphoproliferative disease of the gastrointestinal tract. Blood 122 (22): 3599-606, 2013. [PUBMED Abstract]
  3. Sanguedolce F, Zanelli M, Zizzo M, et al.: Indolent T-Cell Lymphoproliferative Disorders of the Gastrointestinal Tract (iTLPD-GI): A Review. Cancers (Basel) 13 (11): , 2021. [PUBMED Abstract]
  4. Sharma A, Oishi N, Boddicker RL, et al.: Recurrent STAT3-JAK2 fusions in indolent T-cell lymphoproliferative disorder of the gastrointestinal tract. Blood 131 (20): 2262-2266, 2018. [PUBMED Abstract]

Treatment of Hepatosplenic T-Cell Lymphoma

Hepatosplenic T-cell lymphoma (HSTCL) is a rare subtype of peripheral T-cell lymphoma (PTCL) comprising approximately 1% of PTCL. HSTCL often involves young men. HSTCL appears to be localized to the hepatic and splenic sinusoids, with cell surface expression of the gamma delta T-cell receptor.[1–3] Characteristic chromosomal abnormalities such as isochromosome 7q and trisomy 8 are also suggestive of the diagnosis.[4] While in most cases the neoplastic cells express a gamma delta T-cell receptor (hepatosplenic gamma delta T-cell lymphoma), there are reports of alpha beta T-cell receptor expression (hepatosplenic alpha beta T-cell lymphoma).[5] This lymphoma has an extremely poor prognosis and an extremely aggressive clinical course.

Treatment Options for Hepatosplenic T-Cell Lymphoma

HSTCL is treated with induction chemotherapy and stem cell transplant (SCT) consolidation.[3,6]

Evidence (induction chemotherapy and SCT consolidation):

  1. A meta-analysis of 118 patients with HSTCL compared CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) and CHOP-like induction regimens.[7]
    • Non–CHOP-based regimens (containing cytarabine, etoposide, and/or platinum-based treatment) were associated with improved outcomes, including an overall response rate of 82% versus 52% (P = .006) and a median overall survival (OS) of 36.5 months versus 18 months (P = .00014).
    • Consolidation with allogeneic SCT was associated with an improved median OS of 33 months, versus 27 months (P = .016) for autologous SCT.[7][Level of evidence C3]

The use of ICE (ifosfamide, carboplatin, and etoposide) or IVAC (ifosfamide, etoposide, and high-dose cytarabine) has resulted in improved responses when compared with CHOP in other smaller studies as well.[8][Level of evidence D] Given the inadequate responses to CHOP or CHOP-like regimens, many clinicians are using ICE chemotherapy as front-line induction therapy, followed by consolidative allogeneic SCT for patients achieving a first remission. However, the efficacy of this approach is undetermined.

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. Belhadj K, Reyes F, Farcet JP, et al.: Hepatosplenic gammadelta T-cell lymphoma is a rare clinicopathologic entity with poor outcome: report on a series of 21 patients. Blood 102 (13): 4261-9, 2003. [PUBMED Abstract]
  2. Chanan-Khan A, Islam T, Alam A, et al.: Long-term survival with allogeneic stem cell transplant and donor lymphocyte infusion following salvage therapy with anti-CD52 monoclonal antibody (Campath) in a patient with alpha/beta hepatosplenic T-cell non-Hodgkin’s lymphoma. Leuk Lymphoma 45 (8): 1673-5, 2004. [PUBMED Abstract]
  3. Pro B, Allen P, Behdad A: Hepatosplenic T-cell lymphoma: a rare but challenging entity. Blood 136 (18): 2018-2026, 2020. [PUBMED Abstract]
  4. Travert M, Huang Y, de Leval L, et al.: Molecular features of hepatosplenic T-cell lymphoma unravels potential novel therapeutic targets. Blood 119 (24): 5795-806, 2012. [PUBMED Abstract]
  5. Macon WR, Levy NB, Kurtin PJ, et al.: Hepatosplenic alphabeta T-cell lymphomas: a report of 14 cases and comparison with hepatosplenic gammadelta T-cell lymphomas. Am J Surg Pathol 25 (3): 285-96, 2001. [PUBMED Abstract]
  6. 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]
  7. Klebaner D, Koura D, Tzachanis D, et al.: Intensive Induction Therapy Compared With CHOP for Hepatosplenic T-cell Lymphoma. Clin Lymphoma Myeloma Leuk 20 (7): 431-437.e2, 2020. [PUBMED Abstract]
  8. Voss MH, Lunning MA, Maragulia JC, et al.: Intensive induction chemotherapy followed by early high-dose therapy and hematopoietic stem cell transplantation results in improved outcome for patients with hepatosplenic T-cell lymphoma: a single institution experience. Clin Lymphoma Myeloma Leuk 13 (1): 8-14, 2013. [PUBMED Abstract]

Treatment of Adult T-Cell Leukemia/Lymphoma

Adult T-cell leukemia/lymphoma (ATL) is caused by infection with the retrovirus human T-lymphotrophic virus 1 (HTLV1) and is frequently associated with lymphadenopathy, hypercalcemia, circulating leukemic cells, bone and skin involvement, hepatosplenomegaly, a rapidly progressive course, and poor response to combination chemotherapy.[1,2] HTLV1 is endemic to Japan (especially the southern island of Kyushu), central Africa, the Caribbean islands, and some regions of Central and South America, the Middle East, and Australia. This retrovirus is mostly spread by sexual contact or breastfeeding.[3] ATL has been divided into four clinical subtypes:[3]

  • Acute (aggressive course with leukemia, with or without extranodal or nodal involvement).
  • Lymphoma (aggressive course with lymphadenopathy and no leukemia).
  • Chronic (indolent course with leukemia and lymphadenopathy).
  • Smoldering (indolent course with only leukemia).

Treatment Options for Adult T-Cell Leukemia/Lymphoma

Treatment options for ATL include:

  1. Biological and targeted therapies.
  2. Cytotoxic chemotherapy and allogeneic stem cell transplant (SCT).

Biological and targeted therapies

Mogamulizumab

The anti-CCR4 monoclonal antibody mogamulizumab has a targeted lysis of the ATL clone and also reduces the immunosuppressive Treg population, allowing improvement of cell-mediated immunotherapy.[4] Single-agent phase II trials in patients with ATL showed response rates ranging from 30% to 50%.[5–7][Level of evidence C3] In a phase II study that combined mogamulizumab with combination chemotherapy, 101 patients had an overall response rate of 65% (95% confidence interval [CI], 55%–75%), a median progression-free survival of 7.4 months (95% CI, 5.7–9.1), and a median overall survival (OS) of 16 months (95% CI, 10.3–21.8).[8][Level of evidence C3]

A retrospective review evaluated mogamulizumab combined with both the VCAP-AMP-VECP (vincristine, cyclophosphamide, doxorubicin, prednisone; doxorubicin, ranimustine, prednisone; vindesine, etoposide, carboplatin, prednisone) regimen and CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone)-based regimens versus chemotherapy alone. The review concluded that the 4-year OS rate was 46.3% in the mogamulizumab combination groups, compared with 20.6% in the chemotherapy-alone group.[9][Level of evidence C3] The best results were seen with CHOP-based regimens. Mogamulizumab is available in the United States but has not been approved by the U.S. Food and Drug Administration (FDA) for patients with ATL.

Mogamulizumab is often avoided in patients planning allogeneic SCT based on data from Japan that showed an increased risk of severe graft-versus-host disease (GVHD) in patients who received mogamulizumab before allogeneic SCT.[10] The relevance of these findings in other countries and the impact of different GVHD prophylaxis regimens in this setting remains to be determined.

Brentuximab vedotin

Brentuximab vedotin is a monoclonal antibody-drug conjugate directed at CD30 and is a treatment option for patients with ATL whose tumor expresses CD30.[11] Patients with ATL were included in a clinical trial of brentuximab vedotin that mostly involved patients with anaplastic large T-cell lymphoma. A statistical benefit for the very small ATL subgroup could not be established.[11][Level of evidence C3]

Lenalidomide

In a multicenter phase II study (NCT01724177) of 26 patients with relapsed ATL, the overall response rate was 42% (95% CI, 23%–63%) in patients who received the immunomodulatory agent lenalidomide.[12][Level of evidence C3]

Valemetostat

Valemetostat is a selective dual inhibitor of EZH1 and EZH2, which are important histone methyltransferases involved with chromatin folding.[13] A multicenter phase II study (NCT04102150) enrolled 25 patients with relapsed or refractory ATL, 24 of whom had prior therapy with mogamulizumab.[14] With a median follow-up of 6.5 months, the overall response rate was 48% (90% CI, 30.5%–65.9%). There were five complete remissions and seven partial remissions among the heavily pretreated patients.[14][Level of evidence C3] Responses were seen in patients with the acute, lymphoma, and chronic versions of ATL. Although approved for use in Japan, valemetostat is not approved by the FDA for use in the United States.

Zidovudine and interferon alfa

The combination of zidovudine and interferon alfa has activity against ATL, especially among patients with the chronic and smoldering versions of ATL.[15,16] Durable remissions of 8 to 12 months and response rates of 20% to 40% have been reported for patients, some of whom had relapsed disease after prior chemotherapy,[15,16] and some with the acute and lymphoma subtypes of ATL.[17,18]

Cytotoxic chemotherapy and allogeneic SCT

The acute and lymphoma types of ATL respond poorly to combination cytotoxic chemotherapy and allogeneic SCT, with a median OS under 1 year.[19–21] Less than 10% of patients who received combination therapy were alive after 4 years in one retrospective study.[21] Durable remissions have been reported after allogeneic SCT and even after subsequent donor lymphocyte infusion for relapses after transplant.[22–24][Level of evidence C3] Among 815 patients who underwent allogeneic SCT in two retrospective reviews, the 3-year OS rates were 36% and 26%.[25,26][Level of evidence C1]

The cytotoxic chemotherapy backbone for patients with ATL in the United States and Europe is the CHOP or CHO(E)P regimen (cyclophosphamide, doxorubicin, vincristine, etoposide, and prednisone). Brentuximab vedotin has been added to CHOP in rare cases when patients express CD30. For the acute and lymphoma versions of ATL, a series of clinical trials in Japan established VCAP-AMP-VECP as the standard first-line treatment.[2,27,28] This regimen has generally not been implemented outside of Asia since a trial comparing VCAP-AMP-VECP versus CHOP-14 did not show statistically improved OS (3-year OS rate, 24% vs. 13%; P = nonsignificant).

Allogeneic SCT is frequently used for patients achieving first or later remission, although results are largely anecdotal.[29,30]

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. Bangham CRM: HTLV-1 persistence and the oncogenesis of adult T-cell leukemia/lymphoma. Blood 141 (19): 2299-2306, 2023. [PUBMED Abstract]
  2. Cook LB, Phillips AA: How I treat adult T-cell leukemia/lymphoma. Blood 137 (4): 459-470, 2021. [PUBMED Abstract]
  3. Mehta-Shah N, Ratner L, Horwitz SM: Adult T-Cell Leukemia/Lymphoma. J Oncol Pract 13 (8): 487-492, 2017. [PUBMED Abstract]
  4. Sugata K, Yasunaga J, Miura M, et al.: Enhancement of anti-STLV-1/HTLV-1 immune responses through multimodal effects of anti-CCR4 antibody. Sci Rep 6: 27150, 2016. [PUBMED Abstract]
  5. Ishida T, Joh T, Uike N, et al.: Defucosylated anti-CCR4 monoclonal antibody (KW-0761) for relapsed adult T-cell leukemia-lymphoma: a multicenter phase II study. J Clin Oncol 30 (8): 837-42, 2012. [PUBMED Abstract]
  6. Phillips AA, Fields PA, Hermine O, et al.: Mogamulizumab versus investigator’s choice of chemotherapy regimen in relapsed/refractory adult T-cell leukemia/lymphoma. Haematologica 104 (5): 993-1003, 2019. [PUBMED Abstract]
  7. Ureshino H, Kamachi K, Kimura S: Mogamulizumab for the Treatment of Adult T-cell Leukemia/Lymphoma. Clin Lymphoma Myeloma Leuk 19 (6): 326-331, 2019. [PUBMED Abstract]
  8. Yonekura K, Kusumoto S, Choi I, et al.: Mogamulizumab for adult T-cell leukemia-lymphoma: a multicenter prospective observational study. Blood Adv 4 (20): 5133-5145, 2020. [PUBMED Abstract]
  9. Shichijo T, Nosaka K, Tatetsu H, et al.: Beneficial impact of first-line mogamulizumab-containing chemotherapy in adult T-cell leukaemia-lymphoma. Br J Haematol 198 (6): 983-987, 2022. [PUBMED Abstract]
  10. 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]
  11. Horwitz S, O’Connor OA, Pro B, et al.: Brentuximab vedotin with chemotherapy for CD30-positive peripheral T-cell lymphoma (ECHELON-2): a global, double-blind, randomised, phase 3 trial. Lancet 393 (10168): 229-240, 2019. [PUBMED Abstract]
  12. Ishida T, Fujiwara H, Nosaka K, et al.: Multicenter Phase II Study of Lenalidomide in Relapsed or Recurrent Adult T-Cell Leukemia/Lymphoma: ATLL-002. J Clin Oncol 34 (34): 4086-4093, 2016. [PUBMED Abstract]
  13. Chihara D: Synthetic lethality in ATL. Blood 141 (10): 1096-1098, 2023. [PUBMED Abstract]
  14. Izutsu K, Makita S, Nosaka K, et al.: An open-label, single-arm phase 2 trial of valemetostat for relapsed or refractory adult T-cell leukemia/lymphoma. Blood 141 (10): 1159-1168, 2023. [PUBMED Abstract]
  15. Bazarbachi A, Plumelle Y, Carlos Ramos J, et al.: Meta-analysis on the use of zidovudine and interferon-alfa in adult T-cell leukemia/lymphoma showing improved survival in the leukemic subtypes. J Clin Oncol 28 (27): 4177-83, 2010. [PUBMED Abstract]
  16. Bazarbachi A, Suarez F, Fields P, et al.: How I treat adult T-cell leukemia/lymphoma. Blood 118 (7): 1736-45, 2011. [PUBMED Abstract]
  17. Cook LB, Rowan AG, Demontis MA, et al.: Long-term clinical remission maintained after cessation of zidovudine and interferon-α therapy in chronic adult T-cell leukemia/lymphoma. Int J Hematol 107 (3): 378-382, 2018. [PUBMED Abstract]
  18. Hodson A, Crichton S, Montoto S, et al.: Use of zidovudine and interferon alfa with chemotherapy improves survival in both acute and lymphoma subtypes of adult T-cell leukemia/lymphoma. J Clin Oncol 29 (35): 4696-701, 2011. [PUBMED Abstract]
  19. Yamada Y, Tomonaga M, Fukuda H, et al.: A new G-CSF-supported combination chemotherapy, LSG15, for adult T-cell leukaemia-lymphoma: Japan Clinical Oncology Group Study 9303. Br J Haematol 113 (2): 375-82, 2001. [PUBMED Abstract]
  20. Fukushima T, Miyazaki Y, Honda S, et al.: Allogeneic hematopoietic stem cell transplantation provides sustained long-term survival for patients with adult T-cell leukemia/lymphoma. Leukemia 19 (5): 829-34, 2005. [PUBMED Abstract]
  21. Katsuya H, Yamanaka T, Ishitsuka K, et al.: Prognostic index for acute- and lymphoma-type adult T-cell leukemia/lymphoma. J Clin Oncol 30 (14): 1635-40, 2012. [PUBMED Abstract]
  22. Itonaga H, Tsushima H, Taguchi J, et al.: Treatment of relapsed adult T-cell leukemia/lymphoma after allogeneic hematopoietic stem cell transplantation: the Nagasaki Transplant Group experience. Blood 121 (1): 219-25, 2013. [PUBMED Abstract]
  23. Cook LB, Fuji S, Hermine O, et al.: Revised Adult T-Cell Leukemia-Lymphoma International Consensus Meeting Report. J Clin Oncol 37 (8): 677-687, 2019. [PUBMED Abstract]
  24. Yoshimitsu M, Tanosaki R, Kato K, et al.: Risk Assessment in Adult T Cell Leukemia/Lymphoma Treated with Allogeneic Hematopoietic Stem Cell Transplantation. Biol Blood Marrow Transplant 24 (4): 832-839, 2018. [PUBMED Abstract]
  25. Ishida T, Hishizawa M, Kato K, et al.: Allogeneic hematopoietic stem cell transplantation for adult T-cell leukemia-lymphoma with special emphasis on preconditioning regimen: a nationwide retrospective study. Blood 120 (8): 1734-41, 2012. [PUBMED Abstract]
  26. Katsuya H, Ishitsuka K, Utsunomiya A, et al.: Treatment and survival among 1594 patients with ATL. Blood 126 (24): 2570-7, 2015. [PUBMED Abstract]
  27. Hermine O, Ramos JC, Tobinai K: A Review of New Findings in Adult T-cell Leukemia-Lymphoma: A Focus on Current and Emerging Treatment Strategies. Adv Ther 35 (2): 135-152, 2018. [PUBMED Abstract]
  28. Tsukasaki K, Utsunomiya A, Fukuda H, et al.: VCAP-AMP-VECP compared with biweekly CHOP for adult T-cell leukemia-lymphoma: Japan Clinical Oncology Group Study JCOG9801. J Clin Oncol 25 (34): 5458-64, 2007. [PUBMED Abstract]
  29. Bazarbachi AH, Reef D, Narvel H, et al.: Outcome of Stem Cell Transplantation in HTLV-1-Associated North American Adult T-Cell Leukemia/Lymphoma. Clin Hematol Int 5 (2-3): 78-91, 2023. [PUBMED Abstract]
  30. Tanase AD, Colita A, Craciun OG, et al.: Allogeneic Stem Cell Transplantation for Adult T-Cell Leukemia/Lymphoma-Romanian Experience. J Clin Med 9 (8): , 2020. [PUBMED Abstract]

Treatment of T-Cell Prolymphocytic Leukemia

Prolymphocytic leukemia (PLL) is a rare form of lymphocytic leukemia characterized by excessive prolymphocytes in the blood with a typical phenotype that is positive for CD19, CD20, and surface-membrane immunoglobulin and negative for CD5.[1] These patients demonstrate splenomegaly and poor response to low-dose or high-dose chemotherapy.[2,3]

Treatment Options for T-Cell Prolymphocytic Leukemia

Cladribine appears to be an active agent (60% complete remission rate) for patients with de novo B-cell PLL.[4][Level of evidence C3] Anecdotal responses have been seen with venetoclax.[5][Level of evidence C3] Alemtuzumab, an anti-CD52 humanized monoclonal antibody, has been used for 76 patients with T-cell PLL after failure of previous chemotherapy (usually pentostatin or cladribine). The response rate was 51% (95% confidence interval, 40%–63%), and the median time to progression was 4.5 months (range, 0.1–45.4).[6][Level of evidence C3] These response rates have been confirmed by other investigators.[7] Patients with chronic lymphocytic leukemia (CLL) and prolymphocytoid transformation maintain the classic CLL phenotype and have a worse prognosis than patients with PLL.

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. Staber PB, Herling M, Bellido M, et al.: Consensus criteria for diagnosis, staging, and treatment response assessment of T-cell prolymphocytic leukemia. Blood 134 (14): 1132-1143, 2019. [PUBMED Abstract]
  2. Rozman C, Montserrat E: Chronic lymphocytic leukemia. N Engl J Med 333 (16): 1052-7, 1995. [PUBMED Abstract]
  3. Melo JV, Catovsky D, Galton DA: The relationship between chronic lymphocytic leukaemia and prolymphocytic leukaemia. I. Clinical and laboratory features of 300 patients and characterization of an intermediate group. Br J Haematol 63 (2): 377-87, 1986. [PUBMED Abstract]
  4. Saven A, Lee T, Schlutz M, et al.: Major activity of cladribine in patients with de novo B-cell prolymphocytic leukemia. J Clin Oncol 15 (1): 37-43, 1997. [PUBMED Abstract]
  5. Boidol B, Kornauth C, van der Kouwe E, et al.: First-in-human response of BCL-2 inhibitor venetoclax in T-cell prolymphocytic leukemia. Blood 130 (23): 2499-2503, 2017. [PUBMED Abstract]
  6. Keating MJ, Cazin B, Coutré S, et al.: Campath-1H treatment of T-cell prolymphocytic leukemia in patients for whom at least one prior chemotherapy regimen has failed. J Clin Oncol 20 (1): 205-13, 2002. [PUBMED Abstract]
  7. Dearden CE, Matutes E, Catovsky D: Alemtuzumab in T-cell malignancies. Med Oncol 19 (Suppl): S27-32, 2002. [PUBMED Abstract]

Treatment of Relapsed or Refractory Peripheral T-Cell Lymphoma

Treatment Options for Relapsed or Refractory Peripheral T-Cell Lymphoma

Treatment options for relapsed or refractory peripheral T-cell lymphoma include:

  1. Combination chemotherapy.
    • ICE (ifosfamide, carboplatin, and etoposide).[1,2]
    • GEMOX (gemcitabine, oxaliplatin, and dexamethasone).[3]
    • DHAP (dexamethasone, high-dose cytarabine, and cisplatin).[4]
    • ESHAP (etoposide, methylprednisolone, high-dose cytarabine, and cisplatin).[5,6]
    • Hyper-CVAD (cyclophosphamide, vincristine, doxorubicin, and dexamethasone).[7]
  2. Antibody conjugates.
    • Brentuximab vedotin (for CD30-positive patients).
  3. Histone deacetylase inhibitors.
    • Romidepsin.[8]
    • Belinostat.[9,10]
  4. Dihydrofolate reductase inhibitors.
    • Pralatrexate.[11]
  5. Anti-CD52 monoclonal antibodies.
    • Alemtuzumab (only available through a restricted distribution program).
  6. Stem cell transplant.[12–16]

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. Jerkeman M, Leppä S, Kvaløy S, et al.: ICE (ifosfamide, carboplatin, etoposide) as second-line chemotherapy in relapsed or primary progressive aggressive lymphoma–the Nordic Lymphoma Group experience. Eur J Haematol 73 (3): 179-82, 2004. [PUBMED Abstract]
  2. Zelenetz AD, Hamlin P, Kewalramani T, et al.: Ifosfamide, carboplatin, etoposide (ICE)-based second-line chemotherapy for the management of relapsed and refractory aggressive non-Hodgkin’s lymphoma. Ann Oncol 14 (Suppl 1): i5-10, 2003. [PUBMED Abstract]
  3. Shen QD, Wang L, Zhu HY, et al.: Gemcitabine, oxaliplatin and dexamethasone (GemDOx) as salvage therapy for relapsed or refractory diffuse large B-cell lymphoma and peripheral T-cell lymphoma. J Cancer 12 (1): 163-169, 2021. [PUBMED Abstract]
  4. Schmitz N, Truemper L, Bouabdallah K, et al.: A randomized phase 3 trial of autologous vs allogeneic transplantation as part of first-line therapy in poor-risk peripheral T-NHL. Blood 137 (19): 2646-2656, 2021. [PUBMED Abstract]
  5. Velasquez WS, McLaughlin P, Tucker S, et al.: ESHAP–an effective chemotherapy regimen in refractory and relapsing lymphoma: a 4-year follow-up study. J Clin Oncol 12 (6): 1169-76, 1994. [PUBMED Abstract]
  6. Mercadal S, Briones J, Xicoy B, et al.: Intensive chemotherapy (high-dose CHOP/ESHAP regimen) followed by autologous stem-cell transplantation in previously untreated patients with peripheral T-cell lymphoma. Ann Oncol 19 (5): 958-63, 2008. [PUBMED Abstract]
  7. Hapgood G, Stone JM, Zannino D, et al.: A phase II study of a modified hyper-CVAD frontline therapy for patients with adverse risk diffuse large B-cell and peripheral T-cell non-Hodgkin lymphoma. Leuk Lymphoma 60 (4): 904-911, 2019. [PUBMED Abstract]
  8. Iyer SP, Foss FF: Romidepsin for the Treatment of Peripheral T-Cell Lymphoma. Oncologist 20 (9): 1084-91, 2015. [PUBMED Abstract]
  9. Campbell P, Thomas CM: Belinostat for the treatment of relapsed or refractory peripheral T-cell lymphoma. J Oncol Pharm Pract 23 (2): 143-147, 2017. [PUBMED Abstract]
  10. O’Connor OA, Horwitz S, Masszi T, et al.: Belinostat in Patients With Relapsed or Refractory Peripheral T-Cell Lymphoma: Results of the Pivotal Phase II BELIEF (CLN-19) Study. J Clin Oncol 33 (23): 2492-9, 2015. [PUBMED Abstract]
  11. O’Connor OA, Pro B, Pinter-Brown L, et al.: Pralatrexate in patients with relapsed or refractory peripheral T-cell lymphoma: results from the pivotal PROPEL study. J Clin Oncol 29 (9): 1182-9, 2011. [PUBMED Abstract]
  12. Schmitz N, Lenz G, Stelljes M: Allogeneic hematopoietic stem cell transplantation for T-cell lymphomas. Blood 132 (3): 245-253, 2018. [PUBMED Abstract]
  13. Chen AI, McMillan A, Negrin RS, et al.: Long-term results of autologous hematopoietic cell transplantation for peripheral T cell lymphoma: the Stanford experience. Biol Blood Marrow Transplant 14 (7): 741-7, 2008. [PUBMED Abstract]
  14. Hamadani M, Ngoya M, Sureda A, et al.: Outcome of allogeneic transplantation for mature T-cell lymphomas: impact of donor source and disease characteristics. Blood Adv 6 (3): 920-930, 2022. [PUBMED Abstract]
  15. Mehta-Shah N, Kommalapati A, Teja S: Successful treatment of mature T-cell lymphoma with allogeneic stem cell transplantation: the largest multicenter retrospective analysis. [Abstract] Blood 136 (Suppl 1): A-624, 35-36, 2020.
  16. Sterling CH, Hughes MS, Tsai HL, et al.: Allogeneic Blood or Marrow Transplantation with Post-Transplantation Cyclophosphamide for Peripheral T Cell Lymphoma: The Importance of Graft Source. Transplant Cell Ther 29 (4): 267.e1-267.e5, 2023. [PUBMED Abstract]

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 adult peripheral T-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 Peripheral T-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

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PDQ® Adult Treatment Editorial Board. PDQ Peripheral T-Cell Non-Hodgkin Lymphoma Treatment. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: /types/lymphoma/hp/peripheral-t-cell-lymphoma-pdq. Accessed <MM/DD/YYYY>. [PMID: 37437079]

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

Indolent 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 indolent B-cell NHL. For information about B-cell and T-cell lymphomas, see Aggressive B-Cell Non-Hodgkin Lymphoma Treatment, Peripheral T-Cell Non-Hodgkin Lymphoma Treatment and Mycosis Fungoides and Other Cutaneous T-Cell Lymphomas 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] Early-stage (stage I and stage II) indolent NHL can be effectively treated with radiation therapy alone. Most of the indolent NHLs are nodular (or follicular) in morphology.

Aggressive NHL has a worse prognosis in the short term, but a significant number of patients can be cured with intensive combination chemotherapy regimens.

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.[5]

Although indolent NHL responds quickly to immunotherapy, radiation therapy, and chemotherapy, a continuous rate of relapse is usually seen in advanced stages. However, patients can often be re-treated with considerable success if the disease histology remains low grade. 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.[6,7]

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. 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]
  6. 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]
  7. 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]
  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 Indolent 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.
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]

Indolent B-Cell Non-Hodgkin Lymphoma

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

  • Follicular lymphoma (grades 1–3a).
  • Lymphoplasmacytic lymphoma (Waldenström macroglobulinemia).
  • Marginal zone lymphoma.

Follicular Lymphoma (Grades 1–3a)

Follicular lymphoma makes up 20% of all NHL and as many as 70% of the indolent lymphomas reported in American and European clinical trials.[1–3] Most patients with follicular lymphoma are aged 50 years and older and present with widespread disease at diagnosis. Nodal involvement is most common and is often accompanied by splenic and bone marrow disease. Rearrangement of the BCL2 gene is present in more than 90% of patients with follicular lymphoma. Overexpression of the BCL2 protein is associated with the inability to eradicate the lymphoma by inhibiting apoptosis.[4]

Prognosis

Follicular lymphoma is designated as indolent because median survival ranges from 8 to 15 years, even in advanced stages.[5–7] Patients with advanced-stage follicular lymphoma are not cured with current therapeutic options. The rate of relapse is fairly consistent over time, even in patients who have achieved complete responses to treatment.[8] Watchful waiting, the deferring of treatment until the patient becomes symptomatic, is an option for patients with advanced-stage follicular lymphoma.[9,10] An international index for follicular lymphoma (the Follicular Lymphoma International Prognostic Index [FLIPI]) [11–13] identified five significant risk factors prognostic of overall survival (OS):

  1. Age (≤60 years vs. >60 years).
  2. Serum lactate dehydrogenase (LDH) (normal vs. elevated).
  3. Stage (stage I or stage II vs. stage III or stage IV).
  4. Hemoglobin level (≥120 g/L vs. <120 g/L).
  5. Number of nodal areas (≤4 vs. >4).

Patients with zero or one risk factor have a 10-year survival rate of 67%, and four or five risk factors confer a 10-year survival rate of 36%.[11] In a revised FLIPI-2, an elevated beta-2-microglobulin and lymph node size of more than 6 cm are proposed prognostic factors instead of serum LDH and the number of nodal areas.[14] Although the FLIPI and FLIPI-2 indices can predict progression-free survival (PFS) and OS, the scores cannot be used to establish the need for therapy or to predict response to therapy.[11,14] The primary use of FLIPI or FLIPI-2 is to assure a balance of prognostic factors or to define entry requirements in randomized clinical trials. Individuals with an adverse FLIPI score may well benefit from watchful waiting or may respond well to initial therapy. An alternative prognostic index using only beta-2-microglobulin and initial bone marrow involvement (PRIMA-PI) has the disadvantage of requiring an invasive test not usually required outside the context of a clinical trial.[15] The Follicular Lymphoma Evaluation Index (FLEX), an alternative prognostic index using only noninvasive clinical variables, outperformed FLIPI, FLIPI-2, and PRIMA-PI, using data from immunochemotherapy trials.[16] The nine clinical variables of the FLEX model include:

  1. Male sex.
  2. Histological grade 3a disease.
  3. More than two extranodal sites.
  4. Eastern Cooperative Oncology Group performance status score of 2 or higher.
  5. Hemoglobin level less than 120 g/L.
  6. Beta-2 microglobulin level above the upper limit of normal.
  7. LDH level above the upper limit of normal.
  8. Absolute blood natural killer cell count less than 100/μL.
  9. Bulky disease.

Three retrospective analyses, including one pooled analysis of 5,225 patients from 13 randomized clinical trials, identified a high-risk group that had a 5-year OS rate of 50% when relapses occurred within 24 months of induction chemoimmunotherapy.[17–19] A fourth retrospective analysis of 296 patients who received bendamustine and rituximab found a 2-year OS rate of 38% (95% confidence interval [CI], 20%−55%) among those with progression of disease before 24 months (POD24). Most of these patients (76%) had transformed disease (histological progression to diffuse large B-cell lymphoma [DLBCL]).[20] These patients with higher-risk POD24 disease represent a target population for clinical trials.

Therapeutic approaches

Because of the often-indolent clinical course and the lack of symptoms in some patients with follicular lymphoma, watchful waiting remains a standard of care during the initial encounter and for patients with slow asymptomatic relapsing disease. When therapy is required, numerous options may be used in varying sequences with an OS equivalence at 5 to 10 years.[9,21–23] Rituximab can be given alone or in combination with various chemotherapy options.[23–25] Rituximab can also be combined with the immunomodulating-agent lenalidomide to avoid the short- and long-term toxicities of cytotoxic agents.[26–28] Obinutuzumab is a completely humanized anti–CD20 monoclonal antibody that can be given alone or with combination chemotherapy. It may be especially useful for patients who develop severe allergic reactions to rituximab due to human antimouse antibodies.[29] CD19-directed chimeric antigen receptor T cells may be used in patients who have disease progression after two or more prior lines of therapy.[30] Mosunetuzumab, a bispecific CD20-directed CD3 T-cell engager, may also be used in this setting.[31] Consolidation therapy for relapsed disease after reinduction therapy using autologous stem cell transplant (SCT) or allogeneic SCT can be considered.[32]

Outside the context of clinical trials, the use of measurable residual disease (MRD) testing has not been shown to be predictive in directing therapy for patients with follicular lymphoma. In retrospective analyses of two randomized prospective trials, while MRD negativity was prognostic of outcome, maintenance rituximab or obinutuzumab prolonged PFS the most among patients with MRD-negative disease.[33,34][Level of evidence C2] Stopping maintenance rituximab or obinutuzumab was not indicated in patients with MRD-negative disease, negating any possible change in therapy based on that status.

Follicular lymphoma in situ and primary follicular lymphoma of the duodenum are particularly indolent variants that rarely progress or require therapy.[35,36] A so-called pediatric-type nodal follicular lymphoma has indolent behavior and rarely recurs; adult patients with this histological variant have disease characterized by a lack of BCL2 rearrangement in conjunction with a Ki-67 proliferation index greater than 30% and a localized stage I presentation.[37]

Patients with indolent lymphoma may experience a relapse with a more aggressive histology. If the clinical pattern of relapse suggests that the disease is behaving in a more aggressive manner, a biopsy can be performed, if feasible.[38] If disease conversion to a more aggressive histology is confirmed, therapy must change to a regimen applicable to that histological type.[39] Rapid growth or discordant growth between various disease sites may indicate a histological conversion.[38]

In a prospective nonrandomized study, at a median follow-up of 6.8 years, 379 of 2,652 patients (14%) subsequently transformed to a more aggressive histology after an initial diagnosis of follicular lymphoma.[40][Level of evidence C3] The median OS after subsequent transformation was 5 years. However, among 47 patients with evidence of transformation in conjunction with follicular lymphoma at the time of initial diagnosis, the OS was no worse than that of the nontransformed patients (5-year OS rate, 88%; 95% CI, 74%–95%).

Grade 3b follicular lymphoma is managed similarly to DLBCL. For more information, see Aggressive B-Cell Non-Hodgkin Lymphoma Treatment.

Lymphoplasmacytic Lymphoma (Waldenström Macroglobulinemia)

Lymphoplasmacytic lymphoma is usually associated with a monoclonal serum paraprotein of immunoglobulin M (IgM) type (Waldenström macroglobulinemia).[41] Most patients have bone marrow, lymph node, and splenic involvement, and some patients may develop hyperviscosity syndrome. Most patients with Waldenström macroglobulinemia carry the MYD88 variant, which some pathologists consider indicative for the disease.[42] Other lymphomas may also be associated with serum paraproteins. Patients with lymphoplasmacytic lymphoma should be checked for associated hepatitis C virus (HCV) infection.

Asymptomatic patients can be monitored for evidence of disease progression without immediate need for chemotherapy.[9,43,44]

Prognostic factors associated with symptoms requiring therapy include:

  • Aged 70 years or older.
  • Beta-2-microglobulin of 3 mg/dL or more.
  • Increased serum LDH.[43]

An externally validated prognostic model uses age, albumin, and LDH levels.[45]

Therapeutic approaches

The management of lymphoplasmacytic lymphoma is similar to that of other low-grade lymphomas, especially diffuse small lymphocytic lymphoma/chronic lymphocytic leukemia.[46–48] If the serum viscosity relative to water is greater than four, the patient may have symptoms of hyperviscosity. Plasmapheresis is useful for temporary, acute symptoms such as retinopathy, congestive heart failure, and central nervous system (CNS) dysfunction. It can also be combined with chemotherapy for prolonged disease control. Symptomatic patients with a serum viscosity of four or lower are usually treated with chemoimmunotherapy or biologically directed therapies. Therapy may be required to correct hemolytic anemia in patients with chronic cold agglutinin disease; rituximab, bendamustine, and steroids are often used.[44] Occasionally, a heated room is required for patients whose cold agglutinins become activated by even minor chilling. Sutimlimab, an immunoglobulin G4 monoclonal antibody that selectively inhibits the complement pathway at C15, can reduce hemolysis when therapies directed at the lymphoplasmacytic lymphoma are ineffective.[49]

First-line regimens include zanubrutinib (a Bruton tyrosine kinase [BTK] inhibitor), rituximab, and ibrutinib (another BTK inhibitor), rituximab alone, the nucleoside analogues, and alkylating agents, either as single agents or as part of combination chemotherapy.[50–53] In a randomized prospective trial, 150 symptomatic patients (including patients with previously untreated and relapsing disease) received either ibrutinib and rituximab or rituximab and a placebo. With a median follow-up of 50 months, the 4.5-year PFS rate was 68% in the ibrutinib-and-rituximab arm (95% CI, 55%–78%) and 25% in the rituximab-and-placebo arm (95% CI, 15%–37%) (hazard ratio [HR], 0.25; 95% CI, 0.15–0.42; P < .0001). The OS rate at 30 months was no different in the two arms (92%–94%).[52][Level of evidence B1] Zanubrutinib was compared with ibrutinib in a randomized prospective clinical trial of 164 patients with relapsed disease and 38 with previously untreated disease.[53] With a median follow-up of 44.4 months, the PFS rate was similar in both groups at 70% to 78% (HR, 0.63; 95% CI, 0.36–1.12), and the OS rate was similar in both groups at 85% to 87% (HR, 0.75; 95% CI, 0.36–1.59).[54] The zanubrutinib group had fewer cases of atrial fibrillation (11 vs. 1) and 50% fewer cases of hypertension (statistics not provided).[53][Level of evidence C3] BTK inhibition with ibrutinib allowed all 13 patients with cold-antibody–mediated autoimmune hemolytic anemia and acrocyanosis to attain clinical remission regardless of underlying pathology or MYD88 variant status.[55][Level of evidence C3]

Previously untreated patients who received rituximab had response rates of 60% to 80%, but close monitoring of the serum IgM is required because of a sudden rise in this paraprotein at the start of therapy.[56–58][Level of evidence C3] The rise of IgM after rituximab can be avoided with the concomitant use of an alkylating agent, such as cyclophosphamide, or the proteosome inhibitors bortezomib or ixazomib.[44,59–61] A combination of bortezomib, dexamethasone, and rituximab has been used without causing IgM rebound.[62–64] Previously untreated patients with lymphoplasmacytic lymphoma who received the nucleoside analogues cladribine and fludarabine showed similar response rates.[51,65,66][Level of evidence C3] Patients who received single-agent alkylators, bendamustine, bortezomib, venetoclax, and combination chemotherapy with or without rituximab also showed similar response rates.[51,59,61,67–71][Level of evidence C3] In the rare case of lymphoplasmacytic lymphoma involving the CNS (Bing-Neel syndrome), ibrutinib resulted in an 85% response rate in an anecdotal series of 28 patients.[72][Level of evidence C3]

Myeloablative therapy with autologous or allogeneic hematopoietic stem cell support is under clinical evaluation.[73–76] Candidates for this approach should avoid long-term use of alkylating agents or purine nucleoside analogues, which can deplete hematopoietic stem cells or predispose patients to myelodysplasia or acute leukemia.[56,77] After relapse from alkylating-agent therapy, 92 patients with lymphoplasmacytic lymphoma were randomly assigned to receive either fludarabine or cyclophosphamide, doxorubicin, and prednisone. Although relapse-free survival favored fludarabine (median duration of 19 months vs. 3 months; P < .01), no difference was observed in OS.[78][Level of evidence B1]

Marginal Zone Lymphoma

When marginal zone lymphomas involve the nodes, they are called monocytoid B-cell lymphomas or nodal marginal zone B-cell lymphomas. When they involve extranodal sites (e.g., gastrointestinal tract, thyroid, lung, breast, orbit, and skin), they are called mucosa-associated lymphatic tissue (MALT) lymphomas.[79,80] Splenic marginal zone lymphoma is a distinct clinical entity, which usually presents with massive splenomegaly. A variant form of MALT lymphoma is known as immunoproliferative small intestinal disease (IPSID).[80] A prognostic index for all of the marginal zone lymphomas has three adverse prognostic factors: aged 70 years or older, stage III or stage IV disease, and high LDH level.[81] Fewer than 10% of patients transform to a higher-grade lymphoma. In one retrospective review, risk factors for transformation included elevated LDH, more than four nodal sites at the time of initial diagnosis of marginal zone lymphoma, and failure to achieve complete response after initial treatment.[82]

Gastric MALT

Many patients have a history of autoimmune disease, such as Hashimoto thyroiditis or Sjögren syndrome, or of Helicobacter gastritis. Most patients present with stage I or stage II extranodal disease, which is most often in the stomach. Treatment of H. pylori infection may resolve most cases of localized gastric involvement.[83,84] After standard antibiotic regimens, 50% of patients show resolution of gastric MALT by endoscopy after 3 months. Other patients may show resolution after 12 to 18 months of observation. Of the patients who attain complete remission, 30% demonstrate monoclonality by immunoglobulin heavy chain rearrangement on stomach biopsies with a 5-year median follow-up.[85] The clinical implication of this finding is unknown. Translocation t(11;18) in patients with gastric MALT predicts poor response to both antibiotic therapy and oral alkylator therapy, and predicts negative H. pylori testing results.[86–88] Patients with stable asymptomatic disease and persistently positive biopsies have been successfully followed with a watchful waiting approach until disease progression.[84] Patients with disease progression are treated with radiation therapy,[89–94] rituximab,[95] surgery (total gastrectomy or partial gastrectomy plus radiation therapy),[96] chemotherapy,[97] or combined-modality therapy.[98] A single-arm prospective trial enrolled 24 patients with newly diagnosed or relapsed H. pylori–negative gastric MALT.[94] Most patients had a complete response to radiation therapy at 4 Gy, and 20 Gy was applied as salvage therapy. The 3-year local control rate was 96% (95% CI, 88%–100%).[94][Level of evidence C3] Endoscopic ultrasonography may help clinicians monitor responses in these patients.[99] Four case series encompassing more than 100 patients with stage IE or IIE DLBCL with or without associated MALT (but H. pylori-positive) reported durable complete remissions in more than 50% of the patients after treatment of H. pylori.[100–103]

Extragastric MALT

Localized involvement of other sites can be treated with radiation therapy or surgery.[90–92,104–107] Patients with extragastric MALT lymphoma have a higher relapse rate than patients with gastric MALT lymphoma in some series, and relapses can happen many years and even decades later.[108] Many of these recurrences involve different MALT sites than the original location.[109] When disseminated to lymph nodes, bone marrow, or blood, this entity behaves like other low-grade lymphomas.[110,111] A prospective randomized trial of 401 patients with nongastric extranodal MALT compared chlorambucil alone versus rituximab plus chlorambucil versus rituximab alone.[112] With a median follow-up of 7.4 years, the event-free survival was 68% in the rituximab-plus-chlorambucil arm, 51% in the rituximab-alone arm, and 50% in the chlorambucil-alone arm (P = .0009). However, the 5-year OS rate was 90% in all arms.[112] For patients with ocular adnexal MALT, antibiotic therapy using doxycycline that targeted Chlamydia psittaci resulted in durable remissions for almost one-half of the patients in a review of the literature that included 131 patients.[113][Level of evidence C3] These responses to doxycycline are mainly seen in Italian trials and less often in trials conducted in other geographic sites.[114] Large B-cell lymphomas of MALT sites are classified and treated as diffuse large cell lymphomas.[115] A large, retrospective review of primary ocular adnexal MALT found that after 10 years of follow-up, 4% of stage I patients treated with radiation therapy had disease transformation to DLBCL, and 3% developed CNS involvement.[116]

Nodal marginal zone lymphoma

Patients with nodal marginal zone lymphoma (monocytoid B-cell lymphoma) are treated with watchful waiting or therapies as described for lymphoplasmacytic lymphoma. Rituximab alone, obinutuzumab alone, or combinations with cytotoxic agents (such as bendamustine, CVP [cyclophosphamide, vincristine, and prednisone] or CHOP [cyclophosphamide, doxorubicin, vincristine, and prednisone]) can be used.[117–119][Level of evidence C3] Zanubrutinib is approved for patients with disease relapse after a rituximab-containing regimen. This approval was based on a single-arm phase II study.[120] With a median follow-up of 15.7 months, the overall response rate was 68.2%, and the complete response rate was 25.8%. The median duration of response was 93% at 12 months.[120][Level of evidence C3] Ibrutinib also showed similar efficacy in patients with relapsed marginal zone lymphoma.[121][Level of evidence C3] Patients with marginal zone lymphoma comprised a small percentage (about 15%) of the population for a trial that established the benefit of rituximab with lenalidomide in patients with relapsed or refractory indolent lymphoma (AUGMENT trial).[122][Level of evidence C3] Similar to follicular lymphoma, patients with POD24 who required initiation of therapy had a worse prognosis than did the patients without POD24 (3-year OS rate, 53% vs. 95%).[123] Among patients with concomitant HCV infection, 40% to 60% attained a complete or partial remission after loss of detectable HCV RNA with antiviral treatment.[124,125][Level of evidence C3]

Mediterranean abdominal lymphoma

The disease variously known as Mediterranean abdominal lymphoma, heavy-chain disease, or IPSID, which occurs in young adults in eastern Mediterranean countries, is another version of MALT lymphoma. This disease responds to antibiotics in its early stages.[126] Campylobacter jejuni has been identified as one of the bacterial species associated with IPSID, and antibiotic therapy may result in disease remission.[127]

Splenic marginal zone lymphoma

Splenic marginal zone lymphoma is an indolent lymphoma that is marked by massive splenomegaly and peripheral blood and bone marrow involvement, usually without adenopathy.[128,129] This type of lymphoma is also known as splenic lymphoma with villous lymphocytes. Splenectomy may result in prolonged remission.[130,131]

Management is similar to that of other low-grade lymphomas and usually involves rituximab alone or rituximab in combination with purine analogues or alkylating agent chemotherapy.[132] Splenic marginal zone lymphoma responds less well to chemotherapy, which would ordinarily be effective for chronic lymphocytic leukemia.[128,132,133] Among small numbers of patients with splenic marginal zone lymphoma (splenic lymphoma with villous lymphocytes) and HCV infection, most attained a complete or partial remission after loss of detectable HCV RNA with treatment using interferon alfa with or without ribavirin.[124,134]; [135][Level of evidence C3] In contrast, no responses to interferon were seen in six HCV-negative patients.

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  92. Tsai HK, Li S, Ng AK, et al.: Role of radiation therapy in the treatment of stage I/II mucosa-associated lymphoid tissue lymphoma. Ann Oncol 18 (4): 672-8, 2007. [PUBMED Abstract]
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  95. Martinelli G, Laszlo D, Ferreri AJ, et al.: Clinical activity of rituximab in gastric marginal zone non-Hodgkin’s lymphoma resistant to or not eligible for anti-Helicobacter pylori therapy. J Clin Oncol 23 (9): 1979-83, 2005. [PUBMED Abstract]
  96. Cogliatti SB, Schmid U, Schumacher U, et al.: Primary B-cell gastric lymphoma: a clinicopathological study of 145 patients. Gastroenterology 101 (5): 1159-70, 1991. [PUBMED Abstract]
  97. Zinzani PL, Magagnoli M, Galieni P, et al.: Nongastrointestinal low-grade mucosa-associated lymphoid tissue lymphoma: analysis of 75 patients. J Clin Oncol 17 (4): 1254, 1999. [PUBMED Abstract]
  98. Thieblemont C, Bastion Y, Berger F, et al.: Mucosa-associated lymphoid tissue gastrointestinal and nongastrointestinal lymphoma behavior: analysis of 108 patients. J Clin Oncol 15 (4): 1624-30, 1997. [PUBMED Abstract]
  99. Pavlick AC, Gerdes H, Portlock CS: Endoscopic ultrasound in the evaluation of gastric small lymphocytic mucosa-associated lymphoid tumors. J Clin Oncol 15 (5): 1761-6, 1997. [PUBMED Abstract]
  100. 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]
  101. 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]
  102. 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]
  103. 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]
  104. Uno T, Isobe K, Shikama N, et al.: Radiotherapy for extranodal, marginal zone, B-cell lymphoma of mucosa-associated lymphoid tissue originating in the ocular adnexa: a multiinstitutional, retrospective review of 50 patients. Cancer 98 (4): 865-71, 2003. [PUBMED Abstract]
  105. Bayraktar S, Bayraktar UD, Stefanovic A, et al.: Primary ocular adnexal mucosa-associated lymphoid tissue lymphoma (MALT): single institution experience in a large cohort of patients. Br J Haematol 152 (1): 72-80, 2011. [PUBMED Abstract]
  106. Stefanovic A, Lossos IS: Extranodal marginal zone lymphoma of the ocular adnexa. Blood 114 (3): 501-10, 2009. [PUBMED Abstract]
  107. Vazquez A, Khan MN, Sanghvi S, et al.: Extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue of the salivary glands: a population-based study from 1994 to 2009. Head Neck 37 (1): 18-22, 2015. [PUBMED Abstract]
  108. Raderer M, Streubel B, Woehrer S, et al.: High relapse rate in patients with MALT lymphoma warrants lifelong follow-up. Clin Cancer Res 11 (9): 3349-52, 2005. [PUBMED Abstract]
  109. Sretenovic M, Colovic M, Jankovic G, et al.: More than a third of non-gastric malt lymphomas are disseminated at diagnosis: a single center survey. Eur J Haematol 82 (5): 373-80, 2009. [PUBMED Abstract]
  110. Nathwani BN, Drachenberg MR, Hernandez AM, et al.: Nodal monocytoid B-cell lymphoma (nodal marginal-zone B-cell lymphoma). Semin Hematol 36 (2): 128-38, 1999. [PUBMED Abstract]
  111. Raderer M, Wöhrer S, Streubel B, et al.: Assessment of disease dissemination in gastric compared with extragastric mucosa-associated lymphoid tissue lymphoma using extensive staging: a single-center experience. J Clin Oncol 24 (19): 3136-41, 2006. [PUBMED Abstract]
  112. Zucca E, Conconi A, Martinelli G, et al.: Final Results of the IELSG-19 Randomized Trial of Mucosa-Associated Lymphoid Tissue Lymphoma: Improved Event-Free and Progression-Free Survival With Rituximab Plus Chlorambucil Versus Either Chlorambucil or Rituximab Monotherapy. J Clin Oncol 35 (17): 1905-1912, 2017. [PUBMED Abstract]
  113. Kiesewetter B, Raderer M: Antibiotic therapy in nongastrointestinal MALT lymphoma: a review of the literature. Blood 122 (8): 1350-7, 2013. [PUBMED Abstract]
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  115. Kuo SH, Chen LT, Yeh KH, et al.: Nuclear expression of BCL10 or nuclear factor kappa B predicts Helicobacter pylori-independent status of early-stage, high-grade gastric mucosa-associated lymphoid tissue lymphomas. J Clin Oncol 22 (17): 3491-7, 2004. [PUBMED Abstract]
  116. Desai A, Joag MG, Lekakis L, et al.: Long-term course of patients with primary ocular adnexal MALT lymphoma: a large single-institution cohort study. Blood 129 (3): 324-332, 2017. [PUBMED Abstract]
  117. Herold M, Hoster E, Janssens A, et al.: Immunochemotherapy and Maintenance With Obinutuzumab or Rituximab in Patients With Previously Untreated Marginal Zone Lymphoma in the Randomized GALLIUM Trial. Hemasphere 6 (3): e699, 2022. [PUBMED Abstract]
  118. Salar A, Domingo-Domenech E, Panizo C, et al.: Long-term results of a phase 2 study of rituximab and bendamustine for mucosa-associated lymphoid tissue lymphoma. Blood 130 (15): 1772-1774, 2017. [PUBMED Abstract]
  119. Alderuccio JP, Arcaini L, Watkins MP, et al.: An international analysis evaluating frontline bendamustine with rituximab in extranodal marginal zone lymphoma. Blood Adv 6 (7): 2035-2044, 2022. [PUBMED Abstract]
  120. Opat S, Tedeschi A, Linton K, et al.: The MAGNOLIA Trial: Zanubrutinib, a Next-Generation Bruton Tyrosine Kinase Inhibitor, Demonstrates Safety and Efficacy in Relapsed/Refractory Marginal Zone Lymphoma. Clin Cancer Res 27 (23): 6323-6332, 2021. [PUBMED Abstract]
  121. Noy A, de Vos S, Coleman M, et al.: Durable ibrutinib responses in relapsed/refractory marginal zone lymphoma: long-term follow-up and biomarker analysis. Blood Adv 4 (22): 5773-5784, 2020. [PUBMED Abstract]
  122. Leonard JP, Trneny M, Izutsu K, et al.: AUGMENT: A Phase III Study of Lenalidomide Plus Rituximab Versus Placebo Plus Rituximab in Relapsed or Refractory Indolent Lymphoma. J Clin Oncol 37 (14): 1188-1199, 2019. [PUBMED Abstract]
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  125. Merli M, Rattotti S, Spina M, et al.: Direct-Acting Antivirals as Primary Treatment for Hepatitis C Virus-Associated Indolent Non-Hodgkin Lymphomas: The BArT Study of the Fondazione Italiana Linfomi. J Clin Oncol 40 (35): 4060-4070, 2022. [PUBMED Abstract]
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Treatment Option Overview for Indolent B-Cell Non-Hodgkin Lymphoma

Treatment of indolent 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 on 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 Indolent B-Cell Non-Hodgkin Lymphoma (NHL)
Stage Treatment Options
CAR = chimeric antigen receptor; SCT = stem cell transplant.
Indolent Stage I and Indolent, Contiguous Stage II B-cell NHL Radiation therapy
Rituximab with or without chemotherapy
Watchful waiting
Other therapies as designated for patients with advanced-stage disease
Indolent, Noncontiguous Stage II/III/IV B-cell NHL Watchful waiting for asymptomatic patients
Rituximab alone or in combination with cytotoxic agents used in front-line therapy
Lenalidomide and rituximab
Maintenance rituximab
Obinutuzumab alone or in combination with cytotoxic agents used in front-line therapy
Indolent, Recurrent B-cell NHL
Rituximab alone or in combination with cytotoxic agents used in front-line therapy
Obinutuzumab alone or in combination with cytotoxic agents used in front-line therapy
Lenalidomide and rituximab
Zanubrutinib and obinutuzumab
EZH2 inhibitor
Bispecific T-cell engagers
CAR T-cell therapy
SCT
Palliative radiation therapy

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 be included 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]

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]

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 Indolent Stage I and Indolent, Contiguous Stage II B-Cell Non-Hodgkin Lymphoma

Although localized presentations are uncommon in B-cell non-Hodgkin lymphoma (NHL), the goal of treatment is to cure the disease in patients with confirmed localized occurrence after undergoing appropriate staging.

Treatment Options for Indolent Stage I and Indolent, Contiguous Stage II B-Cell NHL

Treatment options for indolent stage I and indolent, contiguous stage II B-cell NHL include:

  1. Radiation therapy.
  2. Rituximab with or without chemotherapy.
  3. Watchful waiting.
  4. Other therapies, as designated for patients with advanced-stage disease.

In a prospective randomized trial, 150 patients with stage I or stage II follicular lymphoma were randomly assigned to 30 Gy of involved-field radiation therapy alone or radiation therapy plus six cycles of R-CVP (rituximab, cyclophosphamide, vincristine, prednisolone). With a median follow-up of 9.6 years, the 10-year progression-free survival (PFS) rate favored combined-modality therapy, at 59% (95% confidence interval [CI], 46%–74%) versus 41% for radiation therapy alone (95% CI, 30%–57%) (P = .033). There was no difference in overall survival (OS) (87% and 95%; P = .40).[1][Level of evidence B1]

The National Lymphocare Study identified 471 patients with stage I follicular lymphoma. Of those patients, 206 were rigorously staged with a bone marrow aspirate and biopsy, and computed tomography (CT) scans or positron emission tomography (PET)-CT scans.[2] Nonrandomized treatments included radiation therapy (27%), rituximab-chemotherapy (R-chemotherapy) (28%), watchful waiting (17%), R-chemotherapy plus radiation therapy (13%), and rituximab alone (12%), although more than one-third of the patients started with watchful waiting. With a median follow-up of 57 months, PFS favored R-chemotherapy or R-chemotherapy plus radiation therapy, but OS was nearly identical, all over 90%.[2][Level of evidence C2] Clinical trials are required to answer the following questions:[3]

  • If the PET-CT scan is clear after excisional biopsy, is watchful waiting or radiation therapy preferred?
  • Should rituximab be added to radiation therapy for stage I follicular lymphoma?
  • Is there any role for R-chemotherapy plus radiation therapy?

Radiation therapy

Long-term disease control within radiation fields can be achieved in a significant number of patients with indolent stage I or stage II NHL by using radiation therapy. This requires dosages of radiation that usually range from 25 Gy to 40 Gy to involved sites or to extended fields that cover adjacent nodal sites.[1,4–6] Almost one-half of all patients treated with radiation therapy alone will have out-of-field relapse within 10 years.[1,6,7]

A retrospective review of 512 patients from an international consortium evaluated patients with early-stage follicular lymphoma who received at least 24 Gy of localized radiation therapy at initial presentation. With a median follow-up of 52 months, 29.1% of patients developed recurrent lymphoma at a median of 23 months (range, 1−143 months).[8] With a median follow-up of 33 months after relapse, the 3-year OS rate was 91.4% after patients received subsequent systemic chemotherapy that involved rituximab.[8]

Very low-dose radiation therapy with 4 Gy (2 Gy × 2 fractions) can result in 50% remission rates for patients who cannot tolerate higher doses.[9] In a multicenter, randomized, prospective trial, 548 patients with follicular or marginal zone lymphoma received radiation therapy, either 4 Gy in 2 fractions or 24 Gy in 12 fractions.[10]

  • At a median follow-up of 73.8 months, the 5-year local complete response rate was 89.9% (85.5%–93.1%) after 24 Gy and 70.4% (64.7%–75.4%) after 4 Gy (hazard ratio, 3.46; 95% CI, 2.25–5.33; P < .0001).[10]
  • Although durable local control was superior for patients who received 24 Gy, the 4 Gy regimen was nearly comparable with reductions in radiation exposure, time undergoing therapy, and cost.

Rituximab with or without chemotherapy

When radiation therapy is contraindicated, or when an alternative treatment is preferred, patients with symptomatic disease who require therapy may receive rituximab with or without chemotherapy (as outlined below for more advanced-stage patients).[11] The value of adjuvant treatment with radiation to decrease relapse, plus rituximab (an anti–CD20 monoclonal antibody) either alone or in combination with chemotherapy, has been extrapolated from trials of patients with advanced-stage disease and has not been confirmed.[12,13]

Watchful waiting

Watchful waiting can be considered for asymptomatic patients.[14] Watchful waiting has never been compared with up-front radiation therapy in a prospective randomized trial. A retrospective analysis of the Surveillance, Epidemiology and End Results (SEER) Program database in patients diagnosed over a span of 30 years showed improved outcomes for up-front radiation therapy.[15]

Other therapies as designated for patients with advanced-stage disease

Patients with disease unable to be encompassed by radiation therapy are treated as outlined for patients with stage III or stage IV low-grade lymphoma.

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. MacManus M, Fisher R, Roos D, et al.: Randomized Trial of Systemic Therapy After Involved-Field Radiotherapy in Patients With Early-Stage Follicular Lymphoma: TROG 99.03. J Clin Oncol 36 (29): 2918-2925, 2018. [PUBMED Abstract]
  2. Friedberg JW, Byrtek M, Link BK, et al.: Effectiveness of first-line management strategies for stage I follicular lymphoma: analysis of the National LymphoCare Study. J Clin Oncol 30 (27): 3368-75, 2012. [PUBMED Abstract]
  3. Montoto S: Management of localized-stage follicular lymphoma: changing the paradigm? J Clin Oncol 30 (27): 3328-9, 2012. [PUBMED Abstract]
  4. Haas RL, Poortmans P, de Jong D, et al.: High response rates and lasting remissions after low-dose involved field radiotherapy in indolent lymphomas. J Clin Oncol 21 (13): 2474-80, 2003. [PUBMED Abstract]
  5. Guckenberger M, Alexandrow N, Flentje M: Radiotherapy alone for stage I-III low grade follicular lymphoma: long-term outcome and comparison of extended field and total nodal irradiation. Radiat Oncol 7: 103, 2012. [PUBMED Abstract]
  6. Brady JL, Binkley MS, Hajj C, et al.: Definitive radiotherapy for localized follicular lymphoma staged by 18F-FDG PET-CT: a collaborative study by ILROG. Blood 133 (3): 237-245, 2019. [PUBMED Abstract]
  7. Guadagnolo BA, Li S, Neuberg D, et al.: Long-term outcome and mortality trends in early-stage, Grade 1-2 follicular lymphoma treated with radiation therapy. Int J Radiat Oncol Biol Phys 64 (3): 928-34, 2006. [PUBMED Abstract]
  8. Binkley MS, Brady JL, Hajj C, et al.: Salvage Treatment and Survival for Relapsed Follicular Lymphoma Following Primary Radiation Therapy: A Collaborative Study on Behalf of ILROG. Int J Radiat Oncol Biol Phys 104 (3): 522-529, 2019. [PUBMED Abstract]
  9. Hoskin PJ, Kirkwood AA, Popova B, et al.: 4 Gy versus 24 Gy radiotherapy for patients with indolent lymphoma (FORT): a randomised phase 3 non-inferiority trial. Lancet Oncol 15 (4): 457-63, 2014. [PUBMED Abstract]
  10. Hoskin P, Popova B, Schofield O, et al.: 4 Gy versus 24 Gy radiotherapy for follicular and marginal zone lymphoma (FoRT): long-term follow-up of a multicentre, randomised, phase 3, non-inferiority trial. Lancet Oncol 22 (3): 332-340, 2021. [PUBMED Abstract]
  11. Cartron G, Bachy E, Tilly H, et al.: Randomized Phase III Trial Evaluating Subcutaneous Rituximab for the First-Line Treatment of Low-Tumor Burden Follicular Lymphoma: Results of a LYSA Study. J Clin Oncol 41 (19): 3523-3533, 2023. [PUBMED Abstract]
  12. Kelsey SM, Newland AC, Hudson GV, et al.: A British National Lymphoma Investigation randomised trial of single agent chlorambucil plus radiotherapy versus radiotherapy alone in low grade, localised non-Hodgkins lymphoma. Med Oncol 11 (1): 19-25, 1994. [PUBMED Abstract]
  13. Seymour JF, Pro B, Fuller LM, et al.: Long-term follow-up of a prospective study of combined modality therapy for stage I-II indolent non-Hodgkin’s lymphoma. J Clin Oncol 21 (11): 2115-22, 2003. [PUBMED Abstract]
  14. Advani R, Rosenberg SA, Horning SJ: Stage I and II follicular non-Hodgkin’s lymphoma: long-term follow-up of no initial therapy. J Clin Oncol 22 (8): 1454-9, 2004. [PUBMED Abstract]
  15. Pugh TJ, Ballonoff A, Newman F, et al.: Improved survival in patients with early stage low-grade follicular lymphoma treated with radiation: a Surveillance, Epidemiology, and End Results database analysis. Cancer 116 (16): 3843-51, 2010. [PUBMED Abstract]

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

Optimal treatment of advanced stages of low-grade non-Hodgkin lymphoma (NHL) is controversial because current therapeutic options result in low cure rates. Numerous clinical trials are in progress to evaluate treatment issues, and patients are urged to participate. The rate of relapse is fairly constant over time, even in patients who have achieved complete response to treatment. Relapse may occur many years after treatment. Currently, no randomized trials provide guidance to clinicians about the initial choice of watchful waiting, rituximab, nucleoside analogues, alkylating agents, combination chemotherapy, radiolabeled monoclonal antibodies, or combinations of these options.[1]; [2][Level of evidence B1]

For patients with indolent, noncontiguous stage II and stage III NHL, central lymphatic radiation therapy has been proposed but is not usually recommended as a form of treatment.[3,4]

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%.[5]

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

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

  1. Watchful waiting for asymptomatic patients.
  2. Rituximab alone or in combination with cytotoxic agents used in front-line therapy.
  3. Lenalidomide and rituximab.
  4. Maintenance rituximab.
  5. Obinutuzumab alone or in combination with cytotoxic agents used in front-line therapy.

Because none of the therapies listed above are curative for advanced-stage disease, innovative approaches are under clinical evaluation.

Watchful waiting for asymptomatic patients

Because relapse may occur many years after treatment, even in patients who have achieved complete responses, deferred treatment (i.e., watchful waiting until the patient becomes symptomatic before initiating treatment) can be considered.[2,6–8] The Follicular Lymphoma International Prognostic Index (FLIPI) and the revised FLIPI-2 can predict progression-free survival (PFS) and overall survival (OS), but the scores cannot be used to establish the need for therapy in asymptomatic patients.[9,10]

Evidence (watchful waiting):

  1. Three randomized trials compared watchful waiting with immediate chemotherapy.[7,11]; [12][Level of evidence A1]
    • All three trials showed no difference in cause-specific survival or OS.
    • For patients randomly assigned to watchful waiting, the median time to require therapy was 2 to 3 years. One-third of patients undergoing watchful waiting never required treatment (one-half died of other causes and the other half remained progression free after 10 years).
  2. A selected group of 107 patients with advanced-stage follicular lymphoma were managed with initial watchful waiting; subsequent therapy was delayed for a median of 55 months. These patients achieved equivalent freedom from treatment failure and OS compared with a similar cohort treated immediately with rituximab.[13][Level of evidence C2] This implies that watchful waiting remains a relevant approach even in the rituximab era.

Rituximab alone or in combination with cytotoxic agents used in front-line therapy

Standard therapy includes rituximab, an anti–CD20 monoclonal antibody, either alone, as was shown in the ECOG-E4402 trial (NCT00075946),[14–19] or in combination with purine nucleoside analogues, such as fludarabine or cladribine, alkylating agents (with or without steroids), or combination chemotherapy. Rituximab may be considered as first-line therapy, either alone or in combination with other agents. Rituximab may be given intravenously (IV) or subcutaneously (SQ), and biosimilar versions, such as CT-P10 and GP2013, have shown equivalent efficacy and safety.[20–22] Combinations include the following:

  • R-bendamustine: rituximab + bendamustine.[23–25]
  • R-F: rituximab + fludarabine.[26]
  • R-CVP: rituximab + cyclophosphamide + vincristine + prednisone.[27–30]
  • R-CHOP: rituximab + cyclophosphamide + doxorubicin + vincristine + prednisone.[29–33] A Cochrane meta-analysis could not identify any OS benefit of adding doxorubicin to chemotherapy regimens with rituximab or to chemotherapy regimens without rituximab.[34][Level of evidence A1]
  • R-FM: rituximab + fludarabine + mitoxantrone.[29,30,35]
  • R-FCM: rituximab + fludarabine + cyclophosphamide + mitoxantrone.[36]

Evidence (rituximab with or without chemotherapy):

  1. A prospective randomized trial of 534 patients with previously untreated, advanced-stage, follicular lymphoma compared R-CHOP, R-FM, and R-CVP.[29]
    • With a median follow-up of 84 months, there was no difference in OS (8-year OS rate, 83%; 95% confidence interval [CI], 79%–87%), but the 8-year PFS rates favored R-CHOP (52%) and R-FM (49%) over R-CVP (42%) (P for the three regimens = .037).[29][Level of evidence B1]
  2. Four randomized prospective studies of previously untreated patients (involving more than 1,300 patients) and one Cochrane meta-analysis that included both untreated and previously treated patients (involving almost 1,000 patients) have compared rituximab plus combination chemotherapy with chemotherapy alone.[28,33,37]; [38][Level of evidence A1]
    • Rituximab plus chemotherapy was superior in terms of event-free survival (EFS) or PFS (ranging from 2–3 years) in all of the studies and in terms of OS in all but one study (absolute benefit ranging from 6%–13% at 4 years, P < .04; hazard ratio [HR], 0.63 [0.51–0.79] for the meta-analysis).
    • All of these trials were performed in symptomatic patients who required therapy. These results do not negate watchful waiting when appropriate.
    • Fluorine F 18-fludeoxyglucose positron emission tomography–computed tomography (18F-FDG PET-CT) scan status at the completion of rituximab plus chemotherapy induction therapy is strongly predictive of outcome. It is not yet known whether acting on the results of the scans translates into better outcomes.[39,40]
  3. In a prospective randomized trial (NCT00991211), 527 patients with indolent and mantle cell lymphoma were randomly assigned to receive either bendamustine and rituximab or R-CHOP.[24][Level of evidence B1]
    • With a median follow-up of 45 months, the median PFS favored the bendamustine arm (69 months vs. 31 months [HR, 0.58; 95% CI, 0.44–0.74; P < .0001]) but with no difference in OS.
    • Compared with the R-CHOP arm, the bendamustine arm was associated with significantly lower rates of alopecia, hematologic toxicity, stomatitis, peripheral neuropathy, and infections.
  4. In a similar prospective randomized trial, 447 patients with indolent and mantle cell lymphoma were assigned to bendamustine and rituximab versus R-CHOP or R-CVP.[25][Level of evidence B1]
    • With a median follow-up of 65 months, the 5-year PFS rate favored bendamustine and rituximab, 65.5% versus 55.8% (HR, 0.61; 95% CI, 0.45–0.85; P = .0025), but with no difference in OS.
    • Increased deaths in the bendamustine-and-rituximab arm from cardiovascular causes (seven vs. one) and from secondary malignancies other than lymphoma (five vs. three) may have contributed to the lack of OS advantage.

Lenalidomide and rituximab

The combination of the immunomodulating agent lenalidomide with rituximab (the so-called R2 regimen) has been proposed as an alternative regimen to combinations involving cytotoxic agents and their subsequent short- and long-term toxicities.

Evidence (lenalidomide and rituximab):

  1. In a randomized prospective trial (RELEVANCE [NCT01650701]) of 1,030 patients with previously untreated follicular lymphoma, rituximab plus lenalidomide for 18 months was compared with rituximab plus chemotherapy (usually R-CHOP).[41,42] All patients received rituximab maintenance for up to 2 years.
    • With a median follow-up of 72 months, the 6-year PFS rates (60% and 59%) and 3-year OS rates (89%) were identical (HR for PFS, 1.03; 95% CI, 0.84–1.27; P = .78) (HR for OS was not reported).[41,42][Level of evidence A1]
    • This trial established that the R2 regimen is as effective as rituximab plus cytotoxic chemotherapy options. The transformation rate to aggressive lymphoma per year was 0.68% in the R2 group and 0.45% in the R-chemotherapy group. With a median follow-up of 72 months, there were no new safety signals.[42]
  2. In a randomized prospective trial of 358 patients with resistant/refractory indolent lymphoma (usually follicular lymphoma), the R2 regimen was compared with rituximab alone.[43]
    • With a median follow-up of 28 months, the median PFS was 39.4 months for R2 and 14.1 months for rituximab alone (P < .0001), with no difference in OS.[43][Level of evidence B1]

Maintenance rituximab

After induction therapy with rituximab only or with rituximab plus chemotherapy, rituximab can be used once every 2 to 3 months as maintenance therapy. Several studies have evaluated this approach.

Evidence (maintenance rituximab for previously untreated patients):

  1. In the PRIMA study (NCT00140582), 1,018 patients with high-risk, previously untreated, symptomatic disease achieved complete response or partial response after induction therapy with immunochemotherapy (usually R-CHOP). Patients were then randomly assigned to 2 years of maintenance rituximab versus no maintenance.[44][Level of evidence B1]
    • With a median follow-up of 9.0 years, median PFS favored rituximab maintenance (10.5 years) compared with observation (4.1 years) (HR, 0.61; 95% CI, 0.52−0.73; P < .001), but with no difference in OS.
  2. In the United Kingdom/International Study (NCT00112931), 379 previously untreated patients with asymptomatic, low-burden disease were randomly assigned to watchful waiting versus rituximab induction only versus rituximab induction followed by 2 years of rituximab maintenance.[45][Level of evidence A3]
    • Although OS and histological transformation rates were not different at 3 years, maintenance rituximab was favored based on quality-of-life studies (Mental Adjustment to Cancer Scale P = .0004 at 7 months; Illness Coping Score P = .0012 at 7 months) and time-to-initiation of new treatment by 3 years (54% for watchful waiting vs. 12% for rituximab maintenance [HR, 0.21; 95% CI, 0.14–0.31; P < .0001]).[45][Level of evidence A3]
    • This study suggested that for some patients, watch and wait resulted in watch and worry.[46] However, from the perspective of OS and histological transformation rates, no benefit could be seen with rituximab maintenance.
  3. In the RESORT study (NCT00075946), 289 previously untreated patients with asymptomatic, low-burden disease were randomly assigned to receive rituximab induction alone, with a re-treatment strategy that used rituximab at relapse versus rituximab induction plus maintenance rituximab every 13 weeks until treatment failure.[47][Level of evidence B3]
    • With a median follow-up of 8.7 years, the 7-year rate for freedom from cytotoxic chemotherapy or radiation therapy was 83% for patients who received maintenance rituximab and 63% for patients who received induction alone (HR, 2.37; 95% CI, 1.5–3.8; P = .0001). There was no difference in the 10-year OS rate (83% vs. 84%; nonsignificant P = .5972). A re-treatment strategy achieved comparable disease control using significantly fewer doses of rituximab.
    • Maintenance rituximab induces prolonged B-cell depletion, but morbidity from infections was not evaluated after 2015, when the full protocol data stopped (12 years after the study began).

    These three randomized trials in previously untreated patients showed no advantage for the use of rituximab maintenance versus observation and reinduction of therapy at the time of relapse. The trials suggest a benefit for maintenance rituximab after reinduction for relapsed disease. Many questions remain about rituximab maintenance, particularly about truncating therapy at 2 years and long-term safety and efficacy. A trial extending rituximab maintenance to 5 years showed similar EFS or OS versus 1 year of maintenance after induction therapy with rituximab in previously untreated patients.[48][Level of evidence A1]

  4. The FOLL12 study (NCT02063685) included 807 patients with previously untreated high-tumor burden follicular lymphoma. Patients received rituximab plus chemotherapy induction and were randomly assigned to either standard rituximab maintenance (every 8 weeks for 2 years) or to postinduction treatment (monitoring, rituximab maintenance, or radioimmunotherapy) based on their complete metabolic response and measurable residual disease (MRD)–negative status.[49]
    • With a median follow-up of 53 months, the 3-year PFS rate was 86% for patients who received standard maintenance and 72% for patients who received response-based treatment (P < .001). The 3-year OS rate was the same in both groups (98% vs. 97%; P = .238).[49][Level of evidence B1]
    • This trial does not support the use of an end-of-treatment PET-CT scan to guide the use of maintenance rituximab.
  5. A prospective trial included 202 patients with previously untreated low-tumor burden follicular lymphoma. Patients were randomly assigned to receive either four weekly doses of IV rituximab (standard dose, 375 mg/m2) or one dose of IV rituximab followed by three weekly doses of SQ rituximab (1,400 mg) and maintenance doses in months 3, 5, 7, and 9.[19]
    • With a median follow-up of 50.2 months, the 4-year PFS rate was 58.1% (95% CI, 47.5%–67.4%) for patients in the SQ arm who received maintenance therapy, and 41.2% (95% CI, 30.6%–51.6%) (HR, 0.585; 0.939–0.871; P = .0076) for the patients in the IV arm who did not receive maintenance therapy.[19][Level of evidence B1]
    • There was no difference in OS or time-to-next treatment.
  6. Outside the context of clinical trials, the use of MRD testing has not been shown to be predictive in directing therapy for patients with follicular lymphoma. In retrospective analyses of two randomized prospective trials, while MRD negativity was prognostic of outcome, maintenance rituximab or obinutuzumab prolonged PFS the most among patients with MRD-negative disease.[49,50][Level of evidence C2] Stopping maintenance rituximab or obinutuzumab was not indicated in patients with MRD-negative disease, negating any possible change in therapy based on that status.

In summary, for previously untreated patients, all of the studies showed improved PFS, with no change in OS.

Evidence (maintenance rituximab for previously treated patients):

  1. In a prospective randomized trial of 465 patients with relapsed follicular lymphoma, responders to R-CHOP or CHOP were further randomly assigned to receive rituximab maintenance (1 dose every 3 months for 2 years) or no maintenance.[51][Level of evidence B1]
    • At a median follow-up of 6 years, rituximab maintenance was better for median PFS (44 months vs. 16 months, P < .001) and borderline for 5-year OS (74% vs. 64%, P = .07).
    • This benefit for maintenance was evident even for patients who received rituximab during induction therapy. Most patients in both arms received extensive rituximab during postprotocol salvage treatment.
  2. In a prospective randomized trial of 280 patients with relapsed follicular lymphoma, responders to chemotherapy and autologous stem cell transplant consolidation were randomly assigned to receive four doses of rituximab maintenance or no maintenance.[52][Level of evidence B1]
    • With an 8.3-year median follow-up, the 10-year PFS rates favored maintenance (54% vs. 37% [HR, 0.66; 95% CI, 0.47–0.91; P = .012]), but there was no difference in OS.
  3. A meta-analysis of nine randomized clinical trials with a total of 2,586 patients with follicular lymphoma, most of whom had relapsed disease, compared rituximab maintenance with no maintenance and showed improved OS for rituximab maintenance in previously treated patients (HRdeath, 0.72; 95% CI, 0.57–0.91).[53][Level of evidence A1]

For previously treated patients, there is more evidence to suggest an OS advantage with the use of rituximab maintenance.

Obinutuzumab alone or in combination with cytotoxic agents used in front-line therapy

Obinutuzumab is a glycoengineered type II anti–CD20 monoclonal antibody with greater antibody-dependent cellular cytotoxicity than rituximab.

Evidence (obinutuzumab):

  1. A prospective randomized trial (NCT01332968) of 1,202 patients with previously untreated follicular lymphoma compared obinutuzumab combined with bendamustine (50%), CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) (33%), or CVP (cyclophosphamide, vincristine, and prednisone) (10%) with rituximab combined with the same chemotherapy regimens (based on investigator choice).[54] After six cycles of combination therapy, patients had 2 years of maintenance therapy, receiving the same antibody every 2 months.
    • With a median follow-up of 34.5 months, the 3-year PFS rate was 80% in the obinutuzumab group and 73.3% in the rituximab group (HR, 0.66; 95% CI, 0.51–0.85; P = .001).[54][Level of evidence B1]
    • There was no difference in OS.
    • Compared with what has been seen historically, there was a high rate of toxic deaths among patients using bendamustine in the obinutuzumab arm (5.6%) and in the rituximab arm (4.4%). For patients with indolent low-grade lymphoma, with median survivals exceeding 15 years, the number of toxic deaths during first-line therapy seems excessive. By comparison, the toxic death rate was 1% to 2% when either antibody was combined with CHOP or CVP.

    Several issues have been raised about this study:

    • The side effects were significantly higher with obinutuzumab in terms of infusion reactions and subsequent adverse events.
    • Obinutuzumab costs significantly more than rituximab.

    In summary, in the absence of any change in OS, switching from rituximab to obinutuzumab in combination with chemotherapy for previously untreated follicular lymphoma is a difficult choice. The PFS differences may be attributable to the imbalance in monoclonal antibody dosing, and the increased side effects and costs are mitigating factors. In this trial, bendamustine combined with either antibody led to unacceptable rates of toxic death.

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. Hagenbeek A, Eghbali H, Monfardini S, et al.: Phase III intergroup study of fludarabine phosphate compared with cyclophosphamide, vincristine, and prednisone chemotherapy in newly diagnosed patients with stage III and IV low-grade malignant Non-Hodgkin’s lymphoma. J Clin Oncol 24 (10): 1590-6, 2006. [PUBMED Abstract]
  2. Gribben JG: How I treat indolent lymphoma. Blood 109 (11): 4617-26, 2007. [PUBMED Abstract]
  3. Jacobs JP, Murray KJ, Schultz CJ, et al.: Central lymphatic irradiation for stage III nodular malignant lymphoma: long-term results. J Clin Oncol 11 (2): 233-8, 1993. [PUBMED Abstract]
  4. Mendenhall NP, Million RR: Comprehensive lymphatic irradiation for stage II-III non-Hodgkin’s lymphoma. Am J Clin Oncol 12 (3): 190-4, 1989. [PUBMED Abstract]
  5. 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]
  6. Eek R, Falkson G: The low-grade lymphoproliferative disorders. Oncology 54 (6): 441-58, 1997 Nov-Dec. [PUBMED Abstract]
  7. Ardeshna KM, Smith P, Norton A, et al.: Long-term effect of a watch and wait policy versus immediate systemic treatment for asymptomatic advanced-stage non-Hodgkin lymphoma: a randomised controlled trial. Lancet 362 (9383): 516-22, 2003. [PUBMED Abstract]
  8. Portlock CS, Rosenberg SA: No initial therapy for stage III and IV non-Hodgkin’s lymphomas of favorable histologic types. Ann Intern Med 90 (1): 10-13, 1979.
  9. Solal-Céligny P, Roy P, Colombat P, et al.: Follicular lymphoma international prognostic index. Blood 104 (5): 1258-65, 2004. [PUBMED Abstract]
  10. Federico M, Bellei M, Marcheselli L, et al.: Follicular lymphoma international prognostic index 2: a new prognostic index for follicular lymphoma developed by the international follicular lymphoma prognostic factor project. J Clin Oncol 27 (27): 4555-62, 2009. [PUBMED Abstract]
  11. Brice P, Bastion Y, Lepage E, et al.: Comparison in low-tumor-burden follicular lymphomas between an initial no-treatment policy, prednimustine, or interferon alfa: a randomized study from the Groupe d’Etude des Lymphomes Folliculaires. Groupe d’Etude des Lymphomes de l’Adulte. J Clin Oncol 15 (3): 1110-7, 1997. [PUBMED Abstract]
  12. Young RC, Longo DL, Glatstein E, et al.: The treatment of indolent lymphomas: watchful waiting v aggressive combined modality treatment. Semin Hematol 25 (2 Suppl 2): 11-6, 1988. [PUBMED Abstract]
  13. Solal-Céligny P, Bellei M, Marcheselli L, et al.: Watchful waiting in low-tumor burden follicular lymphoma in the rituximab era: results of an F2-study database. J Clin Oncol 30 (31): 3848-53, 2012. [PUBMED Abstract]
  14. Ghielmini M, Schmitz SF, Cogliatti SB, et al.: Prolonged treatment with rituximab in patients with follicular lymphoma significantly increases event-free survival and response duration compared with the standard weekly x 4 schedule. Blood 103 (12): 4416-23, 2004. [PUBMED Abstract]
  15. Witzig TE, Vukov AM, Habermann TM, et al.: Rituximab therapy for patients with newly diagnosed, advanced-stage, follicular grade I non-Hodgkin’s lymphoma: a phase II trial in the North Central Cancer Treatment Group. J Clin Oncol 23 (6): 1103-8, 2005. [PUBMED Abstract]
  16. Hainsworth JD, Litchy S, Shaffer DW, et al.: Maximizing therapeutic benefit of rituximab: maintenance therapy versus re-treatment at progression in patients with indolent non-Hodgkin’s lymphoma–a randomized phase II trial of the Minnie Pearl Cancer Research Network. J Clin Oncol 23 (6): 1088-95, 2005. [PUBMED Abstract]
  17. Kahl BS, Hong F, Williams ME, et al.: Rituximab extended schedule or re-treatment trial for low-tumor burden follicular lymphoma: eastern cooperative oncology group protocol e4402. J Clin Oncol 32 (28): 3096-102, 2014. [PUBMED Abstract]
  18. Buske C, Hiddemann W: Rituximab maintenance therapy in indolent NHL: a clinical review. Leuk Res 30 (Suppl 1): S11-5, 2006. [PUBMED Abstract]
  19. Cartron G, Bachy E, Tilly H, et al.: Randomized Phase III Trial Evaluating Subcutaneous Rituximab for the First-Line Treatment of Low-Tumor Burden Follicular Lymphoma: Results of a LYSA Study. J Clin Oncol 41 (19): 3523-3533, 2023. [PUBMED Abstract]
  20. Kim WS, Buske C, Ogura M, et al.: Efficacy, pharmacokinetics, and safety of the biosimilar CT-P10 compared with rituximab in patients with previously untreated advanced-stage follicular lymphoma: a randomised, double-blind, parallel-group, non-inferiority phase 3 trial. Lancet Haematol 4 (8): e362-e373, 2017. [PUBMED Abstract]
  21. Davies A, Merli F, Mihaljević B, et al.: Efficacy and safety of subcutaneous rituximab versus intravenous rituximab for first-line treatment of follicular lymphoma (SABRINA): a randomised, open-label, phase 3 trial. Lancet Haematol 4 (6): e272-e282, 2017. [PUBMED Abstract]
  22. Jurczak W, Moreira I, Kanakasetty GB, et al.: Rituximab biosimilar and reference rituximab in patients with previously untreated advanced follicular lymphoma (ASSIST-FL): primary results from a confirmatory phase 3, double-blind, randomised, controlled study. Lancet Haematol 4 (8): e350-e361, 2017. [PUBMED Abstract]
  23. Robinson KS, Williams ME, van der Jagt RH, et al.: Phase II multicenter study of bendamustine plus rituximab in patients with relapsed indolent B-cell and mantle cell non-Hodgkin’s lymphoma. J Clin Oncol 26 (27): 4473-9, 2008. [PUBMED Abstract]
  24. Rummel MJ, Niederle N, Maschmeyer G, et al.: Bendamustine plus rituximab versus CHOP plus rituximab as first-line treatment for patients with indolent and mantle-cell lymphomas: an open-label, multicentre, randomised, phase 3 non-inferiority trial. Lancet 381 (9873): 1203-10, 2013. [PUBMED Abstract]
  25. Flinn IW, van der Jagt R, Kahl B, et al.: First-Line Treatment of Patients With Indolent Non-Hodgkin Lymphoma or Mantle-Cell Lymphoma With Bendamustine Plus Rituximab Versus R-CHOP or R-CVP: Results of the BRIGHT 5-Year Follow-Up Study. J Clin Oncol 37 (12): 984-991, 2019. [PUBMED Abstract]
  26. Czuczman MS, Koryzna A, Mohr A, et al.: Rituximab in combination with fludarabine chemotherapy in low-grade or follicular lymphoma. J Clin Oncol 23 (4): 694-704, 2005. [PUBMED Abstract]
  27. Marcus R, Imrie K, Belch A, et al.: CVP chemotherapy plus rituximab compared with CVP as first-line treatment for advanced follicular lymphoma. Blood 105 (4): 1417-23, 2005. [PUBMED Abstract]
  28. Marcus R, Imrie K, Solal-Celigny P, et al.: Phase III study of R-CVP compared with cyclophosphamide, vincristine, and prednisone alone in patients with previously untreated advanced follicular lymphoma. J Clin Oncol 26 (28): 4579-86, 2008. [PUBMED Abstract]
  29. Federico M, Luminari S, Dondi A, et al.: R-CVP versus R-CHOP versus R-FM for the initial treatment of patients with advanced-stage follicular lymphoma: results of the FOLL05 trial conducted by the Fondazione Italiana Linfomi. J Clin Oncol 31 (12): 1506-13, 2013. [PUBMED Abstract]
  30. Luminari S, Ferrari A, Manni M, et al.: Long-Term Results of the FOLL05 Trial Comparing R-CVP Versus R-CHOP Versus R-FM for the Initial Treatment of Patients With Advanced-Stage Symptomatic Follicular Lymphoma. J Clin Oncol 36 (7): 689-696, 2018. [PUBMED Abstract]
  31. Czuczman MS, Weaver R, Alkuzweny B, et al.: Prolonged clinical and molecular remission in patients with low-grade or follicular non-Hodgkin’s lymphoma treated with rituximab plus CHOP chemotherapy: 9-year follow-up. J Clin Oncol 22 (23): 4711-6, 2004. [PUBMED Abstract]
  32. Hainsworth JD, Litchy S, Morrissey LH, et al.: Rituximab plus short-duration chemotherapy as first-line treatment for follicular non-Hodgkin’s lymphoma: a phase II trial of the Minnie Pearl Cancer Research Network. J Clin Oncol 23 (7): 1500-6, 2005. [PUBMED Abstract]
  33. Hiddemann W, Kneba M, Dreyling M, et al.: Frontline therapy with rituximab added to the combination of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) significantly improves the outcome for patients with advanced-stage follicular lymphoma compared with therapy with CHOP alone: results of a prospective randomized study of the German Low-Grade Lymphoma Study Group. Blood 106 (12): 3725-32, 2005. [PUBMED Abstract]
  34. Itchaki G, Gafter-Gvili A, Lahav M, et al.: Anthracycline-containing regimens for treatment of follicular lymphoma in adults. Cochrane Database Syst Rev 7: CD008909, 2013. [PUBMED Abstract]
  35. Zinzani PL, Pulsoni A, Perrotti A, et al.: Fludarabine plus mitoxantrone with and without rituximab versus CHOP with and without rituximab as front-line treatment for patients with follicular lymphoma. J Clin Oncol 22 (13): 2654-61, 2004. [PUBMED Abstract]
  36. Forstpointner R, Dreyling M, Repp R, et al.: The addition of rituximab to a combination of fludarabine, cyclophosphamide, mitoxantrone (FCM) significantly increases the response rate and prolongs survival as compared with FCM alone in patients with relapsed and refractory follicular and mantle cell lymphomas: results of a prospective randomized study of the German Low-Grade Lymphoma Study Group. Blood 104 (10): 3064-71, 2004. [PUBMED Abstract]
  37. Herold M, Haas A, Srock S, et al.: Rituximab added to first-line mitoxantrone, chlorambucil, and prednisolone chemotherapy followed by interferon maintenance prolongs survival in patients with advanced follicular lymphoma: an East German Study Group Hematology and Oncology Study. J Clin Oncol 25 (15): 1986-92, 2007. [PUBMED Abstract]
  38. Salles GA, Mounier N, de Guibert S, et al.: Rituximab combined with chemotherapy and interferon in follicular lymphoma patients: final analysis of the GELA-GOELAMS FL2000 study with a 5-year follow-up. [Abstract] Blood 110 (11): A-792, 2007.
  39. Dupuis J, Berriolo-Riedinger A, Julian A, et al.: Impact of [(18)F]fluorodeoxyglucose positron emission tomography response evaluation in patients with high-tumor burden follicular lymphoma treated with immunochemotherapy: a prospective study from the Groupe d’Etudes des Lymphomes de l’Adulte and GOELAMS. J Clin Oncol 30 (35): 4317-22, 2012. [PUBMED Abstract]
  40. Trotman J, Fournier M, Lamy T, et al.: Positron emission tomography-computed tomography (PET-CT) after induction therapy is highly predictive of patient outcome in follicular lymphoma: analysis of PET-CT in a subset of PRIMA trial participants. J Clin Oncol 29 (23): 3194-200, 2011. [PUBMED Abstract]
  41. Morschhauser F, Fowler NH, Feugier P, et al.: Rituximab plus Lenalidomide in Advanced Untreated Follicular Lymphoma. N Engl J Med 379 (10): 934-947, 2018. [PUBMED Abstract]
  42. Morschhauser F, Nastoupil L, Feugier P, et al.: Six-Year Results From RELEVANCE: Lenalidomide Plus Rituximab (R2) Versus Rituximab-Chemotherapy Followed by Rituximab Maintenance in Untreated Advanced Follicular Lymphoma. J Clin Oncol 40 (28): 3239-3245, 2022. [PUBMED Abstract]
  43. Leonard JP, Trneny M, Izutsu K, et al.: AUGMENT: A Phase III Study of Lenalidomide Plus Rituximab Versus Placebo Plus Rituximab in Relapsed or Refractory Indolent Lymphoma. J Clin Oncol 37 (14): 1188-1199, 2019. [PUBMED Abstract]
  44. Bachy E, Seymour JF, Feugier P, et al.: Sustained Progression-Free Survival Benefit of Rituximab Maintenance in Patients With Follicular Lymphoma: Long-Term Results of the PRIMA Study. J Clin Oncol 37 (31): 2815-2824, 2019. [PUBMED Abstract]
  45. Ardeshna KM, Qian W, Smith P, et al.: Rituximab versus a watch-and-wait approach in patients with advanced-stage, asymptomatic, non-bulky follicular lymphoma: an open-label randomised phase 3 trial. Lancet Oncol 15 (4): 424-35, 2014. [PUBMED Abstract]
  46. Ansell SM: Follicular lymphoma: watch and wait is watch and worry. Lancet Oncol 15 (4): 368-9, 2014. [PUBMED Abstract]
  47. Kahl BS, Jegede OA, Peterson C, et al.: Long-Term Follow-Up of the RESORT Study (E4402): A Randomized Phase III Comparison of Two Different Rituximab Dosing Strategies for Low-Tumor Burden Follicular Lymphoma. J Clin Oncol 42 (7): 774-778, 2024. [PUBMED Abstract]
  48. Taverna C, Martinelli G, Hitz F, et al.: Rituximab Maintenance for a Maximum of 5 Years After Single-Agent Rituximab Induction in Follicular Lymphoma: Results of the Randomized Controlled Phase III Trial SAKK 35/03. J Clin Oncol 34 (5): 495-500, 2016. [PUBMED Abstract]
  49. Luminari S, Manni M, Galimberti S, et al.: Response-Adapted Postinduction Strategy in Patients With Advanced-Stage Follicular Lymphoma: The FOLL12 Study. J Clin Oncol 40 (7): 729-739, 2022. [PUBMED Abstract]
  50. Pott C, Jurinovic V, Trotman J, et al.: Minimal Residual Disease Status Predicts Outcome in Patients With Previously Untreated Follicular Lymphoma: A Prospective Analysis of the Phase III GALLIUM Study. J Clin Oncol 42 (5): 550-561, 2024. [PUBMED Abstract]
  51. van Oers MH, Tönnissen E, Van Glabbeke M, et al.: BCL-2/IgH polymerase chain reaction status at the end of induction treatment is not predictive for progression-free survival in relapsed/resistant follicular lymphoma: results of a prospective randomized EORTC 20981 phase III intergroup study. J Clin Oncol 28 (13): 2246-52, 2010. [PUBMED Abstract]
  52. Pettengell R, Schmitz N, Gisselbrecht C, et al.: Rituximab purging and/or maintenance in patients undergoing autologous transplantation for relapsed follicular lymphoma: a prospective randomized trial from the lymphoma working party of the European group for blood and marrow transplantation. J Clin Oncol 31 (13): 1624-30, 2013. [PUBMED Abstract]
  53. Vidal L, Gafter-Gvili A, Salles G, et al.: Rituximab maintenance for the treatment of patients with follicular lymphoma: an updated systematic review and meta-analysis of randomized trials. J Natl Cancer Inst 103 (23): 1799-806, 2011. [PUBMED Abstract]
  54. Marcus R, Davies A, Ando K, et al.: Obinutuzumab for the First-Line Treatment of Follicular Lymphoma. N Engl J Med 377 (14): 1331-1344, 2017. [PUBMED Abstract]

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

In general, treatment with standard agents rarely produces a cure in patients with relapsed B-cell non-Hodgkin Lymphoma (NHL). Sustained remissions after relapse can often be obtained in patients with indolent lymphomas, but relapse will usually ensue. Favorable survival after relapse has been associated with an age younger than 60 years, complete remission rather than partial remission, and duration of response longer than 2 years.[1] Even patients in the most favorable subset, however, have a tenfold greater mortality compared with age-adjusted U.S. population rates.[2]

Patients who experience a relapse of indolent lymphoma can often achieve disease control with single-agent or combination chemotherapy, rituximab (an anti–CD20 monoclonal antibody), lenalidomide, radiolabeled anti–CD20 monoclonal antibodies, or palliative radiation therapy.[3,4] However, long-term freedom from second relapse is uncommon and multiple relapses usually occur. Patients with indolent lymphoma may experience a relapse with a more aggressive histology. If the clinical pattern of relapse suggests that the disease is behaving in a more aggressive manner, a biopsy can be performed. If a more aggressive histology is confirmed, therapy must change to a regimen applicable to that histological type.[5] Rapid growth or discordant growth between various disease sites may indicate a histological conversion.

In a retrospective review of 325 patients diagnosed between 1972 and 1999, the 10-year risk of histological transformation was 30%.[6] In this series, high-risk factors for subsequent histological transformation were advanced stage, high-risk Follicular Lymphoma International Prognostic Index, and watchful waiting (as opposed to treatment being initiated at diagnosis). The median survival after transformation was 1 to 2 years, with 25% of patients alive at 5 years and with approximately 10% to 20% of patients alive 10 years after re-treatment.[7]

A prospective trial of 631 patients with follicular lymphoma and with a median follow-up of 60 months in the rituximab era (2002–2009) found a 5-year transformation rate to a higher-grade histology of 11%.[8] The median overall survival (OS) after transformation was 50 months, and the 5-year OS rate was 66%, if the transformation occurred more than 18 months after a diagnosis of follicular lymphoma. This series described a better prognosis for patients with transformation than in the era before rituximab.

For descriptions of the regimens used to treat histological conversions, see the Treatment of Aggressive, Recurrent B-Cell Non-Hodgkin Lymphoma section in Aggressive B-Cell Non-Hodgkin Lymphoma Treatment. The durability of the second remission may be short, and clinical trials can be considered.

Treatment Options for Indolent, Recurrent B-Cell NHL

Treatment options for indolent, recurrent B-cell NHL include:

  1. Rituximab alone or in combination with cytotoxic agents used in front-line therapy.
  2. Obinutuzumab alone or in combination with cytotoxic agents used in front-line therapy.
  3. Lenalidomide and rituximab.
  4. Zanubrutinib and obinutuzumab.
  5. EZH2 inhibitor.
  6. Bispecific T-cell engagers.
  7. Chimeric antigen receptor (CAR) T-cell therapy.
  8. Stem cell transplant (SCT).
  9. Palliative radiation therapy.

Rituximab alone or in combination with cytotoxic agents used in front-line therapy

Rituximab results in a 40% to 50% response rate in patients with relapsed indolent B-cell lymphomas.[9–13] Rituximab can also be combined with combination chemotherapy.[14,15]

Evidence (rituximab):

  1. In three randomized, prospective studies involving previously treated patients with relapsed indolent lymphoma, patients were randomly assigned to rituximab maintenance after re-treatment with combination chemotherapy (with or without rituximab during induction) or rituximab alone.[16–18]
    • All trials showed prolongation of response duration.[16–18] One trial with a median follow-up of 39 months demonstrated improvement in median progression-free survival (PFS) (3.7 years vs. 1.3 years, P < .001) and 5-year OS rate (74% vs. 64%, P = .07), favoring maintenance rituximab.[17]

Obinutuzumab alone or in combination with cytotoxic agents used in front-line therapy

Obinutuzumab is a CD20-binding monoclonal antibody with alternative epitope binding.

Evidence (obinutuzumab):

  1. A randomized prospective trial (NCT01059630) included 396 patients with rituximab-refractory indolent lymphoma (mostly follicular lymphoma). Patients received obinutuzumab plus bendamustine, followed by obinutuzumab maintenance therapy, for 2 years versus bendamustine alone with no maintenance therapy.[19,20][Level of evidence A1]
    • With a median follow-up of 31.8 months, the 2-year OS rate favored the obinutuzumab combination (74.5% vs. 65.1%) (hazard ratio [HR], 0.67; 95% confidence interval [CI], 0.47–0.96; P = .027). The median PFS also favored the obinutuzumab combination (25.8 months [95% CI, 19.5–41.1] vs. 14.1 months [95% CI, 12.6–16.0]) (HR, 0.57; 95% CI, 0.44–0.73; P < .001).[20][Level of evidence A1]
    • The contribution of maintenance therapy to the outcome could not be assessed in this design.

Lenalidomide and rituximab

Responses of 20% to 56% have been reported for lenalidomide, especially in patients with follicular lymphoma and small lymphocytic lymphoma, with even higher responses noted for the combination of lenalidomide and rituximab.[21,22][Level of evidence C3]

Zanubrutinib and obinutuzumab

Evidence (zanubrutinib and obinutuzumab):

  1. A randomized, multicenter, phase II study (ROSEWOOD [NCT03332017]) included 217 patients with relapsed or refractory follicular lymphoma after receiving two or more prior lines of therapy. Patients received either the oral Bruton tyrosine kinase inhibitor zanubrutinib plus obinutuzumab or obinutuzumab alone until disease progression.[23][Level of evidence B1]
    • With a median follow-up of 19.0 months, the median PFS was 28.0 months for patients who received zanubrutinib plus obinutuzumab and 10.4 months for patients who received obinutuzumab alone (HR, 0.50; 95% CI, 0.33–0.75; P < .001).
    • The overall response rate was 69% (95% CI, 61%–76%) in the zanubrutinib-plus-obinutuzumab arm and 46% (95% CI, 34%–58%) in the obinutuzumab-alone arm (P = .0012).

The U.S. Food and Drug Administration approved zanubrutinib and obinutuzumab for patients with relapsed or refractory follicular lymphoma after two or more prior lines of therapy.

EZH2 inhibitor

Tazemetostat

Tazemetostat is an inhibitor of EZH2, a histone methyltransferase essential to the formation of lymph node germinal centers, especially with activating variants of EZH2.

Evidence (tazemetostat):

  1. A phase II study included 99 patients with relapsed or refractory follicular lymphoma, 45 of whom had activating EZH2 variants, and 54 of whom had wild-type EZH2.[24]
    • Treatment with tazemetostat resulted in an objective response rate of 69% (95% CI, 53%–82%) for patients with activating EZH2 variants versus 35% (95% CI, 23%–49%) for patients with wild-type EZH2.[24]
    • With a median follow-up of 22 months, the median PFS was 13.8 months (95% CI, 10.7–22.0) for patients with activating EZH2 variants and 11.1 months (95% CI, 3.7–14.6) for patients with wild-type EZH2.[24][Level of evidence C3]
    • Grade 3 or 4 treatment-related adverse events occurred in 4% of patients.

Bispecific T-cell engagers

Bispecific T-cell engagers bind to CD20 (or CD19) and to CD3 to direct T cells to eliminate malignant B cells.[25,26] Similar to CAR T-cell therapy, almost one-half of patients who receive this therapy experience cytokine release syndrome.

Mosunetuzumab

Mosunetuzumab is a bispecific T-cell engager that binds to CD20 and CD3.[25]

Evidence (mosunetuzumab):

  1. A single-arm, multicenter, phase II study included 90 patients with relapsed or refractory follicular lymphoma who had received two or more prior lines of therapy (including an anti-CD20 therapy and an alkylating agent). Patients received mosunetuzumab.[27]
    • With a median follow-up of 37.4 months, the objective response rate was 77.8% (95% CI, 67.8%–85.9%), and the complete response rate was 60.0% (95% CI, 49.1%–70.2%), per investigator assessment. The median PFS (per investigator assessment) was 24.0 months. The 3-year OS rate was 82.4% (95% CI, 73.8%–91.0%).[27][Level of evidence C1]
    • Cytokine release syndrome occurred in 44.4% of patients; 97.2% of cases were grade 1 or 2 in severity.
Epcoritamab

Epcoritamab is a bispecific T-cell engager that binds to CD20 and CD3.

Evidence (epcoritamab):

  1. A single-arm multicenter study (NCT03625037), included 128 patients with relapsed or refractory follicular lymphoma who had received two or more lines of therapy. Patients received epcoritamab.[28]
    • With a median follow-up of 17.4 months, the overall response rate was 82.0 % (95% CI, 74.3%–88.3%) and the complete response rate was 62.5% (95% CI, 53.5%–70.9%).[28][Level of evidence C3]
    • Only 2% of patients had grade 3 or higher cytokine release syndrome events.

Chimeric antigen receptor (CAR) T-cell therapy

CAR T-cell therapy, with the autologous anti-CD19 therapeutics axicabtagene ciloleucel (axi-cel), lisocabtagene maraleucel (liso-cel), or tisagenlecleucel (tisa-cel), has been approved for patients with relapsed follicular lymphoma after two or more lines of prior therapy.

Evidence (CAR T-cell therapy):

  1. In a phase II trial, 159 patients with relapsed or refractory follicular lymphoma (n = 127), marginal zone lymphoma (n = 31), or diffuse large B-cell lymphoma (n = 1) received axi-cel.[29,30]
    • With a median follow-up of 41.7 months, the overall response rate was 92% (95% CI, 85%–97%), and the complete response rate was 74%.
    • The 18-month PFS rate was 64.8% (95% CI, 54.2%–73.5%).[29][Level of evidence C2]
    • The median PFS was 40.2 months for patients with follicular lymphoma and was not reached for patients with marginal zone lymphoma.[30][Level of evidence C2]
    • Cytokine release syndrome occurred in 78% of patients and was grade 3 or 4 in 6% of patients.
    • Tocilizumab was required in 50% of all patients, and 5% required vasopressors. Grade 3 or 4 neurological events occurred in 15% of patients.
  2. In a phase II trial, 98 patients with relapsed or refractory follicular lymphoma after two or more lines of prior therapy received anti-CD19 CAR T-cell therapy with tisa-cel.[31]
    • With a median follow-up of 16.6 months, the complete response rate was 69.1% (95% CI, 58.8%–78.3%), and the overall response rate was 86.2% (95% CI, 77.5%–92.4%).[31][Level of evidence C3]
    • Grade 3 or 4 cytokine release syndrome occurred in 48.5% of patients, and 37.1% had grade 3 or 4 neurotoxicity.
  3. A phase II trial (NCT04245839) included 130 patients with relapsed or refractory follicular lymphoma who had received two or more prior lines of therapy. Patients had high-risk features (progression of disease within 24 months after first-line chemoimmunotherapy or disease refractory to rituximab and alkylators). Patients received liso-cel.[32]
    • With a median follow-up of 18.9 months, the overall response rate was 97% (95% CI, 91.6%–99.4%), and the complete response rate was 94% (95% CI, 87.5%–97.8%).[32][Level of evidence C3]
    • Cytokine release syndrome occurred in 56% of patients and was grade 3 or higher in 1% of patients. Neurological side effects occurred in 15% of patients and was grade 3 or higher in 2% of patients.

CAR T cells are being used for high-risk patients whose disease has relapsed rapidly after chemoimmunotherapy. Such an approach is considered in the context of numerous other available agents.

Stem cell transplant

In many institutions, autologous or allogeneic SCTs are being used for high-risk patients whose disease has relapsed rapidly after chemoimmunotherapy. Such an approach is considered in the context of numerous other available agents.[33–37]

Evidence (SCT):

  1. The German Low-Grade Lymphoma Study Group treated 307 patients with follicular lymphoma with two cycles of CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone)-like induction chemotherapy and then randomly assigned them to receive autologous SCT or interferon maintenance.[38]
    • With a median follow-up of 4.2 years, the 5-year PFS rate was 65% for patients who received a transplant versus 33% for patients who received interferon (P < .001). There was no difference in OS.[38][Level of evidence B1]

Palliative radiation therapy

Palliation may be achieved with very low-dose (4 Gy) involved-field radiation therapy in two fractions for patients with indolent and aggressive relapsed disease.[39] In a prospective randomized trial, treatment with 4 Gy was inferior to treatment with 24 Gy in 12 fractions in PFS (77% vs. 92%, P < .0001).[40][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
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  2. Weisdorf DJ, Andersen JW, Glick JH, et al.: Survival after relapse of low-grade non-Hodgkin’s lymphoma: implications for marrow transplantation. J Clin Oncol 10 (6): 942-7, 1992. [PUBMED Abstract]
  3. Peterson BA: Current treatment of follicular low-grade lymphomas. Semin Oncol 26 (5 Suppl 14): 2-11, 1999. [PUBMED Abstract]
  4. Haas RL, Poortmans P, de Jong D, et al.: High response rates and lasting remissions after low-dose involved field radiotherapy in indolent lymphomas. J Clin Oncol 21 (13): 2474-80, 2003. [PUBMED Abstract]
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  6. Montoto S, Davies AJ, Matthews J, et al.: Risk and clinical implications of transformation of follicular lymphoma to diffuse large B-cell lymphoma. J Clin Oncol 25 (17): 2426-33, 2007. [PUBMED Abstract]
  7. 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]
  8. Link BK, Maurer MJ, Nowakowski GS, et al.: Rates and outcomes of follicular lymphoma transformation in the immunochemotherapy era: a report from the University of Iowa/MayoClinic Specialized Program of Research Excellence Molecular Epidemiology Resource. J Clin Oncol 31 (26): 3272-8, 2013. [PUBMED Abstract]
  9. Davis TA, White CA, Grillo-López AJ, et al.: Single-agent monoclonal antibody efficacy in bulky non-Hodgkin’s lymphoma: results of a phase II trial of rituximab. J Clin Oncol 17 (6): 1851-7, 1999. [PUBMED Abstract]
  10. Piro LD, White CA, Grillo-López AJ, et al.: Extended Rituximab (anti-CD20 monoclonal antibody) therapy for relapsed or refractory low-grade or follicular non-Hodgkin’s lymphoma. Ann Oncol 10 (6): 655-61, 1999. [PUBMED Abstract]
  11. Davis TA, Grillo-López AJ, White CA, et al.: Rituximab anti-CD20 monoclonal antibody therapy in non-Hodgkin’s lymphoma: safety and efficacy of re-treatment. J Clin Oncol 18 (17): 3135-43, 2000. [PUBMED Abstract]
  12. Hainsworth JD, Litchy S, Shaffer DW, et al.: Maximizing therapeutic benefit of rituximab: maintenance therapy versus re-treatment at progression in patients with indolent non-Hodgkin’s lymphoma–a randomized phase II trial of the Minnie Pearl Cancer Research Network. J Clin Oncol 23 (6): 1088-95, 2005. [PUBMED Abstract]
  13. Lockmer S, Østenstad B, Hagberg H, et al.: Chemotherapy-Free Initial Treatment of Advanced Indolent Lymphoma Has Durable Effect With Low Toxicity: Results From Two Nordic Lymphoma Group Trials With More Than 10 Years of Follow-Up. J Clin Oncol : JCO1800262, 2018. [PUBMED Abstract]
  14. Forstpointner R, Dreyling M, Repp R, et al.: The addition of rituximab to a combination of fludarabine, cyclophosphamide, mitoxantrone (FCM) significantly increases the response rate and prolongs survival as compared with FCM alone in patients with relapsed and refractory follicular and mantle cell lymphomas: results of a prospective randomized study of the German Low-Grade Lymphoma Study Group. Blood 104 (10): 3064-71, 2004. [PUBMED Abstract]
  15. Canellos GP: CHOP may have been part of the beginning but certainly not the end: issues in risk-related therapy of large-cell lymphoma. J Clin Oncol 15 (5): 1713-6, 1997. [PUBMED Abstract]
  16. van Oers MH, Van Glabbeke M, Giurgea L, et al.: Rituximab maintenance treatment of relapsed/resistant follicular non-Hodgkin’s lymphoma: long-term outcome of the EORTC 20981 phase III randomized intergroup study. J Clin Oncol 28 (17): 2853-8, 2010. [PUBMED Abstract]
  17. van Oers MH, Klasa R, Marcus RE, et al.: Rituximab maintenance improves clinical outcome of relapsed/resistant follicular non-Hodgkin lymphoma in patients both with and without rituximab during induction: results of a prospective randomized phase 3 intergroup trial. Blood 108 (10): 3295-301, 2006. [PUBMED Abstract]
  18. Martinelli G, Schmitz SF, Utiger U, et al.: Long-term follow-up of patients with follicular lymphoma receiving single-agent rituximab at two different schedules in trial SAKK 35/98. J Clin Oncol 28 (29): 4480-4, 2010. [PUBMED Abstract]
  19. Sehn LH, Chua N, Mayer J, et al.: Obinutuzumab plus bendamustine versus bendamustine monotherapy in patients with rituximab-refractory indolent non-Hodgkin lymphoma (GADOLIN): a randomised, controlled, open-label, multicentre, phase 3 trial. Lancet Oncol 17 (8): 1081-93, 2016. [PUBMED Abstract]
  20. Cheson BD, Chua N, Mayer J, et al.: Overall Survival Benefit in Patients With Rituximab-Refractory Indolent Non-Hodgkin Lymphoma Who Received Obinutuzumab Plus Bendamustine Induction and Obinutuzumab Maintenance in the GADOLIN Study. J Clin Oncol 36 (22): 2259-2266, 2018. [PUBMED Abstract]
  21. Witzig TE, Wiernik PH, Moore T, et al.: Lenalidomide oral monotherapy produces durable responses in relapsed or refractory indolent non-Hodgkin’s Lymphoma. J Clin Oncol 27 (32): 5404-9, 2009. [PUBMED Abstract]
  22. Leonard JP, Jung SH, Johnson J, et al.: Randomized Trial of Lenalidomide Alone Versus Lenalidomide Plus Rituximab in Patients With Recurrent Follicular Lymphoma: CALGB 50401 (Alliance). J Clin Oncol 33 (31): 3635-40, 2015. [PUBMED Abstract]
  23. Zinzani PL, Mayer J, Flowers CR, et al.: ROSEWOOD: A Phase II Randomized Study of Zanubrutinib Plus Obinutuzumab Versus Obinutuzumab Monotherapy in Patients With Relapsed or Refractory Follicular Lymphoma. J Clin Oncol 41 (33): 5107-5117, 2023. [PUBMED Abstract]
  24. Morschhauser F, Tilly H, Chaidos A, et al.: Tazemetostat for patients with relapsed or refractory follicular lymphoma: an open-label, single-arm, multicentre, phase 2 trial. Lancet Oncol 21 (11): 1433-1442, 2020. [PUBMED Abstract]
  25. Budde LE, Sehn LH, Matasar M, et al.: Safety and efficacy of mosunetuzumab, a bispecific antibody, in patients with relapsed or refractory follicular lymphoma: a single-arm, multicentre, phase 2 study. Lancet Oncol 23 (8): 1055-1065, 2022. [PUBMED Abstract]
  26. Hutchings M, Mous R, Clausen MR, et al.: Dose escalation of subcutaneous epcoritamab in patients with relapsed or refractory B-cell non-Hodgkin lymphoma: an open-label, phase 1/2 study. Lancet 398 (10306): 1157-1169, 2021. [PUBMED Abstract]
  27. Sehn LH, Bartlett NL, Matasar MJ, et al.: Long-term 3-year follow-up of mosunetuzumab in relapsed or refractory follicular lymphoma after ≥2 prior therapies. Blood 145 (7): 708-719, 2025. [PUBMED Abstract]
  28. Linton KM, Vitolo U, Jurczak W, et al.: Epcoritamab monotherapy in patients with relapsed or refractory follicular lymphoma (EPCORE NHL-1): a phase 2 cohort of a single-arm, multicentre study. Lancet Haematol 11 (8): e593-e605, 2024. [PUBMED Abstract]
  29. Jacobson CA, Chavez JC, Sehgal AR, et al.: Axicabtagene ciloleucel in relapsed or refractory indolent non-Hodgkin lymphoma (ZUMA-5): a single-arm, multicentre, phase 2 trial. Lancet Oncol 23 (1): 91-103, 2022. [PUBMED Abstract]
  30. Neelapu SS, Chavez JC, Sehgal AR, et al.: Three-year follow-up analysis of axicabtagene ciloleucel in relapsed/refractory indolent non-Hodgkin lymphoma (ZUMA-5). Blood 143 (6): 496-506, 2024. [PUBMED Abstract]
  31. Fowler NH, Dickinson M, Dreyling M, et al.: Tisagenlecleucel in adult relapsed or refractory follicular lymphoma: the phase 2 ELARA trial. Nat Med 28 (2): 325-332, 2022. [PUBMED Abstract]
  32. Morschhauser F, Dahiya S, Palomba ML, et al.: Lisocabtagene maraleucel in follicular lymphoma: the phase 2 TRANSCEND FL study. Nat Med 30 (8): 2199-2207, 2024. [PUBMED Abstract]
  33. Freedman A, Friedberg JW, Gribben J: High-dose therapy for follicular lymphoma. Oncology (Huntingt) 14 (3): 321-6, 329; discussion 330-2, 338, 2000. [PUBMED Abstract]
  34. Brice P, Simon D, Bouabdallah R, et al.: High-dose therapy with autologous stem-cell transplantation (ASCT) after first progression prolonged survival of follicular lymphoma patients included in the prospective GELF 86 protocol. Ann Oncol 11 (12): 1585-90, 2000. [PUBMED Abstract]
  35. Khouri IF, McLaughlin P, Saliba RM, et al.: Eight-year experience with allogeneic stem cell transplantation for relapsed follicular lymphoma after nonmyeloablative conditioning with fludarabine, cyclophosphamide, and rituximab. Blood 111 (12): 5530-6, 2008. [PUBMED Abstract]
  36. Sebban C, Brice P, Delarue R, et al.: Impact of rituximab and/or high-dose therapy with autotransplant at time of relapse in patients with follicular lymphoma: a GELA study. J Clin Oncol 26 (21): 3614-20, 2008. [PUBMED Abstract]
  37. Thomson KJ, Morris EC, Milligan D, et al.: T-cell-depleted reduced-intensity transplantation followed by donor leukocyte infusions to promote graft-versus-lymphoma activity results in excellent long-term survival in patients with multiply relapsed follicular lymphoma. J Clin Oncol 28 (23): 3695-700, 2010. [PUBMED Abstract]
  38. Lenz G, Dreyling M, Schiegnitz E, et al.: Myeloablative radiochemotherapy followed by autologous stem cell transplantation in first remission prolongs progression-free survival in follicular lymphoma: results of a prospective, randomized trial of the German Low-Grade Lymphoma Study Group. Blood 104 (9): 2667-74, 2004. [PUBMED Abstract]
  39. 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]
  40. Hoskin PJ, Kirkwood AA, Popova B, et al.: 4 Gy versus 24 Gy radiotherapy for patients with indolent lymphoma (FORT): a randomised phase 3 non-inferiority trial. Lancet Oncol 15 (4): 457-63, 2014. [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]

Latest Updates to This Summary (05/14/2025)

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.

General Information About B-Cell Non-Hodgkin Lymphoma

Revised text to state that aggressive non-Hodgkin lymphoma (NHL) has a worse prognosis in the short term, but a significant number of patients can be cured with intensive combination chemotherapy regimens. More than 70% of patients with aggressive NHL can be cured.

Indolent B-Cell Non-Hodgkin Lymphoma

Revised text about the Follicular Lymphoma International Prognostic Index to state that patients with zero or one risk factor have a 10-year survival rate of 67%, and four or five risk factors confer a 10-year survival rate of 36%. Also added text about the nine prognostic variables identified by the Follicular Lymphoma Evaluation Index model.

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

Revised text about the results of a single-arm, multicenter, phase II study of 90 patients with relapsed or refractory follicular lymphoma who received mosunetuzumab (cited Sehn et al. as reference 27 and level of evidence C1).

Revised text about the results of a phase II trial of 159 patients with relapsed or refractory follicular lymphoma, marginal zone lymphoma, or diffuse large B-cell lymphoma who received axicabtagene ciloleucel (cited Neelapu et al. as reference 30 and level of evidence C2).

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 indolent adult 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 Indolent 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 Indolent B-Cell Non-Hodgkin Lymphoma Treatment. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: /types/lymphoma/hp/indolent-b-cell-lymphoma-treatment-pdq. Accessed <MM/DD/YYYY>. [PMID: 37437080]

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Advances in Leukemia Research

Advances in Leukemia Research

Human cells with acute myelocytic leukemia as seen through a microscope

Human cells with acute myelocytic leukemia.

Credit: National Cancer Institute

NCI-funded researchers are working to advance our understanding of how to treat leukemia. With progress in both targeted therapies and immunotherapies, leukemia treatment has the potential to become more effective and less toxic.

This page highlights some of the latest research in leukemia, including clinical advances that may soon translate into improved care, NCI-supported programs that are fueling progress, and research findings from recent studies.

Leukemia Treatment for Adults

The mainstays of leukemia treatment for adults have been chemotherapy, radiation therapy, and stem cell transplantation. Over the last two decades, targeted therapies have also become part of the standard of care for some types of leukemia. These treatments target proteins that control how cancer cells grow, divide, and spread. Different types of leukemia require different combinations of therapies.  For a complete list of all currently approved drugs, see Drugs Approved for Leukemia.

Although much progress has been made against some types of leukemia, others still have relatively poor rates of survival. And, as the population ages, there is a greater need for treatment regimens that are more effective and less toxic than standard chemotherapy.

Acute Lymphoblastic Leukemia (ALL) Treatment

Adult acute lymphoblastic leukemia (ALL) is a type of cancer in which the bone marrow makes too many lymphocytes (a type of white blood cell). It usually gets worse quickly and needs rapid treatment. Some recent research includes:

Combining less-toxic therapies

The intensive chemotherapy treatments used for ALL have serious side effects that many older patients cannot tolerate. Targeted therapies may have fewer side effects than chemotherapy. Clinical trials are now testing whether combinations of these types of therapies can be used instead of chemotherapy for older patients with a form of ALL called B-cell ALL.

Immunotherapy

Immunotherapies are treatments that help the body’s immune system fight cancer more effectively. Immunotherapy strategies being used or tested in ALL include:

CAR T-cell therapy

CAR T-cell therapy is a type of treatment in which a patient’s own immune cells are genetically modified to treat their cancer.

CAR T cell therapies are now being explored for other uses in ALL. For example, scientists hope that it will be possible to use CAR T-cell therapy to delay—or even replace—stem-cell transplantation in older, frailer patients.

Bispecific T-cell engagers

Another immunotherapy being tested in ALL is bispecific T-cell engagers (BiTEs). These drugs attach to immune cells and cancer cells, enabling the immune cells to easily find and destroy the cancer cell by bringing them closer together.

Once such BiTE, called blinatumomab (Blincyto), was recently shown to improve survival for people with ALL who are in remission after chemotherapy, even when there is no trace of their disease. In 2024, FDA approved blinatumomab for adult and pediatric patients one month and older with a specific type of B-cell precursor ALL. The approval is for use as part of consolidation chemotherapy, which is treatment that is given after cancer has disappeared following initial therapy.

Improving treatment for adolescents and young adults (AYAs)

An intensive treatment regimen developed for children with ALL has been found to also improve outcomes for newly diagnosed AYA patients. The pediatric regimen more than doubled the median length of time people lived without their cancer returning compared with an adult treatment regimen. Further studies are now testing the addition of targeted therapies to the combination.

Acute Myeloid Leukemia (AML) Treatment

Acute myeloid leukemia (AML) is the most common type of acute leukemia in adults. It can cause a buildup of abnormal red blood cells, white blood cells, or platelets.

AML tends to be aggressive and is harder to treat than ALL. However, AML cells sometimes have gene changes that cause the tumors to grow but can be targeted with new drugs. Researchers are starting to look at whether genomic sequencing of tumor cells can help doctors choose the best treatment (such as chemotherapy, targeted therapy, stem-cell transplant, or a combination of therapies) for each patient. Scientists are also testing other ways to treat AML.

A nurse holds the arm of a sitting patient: an elderly woman with a head covering. A blurry IV bag is in the foreground; the background indicates a treatment center.

New Treatment Option for Some People with AML

Combining ivosidenib with chemo is effective for AML with an IDH1 gene mutation.

Targeted therapies

Targeted therapies recently approved to treat AML with certain gene changes include Enasidenib (Idhifa), Olutasidenib (Rezlidhia), Ivosidenib (Tibsovo), Venetoclax (Venclexta), Gemtuzumab ozogamicin (Mylotarg), Midostaurin (Rydapt), Gilteritinib (Xospata), Glasdegib (Daurismo), and Quizartinib (Vanflyta). 

An NCI-supported precision medicine study called MyeloMATCH is now enrolling people with newly diagnosed AML or a related but less aggressive cancer called myelodysplastic syndrome (MDS). Participants will undergo genomic testing of blood and bone marrow samples to see if they have specific genetic alterations that can be matched to corresponding targeted therapies.

Other ways to treat AML

  • Testing newer targeted therapies. Researchers continue to develop new drugs to shut down proteins that some leukemias need to grow. For example, new drugs called menin inhibitors stop cancer-promoting genes from being expressed. 
  • Studying ways to target AML cells indirectly. These include testing ways to make cancer cells more vulnerable to new and existing treatments.
  • Targeting AML and related conditions. MDS can eventually progress to AML. Researchers are testing HDAC inhibitors and other drugs that alter how genes are switched on and off in both MDS and AML.
  • Reducing side effects. Some older adults cannot tolerate the intensive treatments most commonly used for AML. Studies have recently found that several drug combinations can help older people with AML live longer while avoiding many serious side effects. New treatments to relieve symptoms of MDS have also been developed.
  • Immunotherapy. CAR T cells and BiTEs are being tested in people with AML.

Chronic Myelogenous Leukemia (CML) Treatment

Chronic myelogenous leukemia (CML) is a type of cancer in which the bone marrow makes too many granulocytes (a type of white blood cell). These granulocytes are abnormal and can build up in the blood and bone marrow so there is less room for healthy white blood cells, red blood cells, and platelets. CML usually gets worse slowly over time.

Blocking an abnormal protein

Most people with CML have a specific chromosome alteration called the Philadelphia chromosome, which produces an abnormal protein that drives the growth of leukemia cells. Targeted therapies that block this abnormal protein—imatinib (Gleevec), nilotinib (Tasigna), dasatinib (Sprycel), and ponatinib (Iclusig)—have radically changed the outlook for people with CML, who now have close to a normal life expectancy.

Testing new combination therapies

Some people with CML continue to have detectable cancer cells in their body even after long-term treatment with drugs that target the protein produced by the Philadelphia chromosome. NCI-supported trials are testing whether the addition of immunotherapy or other targeted therapies to these drugs can reduce the number of CML cells in such patients.

Looking at whether patients can stop taking therapy

Researchers have found that some drugs that target the protein produced by the Philadelphia chromosome can be safely stopped in some CML patients rather than taken for life. These patients must undergo regular testing to ensure the disease has not come back.

Chronic Lymphocytic Leukemia (CLL) Treatment

Like ALL, chronic lymphocytic leukemia (CLL) is a type of cancer in which the bone marrow makes too many lymphocytes (a type of white blood cell). But unlike ALL, CLL is slow growing and worsens over time.

Targeted therapy

Ibrutinib (Imbruvica). The targeted therapy ibrutinib (Imbruvica) was the first non-chemotherapy drug approved to treat CLL. It shuts down a signaling pathway called the B-cell receptor signaling pathway, which is commonly overactive in CLL cells. Depending on people’s age, ibrutinib may be given in combination with another targeted drug, rituximab (Rituxan).

Clinical trials have shown that ibrutinib benefits both younger and older patients with CLL.

Venetoclax (Venclexta) and obinutuzumab (Gazyva). In 2019, the Food and Drug Administration (FDA) approved the second chemotherapy-free initial treatment regimen for CLL, containing the targeted therapies venetoclax (Venclexta) and obinutuzumab (Gazyva).

Other combinations of these drugs plus ibrutinib are now being used or tested for CLL, including
•    ibrutinib and venetoclax in people with newly diagnosed CLL
•    ibrutinib, obinutuzumab, and venetoclax in older adults with newly diagnosed CLL
•    ibrutinib and obinutuzumab with or without venetoclax in younger adults with newly diagnosed CLL

An ongoing trial at NCI is also testing whether giving the combination of venetoclax and obinutuzumab to some people with CLL before symptoms develop can help them live longer overall.

Zanubrutinib (Brukinsa). In early 2023, the FDA approved a drug that works in a similar manner to ibrutinib, called zanubrutinib (Brukinsa), for people with CLL. A large study showed that zanubrutinib alone has fewer side effects and is more effective than ibrutinib for people whose leukemia has returned after initial treatment. More research is now needed to understand how to best combine zanubrutinib with other newer therapies, such as venetoclax.

CAR T-cell therapy

CAR T-cell therapy is also being tested in adults with CLL. Researchers would like to know if using this type of immunotherapy early in the course of treatment would be more effective than waiting until the cancer recurs.

Hairy Cell Leukemia (HCL) Treatment

Hairy cell leukemia (HCL) is a type of cancer in which the bone marrow makes too many lymphocytes (a type of white blood cell). The disease is called hairy cell leukemia because the abnormal lymphocytes look “hairy” when viewed under a microscope. This rare type of leukemia gets worse slowly, or sometimes does not get worse at all.

Combinations of drugs

Researchers are studying combinations of drugs to treat HCL. For example, in a recent small study, a combination of two targeted therapies—vemurafenib (Zelboraf) and rituximab (Rituxan)—led to long-lasting remissions for most participants with HCL that had come back after previous treatments. More drug combinations are currently being tested in clinical trials.

Leukemia Treatment for Children

For the two most common types of leukemia, AML and ALL, standard leukemia treatments for children have been chemotherapy, radiation therapy, and stem-cell transplant. Despite great improvements in survival for children with many types of leukemia, some treatments don’t always work. Also, some children later experience a relapse of their disease. Others live with the side effects of chemotherapy and radiation therapy for the rest of their lives, highlighting the need for less toxic treatments.

Now researchers are focusing on targeted drugs and immunotherapies for the treatment of leukemia in children. Newer chemotherapy drugs are also being tested.

Targeted Therapies

Targeted therapies that have been approved or are being studied for children with leukemia include:

More possible targets for the treatment of childhood cancers are discovered every year, and many new drugs that could potentially be used to treat cancers that have these targets are being tested through the Pediatric Preclinical In Vivo Testing Consortium (PIVOT).

Immunotherapy

CAR T-cell therapy has recently generated great excitement for the treatment of children with relapsed ALL. One CAR T-cell therapy, tisagenlecleucel (Kymriah), was approved in 2017 for some children with relapsed ALL.

Researchers continue to address remaining challenges about the use of CAR T-cell therapy in children with leukemia:

  • Sometimes, leukemia can become resistant to tisagenlecleucel. Researchers in NCI’s Pediatric Oncology Branch have developed CAR T cells that target leukemia cells in a different way. An ongoing clinical trial is testing whether the combination of these two types of CAR T cells can provide longer-lasting remissions.
  • CAR T cells are currently only approved for use in leukemia that has relapsed or proved resistant to standard treatment. A clinical trial from the Children’s Oncology Group (COG) is now testing tisagenlecleucel as part of first-line therapy in children with ALL at high risk of relapse.
  • More research is needed to understand which children who receive CAR T cells are at high risk of developing resistance to treatment. Researchers also plan to test whether strategies such as combining CAR T-cell therapy with other immunotherapies may help prevent resistance from developing. 
  • Other research, both in NCI’s Pediatric Oncology Branch and at other institutions, is focused on creating CAR T-cell therapies that work for children with other types of childhood leukemia, such as AML. Several clinical trials of these treatments, including one led by NCI researchers, are now under way.

Two other drugs that use the body’s immune system to fight cancer have shown promise for children with leukemia:

  • A drug called blinatumomab (Blincyto) is a type of immunotherapy called a bispecific T-cell engager (BiTE). These drugs attach to immune cells and cancer cells, enabling the immune cells to easily find and destroy the cancer cell by bringing them closer together.  Blinatumomab has been approved by the FDA for children with ALL who have relapsed after initial treatment.
  • A drug called inotuzumab ozogamicin (Besponsa) is being tested in children with relapsed B-cell ALL. This drug consists of an antibody that can bind to cancer cells linked to a drug that can kill those cells. An NCI-supported trial is also testing the drug as part of treatment for newly diagnosed ALL in children and adolescents at higher risk of relapse.

Chemotherapy

In addition to targeted therapies and immunotherapies, researchers are also working to develop new chemotherapy drugs for leukemia and find better ways to use existing drugs. In 2018, a large clinical trial showed that adding the drug nelarabine (Arranon) to standard chemotherapy improves survival for children and young adults newly diagnosed with T-cell ALL.

Other drugs are being tested that may make standard chemotherapy drugs more effective. These drugs include venetoclax, which has been approved for older adults with some types of leukemia and is now being tested in children.

Survivorship

Children’s developing brains and bodies can be particularly sensitive to the harmful effects of cancer treatment. Because many children treated for cancer go on to live long lives, they may be dealing with these late effects for decades to come.

The NCI-funded Childhood Cancer Survivor Study, ongoing since 1994, tracks the long-term harmful effects of treatments for childhood cancer and studies ways to minimize these effects. NCI also funds research into addressing ways to help cancer survivors cope with and manage health issues stemming from cancer treatment, as well as into altering existing treatment regimens to make them less toxic in the long term.

For example, one study found that, in children with ALL, radiation therapy to prevent the cancer from returning in the brain is likely unnecessary. The study found that radiation can even be omitted for children at the highest risk of the cancer coming back, reducing the risk of future problems with thinking and memory, hormone dysfunction, and other side effects of radiation to the brain.

Preventing and Treating Graft Versus Host Disease

Many people with leukemia—both adults and children—have a stem-cell transplant as part of their treatment. If the new stem cells come from a donor, the immune cells they produce may be able to attack any cancer cells that remain in the body.

But sometimes, immune cells produced by donor stem cells attack healthy tissues of the body instead. This condition, called graft versus host disease (GVHD), can affect nearly every organ and can cause many painful and debilitating symptoms. 

In recent years, several drugs have been approved by the FDA for the treatment of GVHD, including:

•    ibrutinib, which is also used as a treatment for some types of leukemia
•    ruxolitinib (Jakafi)
•    belumosudil (Rezurock)

Researchers are also testing ways to prevent GVHD from developing in the first place. For example, a recent study found that removing certain immune cells from donated stem cells before they are transplanted may reduce the risk of chronic GVHD without any apparent increase in the likelihood of relapse.

NCI-Supported Research Programs

Many NCI-funded researchers working at the NIH campus and across the United States and the world are seeking ways to address leukemia more effectively. Some research is basic, exploring questions as diverse as the biological underpinnings of cancer. And some is more clinical, seeking to translate this basic information into improving patient outcomes. The programs listed below are a small sampling of NCI’s research efforts in leukemia.

NCI’s Leukemia Specialized Programs of Research Excellence (SPORE) promotes collaborative, interdisciplinary research. SPORE grants involve both basic and clinical/applied scientists working together. They support the efficient movement of basic scientific findings into clinical settings, as well as studies to determine the biological basis for observations made in individuals with cancer or in populations at risk for cancer.

The Targeting Fusion Oncoproteins in Childhood Cancers (TFCC) Network is forming a collaborative team of investigators to advance the understanding of how fusion proteins contribute to pediatric cancers, and how they might be targeted with new treatments. Fusion proteins, which can occur when parts of different chromosomal regions are joined, may drive the development of many cancers in children.

NCI has also formed partnerships with the pharmaceutical industry, academic institutions, and individual investigators for the early clinical evaluation of innovative cancer therapies. The Experimental Therapeutics Clinical Trials Network (ETCTN) was created to evaluate these therapies using a coordinated, collaborative approach to early-phase clinical trials.

The Pediatric Early-Phase Clinical Trials Network was established to help identify and develop effective new drugs for children and adolescents with cancer. The network’s focus is on phase I and early phase II trials, as well as pilot studies of novel drugs and treatment regimens to determine their tolerability.

NCI’s Pediatric Preclinical In Vivo Testing Consortium (PIVOT) develops mouse models to allow early, rapid testing of new drugs for pediatric cancers, including leukemia. The models are all derived from tissue samples taken from patients’ tumors. The consortium partners both with commercial drug companies and with drug development efforts at universities and cancer centers.

The NCI-supported Children’s Oncology Group develops and conducts both clinical trials of initial treatments and clinical trials for after cancer relapse for children and adolescents with ALL, AML, and CML.

Researchers in NCI’s Division of Cancer Epidemiology and Genetics (DCEG) investigate novel, molecular biomarkers for leukemia, as well as clarify relationships of established risk factors. Studies include those looking at environmental and workplace exposure, families with multiple leukemia cases, and inherited bone marrow failure syndromes to name a few.

Clinical Trials

NCI funds and oversees both early- and late-phase clinical trials to develop new treatments and improve patient care. Search NCI-Supported Clinical Trials to find leukemia-related trials now accepting patients. 

Leukemia Research Results

The following are some of our latest news articles on leukemia research:

Lymphoma—Patient Version

Lymphoma—Patient Version

Overview

Lymphoma is a broad term for cancer that begins in cells of the lymph system. The two main types are Hodgkin lymphoma and non-Hodgkin lymphoma (NHL). Hodgkin lymphoma can often be cured. The prognosis of NHL depends on the specific type. Explore the links on this page to learn more about lymphoma treatment, research, and clinical trials.

Treatment

PDQ Treatment Information for Patients

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Causes & Prevention

NCI does not have PDQ evidence-based information about prevention of lymphoma.

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Screening

NCI does not have PDQ evidence-based information about screening for lymphoma.

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Research

Coping with Cancer

The information in this section is meant to help you cope with the many issues and concerns that occur when you have cancer.

Emotions and Cancer Adjusting to Cancer Support for Caregivers Survivorship Advanced Cancer Managing Cancer Care

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Lymphoma—Health Professional Version

Lymphoma—Health Professional Version

Treatment

PDQ Treatment Information for Health Professionals

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Causes & Prevention

NCI does not have PDQ evidence-based information about prevention of lymphoma.

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Genetics

PDQ Genetics Information for Health Professionals

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NCI does not have PDQ evidence-based information about screening for lymphoma.

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Research

Supportive & Palliative Care

We offer evidence-based supportive and palliative care information for health professionals on the assessment and management of cancer-related symptoms and conditions.

Cancer Pain Nausea and Vomiting Nutrition in Cancer Care Transition to End-of-Life Care Last Days of Life View all Supportive and Palliative Care Summaries

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Childhood Acute Myeloid Leukemia/Other Myeloid Malignancies Treatment (PDQ®)–Patient Version

Childhood Acute Myeloid Leukemia/Other Myeloid Malignancies Treatment (PDQ®)–Patient Version

General Information About Childhood Acute Myeloid Leukemia and Other Myeloid Malignancies

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Key Points

  • Childhood acute myeloid leukemia (AML) is a type of cancer in which the bone marrow makes a large number of abnormal blood cells.
  • Leukemia and other diseases of the blood and bone marrow may affect red blood cells, white blood cells, and platelets.
  • Other myeloid diseases can affect the blood and bone marrow.
    • Transient abnormal myelopoiesis (TAM)
    • Acute promyelocytic leukemia (APL)
    • Juvenile myelomonocytic leukemia (JMML)
    • Chronic myelogenous leukemia (CML)
    • Myelodysplastic syndromes (MDS)
  • AML or MDS may occur after treatment with certain chemotherapy drugs and/or radiation therapy.
  • The risk factors for childhood acute myeloid leukemia and other myeloid malignancies are similar.
  • Signs and symptoms of childhood acute myeloid leukemia and other myeloid malignancies include fever, feeling tired, and easy bleeding or bruising.
  • Tests that examine the blood and bone marrow are used to diagnose and find any spread of childhood acute myeloid leukemia and other myeloid malignancies.
  • Certain factors affect prognosis (chance of recovery) and treatment options.

Childhood acute myeloid leukemia (AML) is a type of cancer in which the bone marrow makes a large number of abnormal blood cells.

Childhood acute myeloid leukemia (AML) is a cancer of the blood and bone marrow. AML is also called acute myelogenous leukemia and acute nonlymphocytic leukemia. Cancers that are acute usually get worse quickly if they are not treated. Cancers that are chronic usually get worse slowly.

EnlargeAnatomy of the bone; drawing shows spongy bone, red marrow, and yellow marrow. A cross section of the bone shows compact bone and blood vessels in the bone marrow. Also shown are red blood cells, white blood cells, platelets, and a blood stem cell.
Anatomy of the bone. The bone is made up of compact bone, spongy bone, and bone marrow. Compact bone makes up the outer layer of the bone. Spongy bone is found mostly at the ends of bones and contains red marrow. Bone marrow is found in the center of most bones and has many blood vessels. There are two types of bone marrow: red and yellow. Red marrow contains blood stem cells that can become red blood cells, white blood cells, or platelets. Yellow marrow is made mostly of fat.

This summary is about the treatment of childhood AML, transient abnormal myelopoiesis, childhood acute promyelocytic leukemia, juvenile myelomonocytic leukemia, childhood chronic myelogenous leukemia, and childhood myelodysplastic syndromes. For information about the treatment of childhood acute lymphoblastic leukemia, see Childhood Acute Lymphoblastic Leukemia Treatment.

Leukemia and other diseases of the blood and bone marrow may affect red blood cells, white blood cells, and platelets.

In healthy children, the bone marrow makes blood stem cells (immature cells) that become mature blood cells over time. A blood stem cell may become a myeloid stem cell or a lymphoid stem cell. A lymphoid stem cell becomes a type of white blood cell.

A myeloid stem cell becomes one of three types of mature 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 AML, the myeloid stem cells usually become a type of immature white blood cell called myeloblasts (or myeloid blasts). The myeloblasts, or leukemia cells, in AML are abnormal and do not become healthy white blood cells. The leukemia cells can build up in the blood and bone marrow so there is less room for healthy white blood cells, red blood cells, and platelets. This may lead to infection, anemia, or easy bleeding.

The leukemia cells can spread outside the blood to other parts of the body, including the central nervous system (brain and spinal cord), skin, and gums. Sometimes leukemia cells form a solid tumor called a myeloid sarcoma. Myeloid sarcoma is also called granulocytic sarcoma or chloroma.

Other myeloid diseases can affect the blood and bone marrow.

Transient abnormal myelopoiesis (TAM)

TAM is a disorder of the bone marrow that can develop in newborns who have Down syndrome. TAM usually goes away on its own within the first 3 months of life. Infants who have TAM have an increased chance of developing AML before the age of 3 years. TAM is also called transient myeloproliferative disorder or transient leukemia.

Acute promyelocytic leukemia (APL)

APL is a subtype of AML. In APL, some genes on chromosome 15 switch places with some genes on chromosome 17 and an abnormal gene called PML-RARA is made. The PML-RARA gene sends a message that stops promyelocytes (a type of white blood cell) from maturing. The promyelocytes (leukemia cells) can build up in the blood and bone marrow so there is less room for healthy white blood cells, red blood cells, and platelets. Problems with severe bleeding and blood clots may also occur. This is a serious health problem that needs treatment as soon as possible.

Juvenile myelomonocytic leukemia (JMML)

JMML is a rare childhood cancer that is most common in children around the age of 2 years and is more common in boys. In JMML, too many myeloid blood stem cells become myelocytes and monocytes (two types of white blood cells). Some of these myeloid blood stem cells never become mature white blood cells. These immature cells, called blasts, are unable to do their usual work. Over time, the myelocytes, monocytes, and blasts crowd out the healthy white blood cells, red blood cells, and platelets in the bone marrow. When this happens, infection, anemia, or easy bleeding may occur.

Chronic myelogenous leukemia (CML)

CML often begins in an early myeloid blood cell when a certain gene change occurs. A section of genes, that includes the ABL gene, on chromosome 9 changes place with a section of genes on chromosome 22, which has the BCR gene. This makes a very short chromosome 22 (called the Philadelphia chromosome) and a very long chromosome 9. An abnormal BCR-ABL gene is formed on chromosome 22. The BCR-ABL gene tells the blood cells to make too much of a protein called tyrosine kinase. Tyrosine kinase causes too many abnormal white blood cells (leukemia cells) to be made in the bone marrow. The leukemia cells can build up in the blood and bone marrow so there is less room for healthy white blood cells, red blood cells, and platelets. This can lead to infection, anemia, or easy bleeding. CML is rare in children.

EnlargePhiladelphia chromosome; three-panel drawing shows a piece of chromosome 9 and a piece of chromosome 22 breaking off and trading places, creating a changed chromosome 22 called the Philadelphia chromosome. In the left panel, the drawing shows a normal chromosome 9 with the ABL1 gene and a normal chromosome 22 with the BCR gene. In the center panel, the drawing shows part of the ABL1 gene breaking off from chromosome 9 and a piece of chromosome 22 breaking off, below the BCR gene. In the right panel, the drawing shows chromosome 9 with the piece from chromosome 22 attached. It also shows a shortened version of chromosome 22 with the piece from chromosome 9 containing part of the ABL1 gene attached. The ABL1 gene joins to the BCR gene on chromosome 22 to form the BCR::ABL1 fusion gene. The changed chromosome 22 with the BCR::ABL1 fusion gene on it is called the Philadelphia chromosome.
The Philadelphia (Ph) chromosome is an abnormal chromosome that is made when pieces of chromosomes 9 and 22 break off and trade places. The ABL1 gene from chromosome 9 joins to the BCR gene on chromosome 22 to form the BCR::ABL1 fusion gene. The changed chromosome 22 with the fusion gene on it is called the Ph chromosome.

Myelodysplastic syndromes (MDS)

MDS occur less often in children than in adults. In MDS, the bone marrow makes too few red blood cells, white blood cells, and platelets. These blood cells may not mature and enter the blood. The type of MDS depends on the type of blood cell that is affected.

The treatment for MDS depends on how low the numbers of red blood cells, white blood cells, or platelets are. Over time, MDS may become AML.

AML or MDS may occur after treatment with certain chemotherapy drugs and/or radiation therapy.

Cancer treatment with certain chemotherapy drugs and/or radiation therapy may cause therapy-related AML (t-AML) or therapy-related MDS (t-MDS). The risk of these therapy-related myeloid diseases depends on the total dose of the chemotherapy drugs used and the radiation dose and treatment field. Some patients also have an inherited risk for t-AML and t-MDS. These therapy-related diseases usually occur within 7 years after treatment, but are rare in children.

The risk factors for childhood acute myeloid leukemia and other myeloid malignancies are similar.

Anything that increases your risk of getting a disease is called a risk factor. Having a risk factor does not mean that you will get cancer; not having risk factors doesn’t mean that you will not get cancer. Talk with your child’s doctor if you think your child may be at risk. These and other factors may increase the risk of childhood AML, APL, JMML, CML, and MDS:

Signs and symptoms of childhood acute myeloid leukemia and other myeloid malignancies include fever, feeling tired, and easy bleeding or bruising.

These and other signs and symptoms may be caused by childhood AML, APL, JMML, CML, or MDS or by other conditions. Check with a doctor if your child has any of the following:

  • Fever with or without an infection.
  • Drenching night sweats.
  • Shortness of breath.
  • Weakness, feeling tired, or looking pale.
  • Easy bruising or bleeding.
  • Petechiae (flat, pinpoint spots under the skin caused by bleeding).
  • Bone or joint pain.
  • Pain or feeling of fullness below the ribs.
  • Painless lumps in the neck, underarm, stomach, groin, or other parts of the body. In childhood AML, these lumps, called leukemia cutis, may be blue or purple.
  • Painless lumps that are sometimes around the eyes. These lumps, called myeloid sarcomas, are sometimes seen in childhood AML and may be blue-green.
  • An eczema-like skin rash.
  • Loss of appetite or weight loss.
  • Headache, trouble seeing, or confusion.

The signs and symptoms of TAM may include the following:

  • Swelling all over the body.
  • Shortness of breath.
  • Trouble breathing.
  • Increased heart rate.
  • Weakness, feeling tired, or looking pale.
  • Easy bleeding or bruising.
  • Petechiae (flat, pinpoint spots under the skin caused by bleeding).
  • Pain below the ribs.
  • Skin rash.
  • Jaundice (yellowing of the skin and whites of the eyes).

Sometimes TAM does not cause any symptoms at all and is diagnosed after a routine blood test.

Tests that examine the blood and bone marrow are used to diagnose and find any spread of childhood acute myeloid leukemia and other myeloid malignancies.

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 habits and past illnesses and treatments will also be taken.
  • Complete blood count (CBC) 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 portion of the blood sample made up of red blood cells.
    • The amount of hemoglobin (the protein that carries oxygen) in the 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.
  • 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.
  • Biopsy: The removal of cells or tissues so they can be viewed under a microscope by a pathologist to check for signs of cancer. Biopsies that may be done include the following:
    • 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.
      EnlargeBone marrow aspiration and biopsy; drawing shows a child lying face down on a table and a bone marrow needle being inserted into the right hip bone. An inset shows the bone marrow needle being inserted through the skin into the bone marrow of the hip bone.
      Bone marrow aspiration and biopsy. After a small area of skin is numbed, a bone marrow needle is inserted into the child’s hip bone. Samples of blood, bone, and bone marrow are removed for examination under a microscope.
    • Tumor biopsy for AML: The removal of cells or tissues from a lump in the testicles, ovaries, or skin using a needle. This may be done if the doctor suspects the leukemia cells may have formed a solid tumor called a myeloid sarcoma.
  • 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 leukemia.
  • 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.

    The following test is a type of cytogenetic analysis:

    • 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.
  • Molecular testing: A laboratory test to check for certain genes, proteins, or other molecules in a sample of tissue, blood, or bone marrow. Molecular tests also check for certain changes in a gene or chromosome that may cause or affect the chance of developing AML. A molecular test may be used to help plan treatment, find out how well treatment is working, or make a prognosis.
  • Lumbar puncture: A procedure used to collect a sample of 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 leukemia cells have spread to the brain and spinal cord. 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.

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

The prognosis and treatment options for childhood acute myeloid leukemia (AML) depend on the following:

  • The age of the child when the cancer is diagnosed.
  • The race or ethnic group of the child.
  • Whether the child is greatly overweight.
  • Number of white blood cells in the blood at diagnosis.
  • Whether the AML occurred after previous cancer treatment.
  • The subtype of AML.
  • Whether there are certain chromosome or gene changes in the leukemia cells.
  • Whether the child has Down syndrome. Most children with AML and Down syndrome can be cured of their leukemia when diagnosed before age 4 years.
  • Whether the leukemia is in the central nervous system (brain and spinal cord).
  • How quickly the leukemia responds to treatment.
  • Whether the AML is newly diagnosed (untreated) or has recurred after treatment.
  • The length of time since treatment ended, for AML that has recurred.

The prognosis and treatment options for childhood acute promyelocytic leukemia (APL) depends on the following:

  • Number of white blood cells in the blood at diagnosis.
  • Whether there are certain chromosome or gene changes in the leukemia cells.
  • Whether the APL is newly diagnosed (untreated) or has recurred after treatment.

The prognosis and treatment options for juvenile myelomonocytic leukemia (JMML) depend on the following:

  • The age of the child when the cancer is diagnosed.
  • The type of gene affected and the number of genes that have changes.
  • How many platelets are in the blood after treatment.
  • How much hemoglobin is in the blood after treatment.
  • Whether the JMML is newly diagnosed (untreated) or has recurred after treatment.

The prognosis and treatment options for childhood chronic myelogenous leukemia (CML) depend on the following:

  • How long it has been since the patient was diagnosed.
  • How many blast cells are in the blood.
  • Whether and how fully the blast cells disappear from the blood and bone marrow after therapy has started.
  • Whether the CML is newly diagnosed (untreated) or has recurred after treatment.

The prognosis and treatment options for myelodysplastic syndromes (MDS) depend on the following:

  • Whether the MDS was caused by previous cancer treatment.
  • How low the numbers of red blood cells, white blood cells, or platelets are.
  • Whether the MDS is newly diagnosed (untreated) or has recurred after treatment.

Stages of Childhood Acute Myeloid Leukemia and Other Myeloid Malignancies

Key Points

  • There is no standard staging system for childhood acute myeloid leukemia and other myelogenous malignancies.
  • Sometimes childhood acute myeloid leukemia and other myeloid malignancies do not respond to treatment or come back after treatment.

There is no standard staging system for childhood acute myeloid leukemia and other myelogenous malignancies.

The extent or spread of cancer is usually described as stages. Instead of stages, treatment is based on one or more of the following:

Newly diagnosed childhood AML

Newly diagnosed childhood AML is cancer that has not been treated except to relieve signs and symptoms such as fever, bleeding, or pain, and has one of the following:

  • More than 20% of the cells in the bone marrow are blasts (leukemia cells).

    or

  • Less than 20% of the cells in the bone marrow are blasts and there is a certain change in the chromosome.

Childhood AML in remission

In childhood AML in remission, the disease has been treated and the following are found:

  • The complete blood count is almost normal.
  • Less than 5% of the cells in the bone marrow are blasts (leukemia cells).
  • There are no signs or symptoms of leukemia in the brain, spinal cord, or other parts of the body.

Sometimes childhood acute myeloid leukemia and other myeloid malignancies do not respond to treatment or come back after treatment.

Refractory leukemia is cancer that does not respond to treatment.

Recurrent leukemia is cancer that has recurred (come back) after it has been treated. The cancer may come back in the blood and bone marrow or in other parts of the body, such as the central nervous system (brain and spinal cord).

Treatment Option Overview

Key Points

  • There are different types of treatment for children with acute myeloid leukemia and other myeloid malignancies.
  • Treatment is planned by a team of health care providers who are experts in treating childhood leukemia and other diseases of the blood.
  • The treatment of childhood AML and other myeloid malignancies usually has two phases.
  • Seven types of standard treatment may be used for childhood AML and other myeloid malignancies.
    • Chemotherapy
    • Radiation therapy
    • Stem cell transplant
    • Targeted therapy
    • Other drug therapy
    • Watchful waiting
    • Supportive care
  • New types of treatment are being tested in clinical trials.
  • Treatment for childhood acute myeloid leukemia and other myeloid malignancies 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 children with acute myeloid leukemia and other myeloid malignancies.

Different types of treatment are available for children with acute myeloid leukemia (AML), transient abnormal myelopoiesis (TAM), acute promyelocytic leukemia (APL), juvenile myelomonocytic leukemia (JMML), chronic myelogenous leukemia (CML), and myelodysplastic syndromes (MDS). 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.

Because AML and other myeloid disorders are rare in children, taking part in a clinical trial should be considered. Some clinical trials are open only to patients who have not yet started treatment.

Treatment is planned by a team of health care providers who are experts in treating childhood leukemia and other diseases of the blood.

Treatment will be overseen by a pediatric oncologist, a doctor who specializes in treating children with cancer. The pediatric oncologist works with other health care providers who are experts in treating children with leukemia and who specialize in certain areas of medicine. These may include the following specialists:

The treatment of childhood AML and other myeloid malignancies usually has two phases.

The treatment of childhood AML is done in phases:

Treatment called central nervous system (CNS) prophylaxis therapy may be given during the induction phase of therapy. Because standard doses of chemotherapy may not reach leukemia cells in the CNS (brain and spinal cord), the leukemia cells are able to hide in the CNS. Intrathecal chemotherapy is able to reach leukemia cells in the CNS. It is given to kill the leukemia cells and lessen the chance the leukemia will recur (come back).

The treatment of childhood APL includes a third phase called maintenance. The goal of maintenance is to kill any remaining leukemia cells that may regrow and cause a relapse. Often the cancer treatments are given in lower doses than those used during the remission induction and consolidation/intensification phases.

Seven types of standard treatment may be used for childhood AML and other myeloid malignancies.

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 chemotherapy drug.

The way the chemotherapy is given depends on the type of cancer being treated. In AML, chemotherapy given by mouth, vein, or into the cerebrospinal fluid is used.

In AML, the leukemia cells may spread to the brain and/or spinal cord. Chemotherapy given by mouth or vein to treat AML may not cross the blood-brain barrier to get into the fluid that surrounds the brain and spinal cord. Instead, chemotherapy is injected into the fluid-filled space to kill leukemia cells that may have spread there (intrathecal chemotherapy).

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.

See Drugs Approved for Acute Myeloid Leukemia for more information.

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.

In childhood AML, external radiation therapy may be used to treat a myeloid sarcoma that does not respond to chemotherapy.

Stem cell transplant

Chemotherapy is given to kill cancer cells or other abnormal blood 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 to the patient through an infusion. These reinfused stem cells grow into (and restore) the body’s blood cells.

EnlargeDonor stem cell transplant; (Panel 1): Drawing of stem cells being collected from a donor's bloodstream using an apheresis machine. Blood is removed from a vein in the donor's arm and flows through the machine where the stem cells are removed. The rest of the blood is then returned to the donor through a vein in their other arm. (Panel 2): Drawing of a health care provider giving a patient an infusion of chemotherapy through a catheter in the patient's chest. The chemotherapy is given to kill cancer cells and prepare the patient's body for the donor stem cells. (Panel 3): Drawing of a patient receiving an infusion of the donor stem cells through a catheter in the chest.
Donor stem cell transplant. (Step 1): Four to five days before donor stem cell collection, the donor receives a medicine to increase the number of stem cells circulating through their bloodstream (not shown). The blood-forming stem cells are then collected from the donor through a large vein in their arm. The blood flows through an apheresis machine that removes the stem cells. The rest of the blood is returned to the donor through a vein in their other arm. (Step 2): The patient receives chemotherapy to kill cancer cells and prepare their body for the donor stem cells. The patient may also receive radiation therapy (not shown). (Step 3): The patient receives an infusion of the donor stem 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. Types of targeted therapy include the following:

  • Tyrosine kinase inhibitor therapy: This treatment blocks the enzyme, tyrosine kinase, that causes stem cells to become more white blood cells (blasts) than the body needs. Tyrosine kinase inhibitors may be used with chemotherapy drugs as adjuvant therapy (treatment given after the initial treatment, to lower the risk that the cancer will come back).
  • 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.
    • Gemtuzumab ozogamicin is a type of monoclonal antibody that is attached to a chemotherapy drug. It is used in the treatment of AML.
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.

See Drugs Approved for Leukemia for more information.

Other drug therapy

Lenalidomide may be used to lessen the need for transfusions in patients who have myelodysplastic syndromes caused by a specific chromosome change.

Arsenic trioxide and tretinoin are drugs that kill certain types of leukemia cells, stop the leukemia cells from dividing, or help the leukemia cells mature into white blood cells. These drugs are used in the treatment of acute promyelocytic leukemia.

See Drugs Approved for Acute Myeloid Leukemia for more information.

Watchful waiting

Watchful waiting is closely monitoring a patient’s condition without giving any treatment until signs or symptoms appear or change. It is sometimes used to treat transient abnormal myelopoiesis (TAM).

Supportive care

Supportive care is given to lessen the problems caused by the disease or its treatment. All patients with leukemia receive supportive care treatments. Supportive care may include the following:

  • Transfusion therapy: A way of giving red blood cells or platelets to replace blood cells destroyed by disease or cancer treatment. The blood may be donated from another person or it may have been taken from the patient earlier and stored until needed.
  • Antifungal agents: Drugs, such as Caspofungin or fluconazole, used to prevent or treat infections caused by a fungus (a type of microorganism). This is important in the care of patients with AML.
  • Drug therapy, such as antibiotics.
  • Leukapheresis: A procedure in which a special machine is used to remove white blood cells from the blood. Blood is taken from the patient and put through a blood cell separator where the white blood cells are removed. The rest of the blood is then returned to the patient’s bloodstream. Leukapheresis is used to treat patients with very high white blood cell counts.

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.

Treatment for childhood acute myeloid leukemia and other myeloid malignancies may cause side effects.

To learn more about side effects that begin during treatment for cancer, visit Side Effects.

Regular follow-up exams are very important. Side effects from cancer treatment that begin after treatment and continue for months or years are called late effects. Late effects of cancer treatment may include the following:

  • Physical problems that affect the following:
  • Changes in mood, feelings, thinking, learning, or memory.
  • Second cancers (new types of cancer), such as breast cancer.

Some late effects may be treated or controlled. It is important that parents of children who are treated for AML or other blood diseases talk with their child’s doctors about the effects cancer treatment can have on their child. (See the PDQ summary on Late Effects of Treatment for Childhood Cancer for more information).

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 your child goes through treatment, they 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 child’s condition has changed or if the cancer has recurred (come back).

Treatment of Childhood Acute Myeloid Leukemia

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

Treatment of newly diagnosed childhood acute myeloid leukemia (AML) during the induction phase may include the following:

Treatment of childhood AML during the remission phase (consolidation/intensification therapy) depends on the subtype of AML and may include the following:

Treatment of refractory childhood AML may include the following:

  • Chemotherapy.
  • Targeted therapy with a monoclonal antibody (gemtuzumab ozogamicin).
  • Radiation therapy to treat a myeloid sarcoma that does not completely respond to chemotherapy.

Treatment of recurrent childhood AML may include the following:

  • Combination chemotherapy.
  • Targeted therapy with a monoclonal antibody (gemtuzumab ozogamicin).
  • Radiation therapy to treat locally recurring myeloid sarcoma.
  • A clinical trial of targeted therapy (midostaurin, sorafenib, or gilteritinib).
  • Combination chemotherapy and stem cell transplant, for patients who have had a second complete remission.
  • A second stem cell transplant, for patients whose disease came back after the first stem cell transplant.

Treatment of Transient Abnormal Myelopoiesis or Children with Down Syndrome and AML

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

Transient abnormal myelopoiesis (TAM) usually goes away on its own. For newly diagnosed TAM that does not go away on its own or causes other health problems, treatment may include the following:

Treatment of newly diagnosed acute myeloid leukemia (AML) in children aged 4 years or younger who have Down syndrome may include the following:

Treatment of newly diagnosed AML in children older than 4 years who have Down syndrome may be the same as treatment for children without Down syndrome.

Treatment of Childhood Acute Promyelocytic Leukemia

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

Treatment of newly diagnosed childhood acute promyelocytic leukemia (APL) may include the following:

Treatment of childhood APL during the remission phase (consolidation/intensification therapy) may include the following:

  • Tretinoin with arsenic trioxide.
  • Tretinoin plus chemotherapy with or without arsenic trioxide.

Treatment of childhood APL during the remission phase (maintenance therapy) may include the following:

Treatment of recurrent childhood APL may include the following:

Treatment of Juvenile Myelomonocytic Leukemia

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

Treatment of newly diagnosed juvenile myelomonocytic leukemia (JMML) may include the following:

Treatment of refractory or recurrent childhood JMML may include the following:

Treatment of Childhood Chronic Myelogenous Leukemia

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

Treatment of newly diagnosed chronic myelogenous leukemia (CML) may include the following:

Treatment of refractory or recurrent childhood CML may include the following:

Treatment of Childhood Myelodysplastic Syndromes

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

Treatment of newly diagnosed childhood myelodysplastic syndromes (MDS) may include the following:

If the MDS becomes acute myeloid leukemia (AML), treatment will be the same as treatment for newly diagnosed AML.

To Learn More About Childhood Acute Myeloid Leukemia and Other Myeloid Malignancies

For more information from the National Cancer Institute about childhood acute myeloid leukemia and other myeloid malignancies, see the following:

For more childhood cancer information and other general cancer resources, 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 childhood acute myeloid leukemia and other myeloid malignancies. 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 Pediatric 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® Pediatric Treatment Editorial Board. PDQ Childhood Acute Myeloid Leukemia/Other Myeloid Malignancies Treatment. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: /types/leukemia/patient/child-aml-treatment-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389303]

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.

Hairy Cell Leukemia Treatment (PDQ®)–Patient Version

Hairy Cell Leukemia Treatment (PDQ®)–Patient Version

General Information About Hairy Cell Leukemia

Go to Health Professional Version

Key Points

  • Hairy cell leukemia is a type of cancer in which the bone marrow makes too many lymphocytes (a type of white blood cell).
  • Leukemia may affect red blood cells, white blood cells, and platelets.
  • Signs and symptoms of hairy cell leukemia include infections, tiredness, and pain below the ribs.
  • Tests that examine the blood and bone marrow are used to diagnose hairy cell leukemia.
  • Certain factors affect treatment options and prognosis (chance of recovery).

Hairy cell leukemia is a type of cancer in which the bone marrow makes too many lymphocytes (a type of white blood cell).

Hairy cell leukemia is a cancer of the blood and bone marrow. This rare type of leukemia gets worse slowly or does not get worse at all. The disease is called hairy cell leukemia because the leukemia cells look “hairy” when viewed under a microscope.

EnlargeAnatomy of the bone; drawing shows spongy bone, red marrow, and yellow marrow. A cross section of the bone shows compact bone and blood vessels in the bone marrow. Also shown are red blood cells, white blood cells, platelets, and a blood stem cell.
Anatomy of the bone. The bone is made up of compact bone, spongy bone, and bone marrow. Compact bone makes up the outer layer of the bone. Spongy bone is found mostly at the ends of bones and contains red marrow. Bone marrow is found in the center of most bones and has many blood vessels. There are two types of bone marrow: red and yellow. Red marrow contains blood stem cells that can become red blood cells, white blood cells, or platelets. Yellow marrow is made mostly of fat.

Leukemia may affect red blood cells, white blood cells, and platelets.

Normally, the bone marrow makes blood stem cells (immature cells) that become mature blood cells over time. A blood stem cell may become a myeloid stem cell or a lymphoid stem cell.

A myeloid stem cell becomes one of three types of mature blood cells:

A lymphoid stem cell becomes a lymphoblast cell 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 hairy cell leukemia, too many blood stem cells become lymphocytes. These lymphocytes are abnormal and do not become healthy white blood cells. The abnormal lymphocytes are also called leukemia cells. The leukemia cells can build up in the blood and bone marrow so there is less room for healthy white blood cells, red blood cells, and platelets. This may cause infection, anemia, and easy bleeding. Some of the leukemia cells may collect in the spleen and cause it to swell.

Signs and symptoms of hairy cell leukemia include infections, tiredness, and pain below the ribs.

These and other signs and symptoms may be caused by hairy cell leukemia or by other conditions. Check with your doctor if you have:

  • Weakness or fatigue (feeling tired).
  • Frequent infections.
  • Easy bruising or bleeding.
  • Shortness of breath.
  • Pain or a feeling of fullness below the ribs.
  • Painless lumps in the neck, underarm, stomach, or groin.

Tests that examine the blood and bone marrow are used to diagnose hairy cell leukemia.

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:

  • Complete blood count (CBC): A procedure in which a sample of blood is drawn and checked for:
    • 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.
  • Peripheral blood smear: A procedure in which a sample of blood is checked for cells that look “hairy,” the number and kinds of white blood cells, the number of platelets, and changes in the shape of blood cells.
  • 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.
  • 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.
  • 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.
  • 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 leukemia.
  • 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.
  • BRAF gene testing: A laboratory test in which a sample of blood or tissue is tested for certain changes in the BRAF gene. A BRAF gene mutation is often found in patients with hairy cell leukemia.
  • 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. A CT scan of the abdomen may be done to check for swollen lymph nodes or a swollen spleen.

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

The treatment options depend on:

  • The number of hairy (leukemia) cells and healthy blood cells in the blood and bone marrow.
  • Whether the spleen is swollen.
  • Whether there are signs or symptoms of leukemia, such as infection.
  • Whether the leukemia has recurred (come back) after previous treatment.

The prognosis depends on:

  • Whether the hairy cell leukemia does not grow or grows so slowly it does not need treatment.
  • Whether the hairy cell leukemia responds to treatment.

Treatment often results in a long-lasting remission (a period during which some or all of the signs and symptoms of the leukemia are gone). If the leukemia returns after it has been in remission, re-treatment often causes another remission.

Stages of Hairy Cell Leukemia

Key Points

  • There is no standard staging system for hairy cell leukemia.
  • Sometimes hairy cell leukemia does not respond to treatment or comes back after treatment.

There is no standard staging system for hairy cell leukemia.

The process used to find out if cancer has spread to other parts of the body is called staging. There is no standard staging system for hairy cell leukemia.

In untreated hairy cell leukemia, some or all of the following conditions occur:

Sometimes hairy cell leukemia does not respond to treatment or comes back after treatment.

Refractory hairy cell leukemia is cancer that does not respond to treatment.

Recurrent hairy cell leukemia is cancer that has recurred (come back) after it has been treated.

Treatment Option Overview

Key Points

  • There are different types of treatment for patients with hairy cell leukemia.
  • The following types of treatment are used:
    • Watchful waiting
    • Chemotherapy
    • Targeted therapy
    • Surgery
  • New types of treatment are being tested in clinical trials.
  • Treatment for hairy cell leukemia 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 care may be needed.

There are different types of treatment for patients with hairy cell leukemia.

Different types of treatment are available for patients with hairy cell leukemia. 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:

Watchful waiting

Watchful waiting is closely monitoring a patient’s condition, without giving any treatment until signs or symptoms appear or change.

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). The way the chemotherapy is given depends on the type and stage of the cancer being treated. Cladribine and pentostatin are anticancer drugs commonly used to treat hairy cell leukemia. These drugs may increase the risk of other types of cancer, especially Hodgkin lymphoma and non-Hodgkin lymphoma. Long-term follow-up for second cancers is very important. Bendamustine is another anticancer drug that is being studied to treat hairy cell leukemia.

Learn more about Drugs Approved for Hairy Cell Leukemia.

Targeted therapy

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

  • Monoclonal antibody therapy: 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 is a type of monoclonal antibody that may be used to treat certain patients with hairy cell leukemia.

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.

Other types of targeted therapies are being studied in the treatment of hairy cell leukemia, including:

  • Vemurafenib, dabrafenib, and trametinib are types of kinase inhibitors that block certain proteins made by the mutated BRAF gene, which may help keep cancer cells from growing.
  • Ibrutinib is a type of targeted therapy that blocks a protein called Bruton’s tyrosine kinase (BTK), which may help keep cancer cells from growing.

Learn more about Drugs Approved for Hairy Cell Leukemia.

Surgery

Splenectomy is a surgical procedure to remove the spleen.

New types of treatment are being tested in clinical trials.

Information about clinical trials is available from the NCI website.

Treatment for hairy cell leukemia 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 care 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 Hairy Cell Leukemia

Treatment of hairy cell leukemia may include:

Learn more about these treatments in the Treatment Option Overview

You and your doctor will discuss what treatment plan is best for you.

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 Hairy Cell Leukemia

For more information from the National Cancer Institute about hairy cell leukemia, 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 hairy cell leukemia. 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 Hairy Cell Leukemia Treatment. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: /types/leukemia/patient/hairy-cell-treatment-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389248]

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.