Myelodysplastic/myeloproliferative neoplasms are a group of diseases in which the bone marrow makes too many white blood cells.
Myelodysplastic/myeloproliferative neoplasms have features of both myelodysplastic syndromes and myeloproliferative neoplasms.
There are two main types of myelodysplastic/myeloproliferative neoplasms.
Tests that examine the blood and bone marrow are used to diagnose myelodysplastic/myeloproliferative neoplasms.
Myelodysplastic/myeloproliferative neoplasms are a group of diseases in which the bone marrow makes too many white blood cells.
Myelodysplastic/myeloproliferative neoplasms are diseases of the blood and bone marrow.
EnlargeAnatomy 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.
Normally, the bone marrow makes blood stem cells (immature cells) that become mature blood cells over time. A blood stem cell may become a myeloidstem cell or a lymphoid stem cell. A lymphoid stem cell becomes a white blood cell. A myeloid stem cell becomes one of three types of mature blood cells:
EnlargeBlood cell development. A blood stem cell goes through several steps to become a red blood cell, platelet, or white blood cell.
Myelodysplastic/myeloproliferative neoplasms have features of both myelodysplastic syndromes and myeloproliferative neoplasms.
In myelodysplastic diseases, the blood stem cells do not mature into healthy red blood cells, white blood cells, or platelets. The immature blood cells, called blasts, do not work the way they should and die in the bone marrow or soon after they enter the blood. As a result, there are fewer healthy red blood cells, white blood cells, and platelets.
In myeloproliferative diseases, a greater than normal number of blood stem cells become one or more types of blood cells and the total number of blood cells slowly increases.
This summary is about neoplasms that have features of both myelodysplastic and myeloproliferative diseases. For more information about related diseases, see:
When a myelodysplastic/myeloproliferative neoplasm does not match any of these types, it is called myelodysplastic/myeloproliferative neoplasm, unclassifiable (MDS/MPN-UC).
Myelodysplastic/myeloproliferative neoplasms may progress to acute leukemia.
Tests that examine the blood and bone marrow are used to diagnose myelodysplastic/myeloproliferative neoplasms.
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). 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 blast cells, 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.
Bone marrow aspiration and biopsy: The removal of a small piece of bone and bone marrow by inserting a needle into the hipbone or breastbone. A pathologist views both the bone and bone marrow samples under a microscope to look for abnormal cells. EnlargeBone 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.
The following tests may be done on the sample of tissue that is removed:
Cytogenetic analysis: A laboratory test in which the chromosomes of cells in a sample of bone marrow or blood 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 cancer cells in myelodysplastic/myeloproliferative neoplasms do not contain the Philadelphia chromosome that is present in chronic myeloid leukemia.
Immunocytochemistry: A laboratory test that uses antibodies to check for certain antigens (markers) in a sample of a patient’s bone marrow. The antibodies are usually linked to an enzyme or a fluorescent dye. After the antibodies bind to the antigen in the sample of the patient’s bone marrow, the enzyme or dye is activated, and the antigen can then be seen under a microscope. This type of test is used to help diagnose cancer and to tell the difference between myelodysplastic/myeloproliferative neoplasms, leukemia, and other conditions.
Chronic Myelomonocytic Leukemia
Key Points
Chronic myelomonocytic leukemia is a disease in which too many myelocytes and monocytes (immature white blood cells) are made in the bone marrow.
Older age and being male increase the risk of chronic myelomonocytic leukemia.
Signs and symptoms of chronic myelomonocytic leukemia include fever, weight loss, and feeling very tired.
Certain factors affect prognosis (chance of recovery) and treatment options.
Chronic myelomonocytic leukemia is a disease in which too many myelocytes and monocytes (immature white blood cells) are made in the bone marrow.
Older age and being male increase the risk of chronic myelomonocytic leukemia.
Anything that increases a person’s chance of getting a disease is called a risk factor. Not every person with one or more of these risk factors will develop CMML, and it will develop in some people who don’t have any known risk factors. Talk with your doctor if you think you may be at risk. Risk factors for CMML include:
older age
being male
being exposed to certain substances at work or in the environment
The leukemia cells in atypical CML and CML look alike under a microscope. However, in atypical CML a certain chromosome change, called the “Philadelphia chromosome,” is not there.
Signs and symptoms of atypical chronic myeloid leukemia include easy bruising or bleeding and feeling tired and weak.
These and other signs and symptoms may be caused by atypical CML or by other conditions. Check with your doctor if you have:
shortness of breath
pale skin
tiredness and weakness
easy bruising or bleeding
petechiae (flat, pinpoint spots under the skin caused by bleeding)
pain or a feeling of fullness below the ribs on the left side
Certain factors affect prognosis (chance of recovery).
The prognosis for atypical CML depends on the number of red blood cells and platelets in the blood.
Myelodysplastic/myeloproliferative neoplasm, unclassifiable, is a disease that has features of both myelodysplastic and myeloproliferative diseases but is not chronic myelomonocytic leukemia or atypical chronic myeloid leukemia.
Signs and symptoms of myelodysplastic/myeloproliferative neoplasm, unclassifiable, include fever, weight loss, and feeling very tired.
Myelodysplastic/myeloproliferative neoplasm, unclassifiable, is a disease that has features of both myelodysplastic and myeloproliferative diseases but is not chronic myelomonocytic leukemia or atypical chronic myeloid leukemia.
In myelodysplastic/myeloproliferative neoplasm, unclassifiable (MDS/MPD-UC), the body tells too many blood stem cells to become red blood cells, white blood cells, or platelets. Some of these blood stem cells never become mature blood cells. These immature blood cells are called blasts. Over time, the abnormal blood cells and blasts in the bone marrow crowd out the healthy red blood cells, white blood cells, and platelets.
MDS/MPN-UC is a very rare disease. Because it is so rare, the factors that affect risk and prognosis are not known.
Signs and symptoms of myelodysplastic/myeloproliferative neoplasm, unclassifiable, include fever, weight loss, and feeling very tired.
These and other signs and symptoms may be caused by MDS/MPN-UC or by other conditions. Check with your doctor if you have:
petechiae (flat, pinpoint spots under the skin caused by bleeding)
pain or a feeling of fullness below the ribs
Stages of Myelodysplastic/ Myeloproliferative Neoplasms
Key Points
There is no standard staging system for myelodysplastic/myeloproliferative neoplasms.
There is no standard staging system for myelodysplastic/myeloproliferative neoplasms.
The process used to find out if cancer has spread is called staging. There is no standard staging system for myelodysplastic/myeloproliferative neoplasms. It is important to know the type of myelodysplastic/myeloproliferative neoplasm in order to plan treatment.
Treatment Option Overview
Key Points
There are different types of treatment for patients with myelodysplastic/myeloproliferative neoplasms.
The following types of treatment are used:
Watchful waiting
Chemotherapy
Other drug therapy
Stem cell transplant
Supportive care
Targeted therapy
New types of treatment are being tested in clinical trials.
Treatment for myelodysplastic/myeloproliferative neoplasms may cause side effects.
Follow-up care may be needed.
There are different types of treatment for patients with myelodysplastic/myeloproliferative neoplasms.
Different types of treatments are available for patients with myelodysplastic/myeloproliferative neoplasms. 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. It is sometimes used to treat chronic myelomonocytic leukemia in patients with no or mild symptoms.
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). Combination chemotherapy is treatment using more than one anticancer drug.
13-cis retinoic acid is a vitamin-like drug that slows the cancer’s ability to make more cancer cells and changes the way these cells look and act.
Stem cell transplant
Chemotherapy is given to kill abnormal cells or cancer cells. Healthy cells, including blood-forming cells, are also destroyed by the cancer treatment. Stem cell transplant is a treatment to replace the blood-forming cells. Stem cells (immature blood cells) are removed from the blood or bone marrow of the patient or a donor and are frozen and stored. After the patient completes chemotherapy, the stored stem cells are thawed and given back to the patient through an infusion. These reinfused stem cells grow into (and restore) the body’s blood cells.
EnlargeDonor 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.
Supportive care
Supportive care is given to lessen the problems caused by the disease or its treatment. Supportive care may include transfusion therapy or drug therapy, such as antibiotics to fight infection.
Targeted therapy
Targeted therapy is a type of treatment that uses drugs or other substances to identify and attack specific cancer cells.
Tyrosine kinase inhibitor (TKI) therapy: TKI therapy blocks signals that tumors need to grow. TKIs block the enzyme tyrosine kinase that causes stem cells to become more blood cells (blasts) than the body needs. Imatinib mesylate (Gleevec) is used to treat myelodysplastic/myeloproliferative neoplasm, unclassifiable.
New types of treatment are being tested in clinical trials.
For some people, joining a clinical trial may be an option. There are different types of clinical trials for people with cancer. For example, a treatment trial tests new treatments or new ways of using current treatments. Supportive care and palliative care trials look at ways to improve quality of life, especially for those who have side effects from cancer and its treatment.
You can use the clinical trial search to find NCI-supported cancer clinical trials accepting participants. The search allows you to filter trials based on the type of cancer, your age, and where the trials are being done. Clinical trials supported by other organizations can be found on the ClinicalTrials.gov website.
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).
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.
Use our clinical trial search to find NCI-supported cancer clinical trials that are accepting patients. You can search for trials based on the type of cancer, the age of the patient, and where the trials are being done. General information about clinical trials is also available.
Treatment of Myelodysplastic/ Myeloproliferative Neoplasm, Unclassifiable
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 Myelodysplastic/ Myeloproliferative Neoplasms
For more information from the National Cancer Institute about myelodysplastic/myeloproliferative neoplasms, visit:
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Purpose of This Summary
This PDQ cancer information summary has current information about the treatment of myelodysplastic/ myeloproliferative neoplasms. 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
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The information in this patient summary was taken from the health professional version, which is reviewed regularly and updated as needed, by the PDQ Adult Treatment Editorial Board.
Clinical Trial Information
A clinical trial is a study to answer a scientific question, such as whether one treatment is better than another. Trials are based on past studies and what has been learned in the laboratory. Each trial answers certain scientific questions in order to find new and better ways to help cancer patients. During treatment clinical trials, information is collected about the effects of a new treatment and how well it works. If a clinical trial shows that a new treatment is better than one currently being used, the new treatment may become “standard.” Patients may want to think about taking part in a clinical trial. Some clinical trials are open only to patients who have not started treatment.
Clinical trials can be found online at NCI’s website. For more information, call the Cancer Information Service (CIS), NCI’s contact center, at 1-800-4-CANCER (1-800-422-6237).
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PDQ® Adult Treatment Editorial Board. PDQ Myelodysplastic/ Myeloproliferative Neoplasms Treatment. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: /types/myeloproliferative/patient/mds-mpd-treatment-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389360]
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The myelodysplastic/myeloproliferative neoplasms (MDS/MPN) are clonal myeloid disorders that have both dysplastic and proliferative features but are not properly classified as either myelodysplastic syndromes (MDS) or chronic myeloproliferative disorders (CMPD).[1–3] This category includes three major myeloid disorders: chronic myelomonocytic leukemia (CMML), juvenile myelomonocytic leukemia (JMML), and atypical chronic myeloid leukemia (aCML). Myeloid disease that shows features of both MDS and CMPD but does not meet the criteria for any of the three major MDS/MPN entities is designated as myelodysplastic/myeloproliferative neoplasm, unclassifiable (MDS/MPN-UC). The World Health Organization created the MDS/MPN category to provide a less restrictive view of myeloid disorders, which in some instances clearly overlap.[1–3]
Incidence and Mortality
The etiology of MDS/MPN is not known. The incidence of MDS/MPN varies widely, ranging from approximately 3 per 100,000 individuals older than 60 years annually for CMML to as few as 0.13 per 100,000 children from birth to 14 years annually for JMML.[4] Reliable data concerning the incidence of aCML, a recently defined entity, are not available. The incidence of MDS/MPN-UC is unknown.
Histopathology
The pathophysiology of MDS/MPN involves abnormalities in the regulation of myeloid pathways for cellular proliferation, maturation, and survival. Clinical symptoms result from the following complications:[5]
Cytopenia(s).
Dysplastic cells that function abnormally.
Leukemic infiltration of various organ systems, especially the spleen and liver.
General constitutional symptoms, such as fever and malaise.
Patients with MDS/MPN do not have a Philadelphia chromosome or a BCR::ABL1 gene fusion.
An international consortium has proposed uniform response criteria to be used in clinical trials because of the spectrum of presentations ranging from the myelodysplastic to the myeloproliferative.[6]
References
Arber DA, Orazi A, Hasserjian R, et al.: The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood 127 (20): 2391-405, 2016. [PUBMED Abstract]
Vardiman JW, Thiele J, Arber DA, et al.: The 2008 revision of the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia: rationale and important changes. Blood 114 (5): 937-51, 2009. [PUBMED Abstract]
Loghavi S, Sui D, Wei P, et al.: Validation of the 2017 revision of the WHO chronic myelomonocytic leukemia categories. Blood Adv 2 (15): 1807-1816, 2018. [PUBMED Abstract]
Vardiman JW, Harris NL, Brunning RD: The World Health Organization (WHO) classification of the myeloid neoplasms. Blood 100 (7): 2292-302, 2002. [PUBMED Abstract]
Bain BJ: The relationship between the myelodysplastic syndromes and the myeloproliferative disorders. Leuk Lymphoma 34 (5-6): 443-9, 1999. [PUBMED Abstract]
Savona MR, Malcovati L, Komrokji R, et al.: An international consortium proposal of uniform response criteria for myelodysplastic/myeloproliferative neoplasms (MDS/MPN) in adults. Blood 125 (12): 1857-65, 2015. [PUBMED Abstract]
Treatment of Chronic Myelomonocytic Leukemia
Disease Overview
The World Health Organization (WHO) classifies chronic myelomonocytic leukemia (CMML) as a myelodysplastic/myeloproliferative neoplasm (MDS/MPN).[1] The WHO recognizes a dysplastic subtype and a proliferative subtype, with prognostic groups differentiated by the circulating white blood cell (WBC) count or the percentage of blasts in the bone marrow (higher percentage with worse prognosis).[2]
CMML is a clonal disorder of a bone marrow stem cell. Monocytosis is a major defining feature. CMML exhibits heterogenous clinical, hematological, and morphological features, varying from predominantly myelodysplastic to predominantly myeloproliferative. Evolution to acute myeloid leukemia (AML) portends a particularly poor prognosis.[3]
Persistent monocytosis is greater than 1 × 109/L in the peripheral blood.
No Philadelphia chromosome or BCR::ABL1 gene fusion.
No PDGFRA and PDGFRB rearrangement.
Fewer than 20% blasts in the blood or bone marrow (including monoblasts/promonocytes).
Dysplasia involving one or more myeloid lineages or, if myelodysplasia is absent or minimal, either an acquired clonal cytogenetic bone marrow abnormality or at least 3 months of persistent peripheral blood monocytosis, if all other causes are ruled out.
In patients with a WBC count that is within reference range or slightly decreased, clinical features may be identical to MDS.
In patients with elevated WBC count, features are more like chronic myeloproliferative disorders, including more frequent splenomegaly and hepatomegaly.
The median age at diagnosis of CMML is 65 to 75 years with a male predominance of 1.5 to 3.1.[4,5] Because CMML is grouped with chronic myeloid leukemia in some epidemiologic surveys and with MDS in others, no reliable incidence data are available for CMML.[6] Although the specific etiology of CMML is unknown, exposure to occupational and environmental carcinogens, ionizing radiation, and cytotoxic agents has been associated in some cases.[6]
Morphologically, the disease is characterized by a persistent peripheral blood monocytosis (always >1 × 109/L) that may exceed 80 × 109/L with monocytes typically accounting for more than 10% of the WBCs.[4,5] Monocytes, though typically mature with an unremarkable morphology, can exhibit abnormal granulation, unusual nuclear lobation, or finely dispersed nuclear chromatin.[7] Fewer than 20% blasts are seen in the blood or bone marrow. Neutrophilia occurs in nearly 50% of patients with neutrophil precursors (e.g., promyelocytes and myelocytes) accounting for more than 10% of the WBCs.[8] Mild normocytic anemia is common. Moderate thrombocytopenia is often present. Bone marrow findings include:[4,5,9,10]
Micromegakaryocytes and/or megakaryocytes with abnormally lobated nuclei (as many as 80% of the cases).
Fibrosis (30% of the cases).
Hepatosplenomegaly may be present.[4,5] Autoimmune phenomena, including pyoderma gangrenosum, vasculitis, and idiopathic thrombocytopenia have been observed in CMML.[11] Care should be taken to identify cases of CMML with eosinophilia, a subtype of CMML, because of its association with severe tissue damage secondary to eosinophil degranulation. In CMML with eosinophilia, all criteria for CMML are present, and the eosinophil count in the peripheral blood is more than 1.5 × 109/L.[6]
Recurrent somatic pathogenic variants have been identified in most patients with CMML, resulting in altered signaling molecules (especially NRAS, KRAS, JAK2, and SETBP1), epigenetic regulators (especially TET2 and ASXL1), splicing factors (especially SRSF2), and transcription factors (especially RUNX1).[12–15] A CMML-specific prognostic scoring system can distinguish four risk groups based on the following factors:[16]
Red blood cell transfusion dependency.
WBC count at least 13 × 109/L.
Bone marrow blasts at least 5%.
Genetic risk group based on cytogenetics (trisomy 8, ≥3 abnormalities on karyotype, or chromosome 7 abnormalities are high risk), and pathogenic variants in ASXL1, NRAS, RUNX1, or SETBP1.
The best prognostic group has a median survival of more than 10 years with no leukemic evolution in the first decade of follow-up. The worst prognostic group has a median survival of 20 months with a 50% evolution to AML by 2 years.[16]
Prognostic factors associated with shorter survival include:[17,18]
Low hemoglobin level.
Low platelet count; high WBC, monocyte, and lymphocyte counts.
Presence of circulating immature myeloid cells.
High percentage of marrow blasts.
Low percentage of marrow erythroid cells.
Abnormal molecular genetic data.
High levels of serum lactate dehydrogenase and beta-2-microglobulin.
Progression to acute leukemia occurs in approximately 15% to 20% of cases.[17,18]
CPSS-Mol is a CMML-specific prognostic scoring system that incorporates molecular genetic data, especially pathogenic variants in RUNX1, NRAS, SETBP1, and ASXL1. This system distinguishes low-risk disease with median survivals longer than 10 years from high-risk disease with median survivals of 2 to 4 years.[16]
Treatment Overview
CMML is a diagnosis typically made after age 70 years. The clinical course of CMML ranges from indolent or smoldering disease to an aggressive disease progression culminating in severe cytopenias or evolution to acute leukemia. Assessment of the risk factors and the pace of disease over time may help to distinguish patients who require therapy from those who would be best managed with a watchful waiting approach. Asymptomatic patients at low risk of progression may be best served by forgoing therapy.[19,20]
Allogeneic stem cell transplant (SCT)
Patients with high-risk disease who are young enough and fit enough may undergo allogeneic SCT. This represents the only potential cure for CMML. Hypomethylating agents like azacitidine and decitabine are usually given prior to allogeneic SCT for cytoreduction or to ameliorate cytopenias.[21,22] Retrospective reports that included small numbers of patients with CMML (range, 12–80) who underwent allogeneic SCT reported recurrence rates of 20% to 40% and 5-year overall survival (OS) rates of approximately 20% to 30%.[23–28][Level of evidence C3]
A retrospective review of 1,114 patients with CMML diagnosed between 2000 and 2014 included 384 patients who underwent allogeneic SCT.[29] With a median follow-up of 51 to 78 months (in two data sets), allogeneic SCT in patients with low-risk CMML was detrimental, with a 5-year OS rates of 20% for patients who underwent allogeneic SCT and 42% for patients who did not undergo allogeneic SCT (P < .001).[29][Level of evidence C1] For patients with high-risk CMML, there was no statistically significant difference in 5-year OS rates among patients treated with or without allogeneic SCT (27% vs. 15%, respectively; P = .13).
Hypomethylating agents
Two randomized prospective clinical trials compared the hypomethylating agent, azacitidine, with best supportive care in patients with myelodysplastic syndromes (MDS). The trials involved large numbers of patients with MDS but also included small numbers of patients (fewer than 25) with CMML.[30,31] The overall response rates exceeded 60% for all patients who received azacitidine, but the data did not allow an assessment specifically for patients with CMML.[30,31][Level of evidence C3] Several phase II trials reported response rates of 30% to 60% for patients with CMML who received hypomethylating agents.[32–36] Azacitidine and decitabine may reverse cytopenias, cytoreduce elevated WBC counts, reduce splenic size, and improve clinical symptoms (like decreased appetite or itching).
Hydroxyurea
Hydroxyurea has been given for other diseases with chronic myeloproliferation, such as thrombocythemia and myelofibrosis. These applications suggest the use of hydroxyurea for CMML with leukocytosis, thrombocytosis, or splenomegaly.[37] In a randomized prospective clinical trial of 105 patients with CMML, hydroxyurea (up to 4 g/day) was compared with etoposide.[38] With a median follow-up of 11 months, the median OS was 20 months in patients who received hydroxyurea and 9 months in patients who received etoposide (P < .0001).[38][Level of evidence A1]
Hypomethylating agent versus hydroxyurea
In a prospective randomized trial, 170 patients with newly diagnosed advanced CMML received intravenous decitabine or hydroxyurea (1–4 g/day). With a median follow-up of 17.5 months, there was no statistically significant difference in event-free survival (12.1 months for patients who received decitabine and 10.3 months for patients who received hydroxyurea; hazard ratio, 0.83; 95% confidence interval [CI], 0.59–1.16; P = .27). There was also no statistically significant difference in median OS (16.3 months for patients who received decitabine and 21.9 months for patients who received hydroxyurea; P = .67).[39][Level of evidence A1] Although decitabine reduced CMML progression or transformation to AML by 38% compared with hydroxyurea, this was offset by a 55% increase in deaths that were not caused by progression (the deaths were usually related to infection). There are no data to suggest that systematic antibiotic prophylaxis would have helped the patients who received decitabine.
Other regimens
In a phase II trial, 13 hypomethylating agent–naive patients with high-risk CMML were treated with azacitidine or decitabine plus venetoclax. With a median follow-up of 14.1 months, the overall response rate was 85% (11 of 13 patients), including two with complete response and a median duration of response of 17.9 months.[40,41][Level of evidence C3] Six of these patients underwent subsequent allogeneic SCT.
A retrospective study included 21 patients with high-risk CMML who received cladribine plus low-dose cytarabine alternating with azacitidine or decitabine. The patients had an objective response rate of 33% (50% in patients with hypomethylating agent–naive CMML and 23% in patients with hypomethylating agent–failure CMML).[41][Level of evidence C3]
A phase I/II study of 23 patients with mostly high-risk MDS and greater than 5% marrow blast cells involved 10 patients with CMML. All patients received azacitidine plus venetoclax. With a median follow-up of 13.2 months, the overall response rate was 87% (95% CI, 66%–97%).[42][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
Orazi A, Germing U: The myelodysplastic/myeloproliferative neoplasms: myeloproliferative diseases with dysplastic features. Leukemia 22 (7): 1308-19, 2008. [PUBMED Abstract]
Arber DA, Orazi A, Hasserjian R, et al.: The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood 127 (20): 2391-405, 2016. [PUBMED Abstract]
Germing U, Strupp C, Knipp S, et al.: Chronic myelomonocytic leukemia in the light of the WHO proposals. Haematologica 92 (7): 974-7, 2007. [PUBMED Abstract]
Aul C, Bowen DT, Yoshida Y: Pathogenesis, etiology and epidemiology of myelodysplastic syndromes. Haematologica 83 (1): 71-86, 1998. [PUBMED Abstract]
Kouides PA, Bennett JM: Morphology and classification of the myelodysplastic syndromes and their pathologic variants. Semin Hematol 33 (2): 95-110, 1996. [PUBMED Abstract]
Bennett JM, Catovsky D, Daniel MT, et al.: The chronic myeloid leukaemias: guidelines for distinguishing chronic granulocytic, atypical chronic myeloid, and chronic myelomonocytic leukaemia. Proposals by the French-American-British Cooperative Leukaemia Group. Br J Haematol 87 (4): 746-54, 1994. [PUBMED Abstract]
Maschek H, Georgii A, Kaloutsi V, et al.: Myelofibrosis in primary myelodysplastic syndromes: a retrospective study of 352 patients. Eur J Haematol 48 (4): 208-14, 1992. [PUBMED Abstract]
Saif MW, Hopkins JL, Gore SD: Autoimmune phenomena in patients with myelodysplastic syndromes and chronic myelomonocytic leukemia. Leuk Lymphoma 43 (11): 2083-92, 2002. [PUBMED Abstract]
Meggendorfer M, Roller A, Haferlach T, et al.: SRSF2 mutations in 275 cases with chronic myelomonocytic leukemia (CMML). Blood 120 (15): 3080-8, 2012. [PUBMED Abstract]
Kosmider O, Gelsi-Boyer V, Ciudad M, et al.: TET2 gene mutation is a frequent and adverse event in chronic myelomonocytic leukemia. Haematologica 94 (12): 1676-81, 2009. [PUBMED Abstract]
Malcovati L, Papaemmanuil E, Ambaglio I, et al.: Driver somatic mutations identify distinct disease entities within myeloid neoplasms with myelodysplasia. Blood 124 (9): 1513-21, 2014. [PUBMED Abstract]
Patnaik MM, Itzykson R, Lasho TL, et al.: ASXL1 and SETBP1 mutations and their prognostic contribution in chronic myelomonocytic leukemia: a two-center study of 466 patients. Leukemia 28 (11): 2206-12, 2014. [PUBMED Abstract]
Elena C, Gallì A, Such E, et al.: Integrating clinical features and genetic lesions in the risk assessment of patients with chronic myelomonocytic leukemia. Blood 128 (10): 1408-17, 2016. [PUBMED Abstract]
Onida F, Kantarjian HM, Smith TL, et al.: Prognostic factors and scoring systems in chronic myelomonocytic leukemia: a retrospective analysis of 213 patients. Blood 99 (3): 840-9, 2002. [PUBMED Abstract]
Germing U, Kündgen A, Gattermann N: Risk assessment in chronic myelomonocytic leukemia (CMML). Leuk Lymphoma 45 (7): 1311-8, 2004. [PUBMED Abstract]
Hunter AM, Zhang L, Padron E: Current Management and Recent Advances in the Treatment of Chronic Myelomonocytic Leukemia. Curr Treat Options Oncol 19 (12): 67, 2018. [PUBMED Abstract]
Patnaik MM, Tefferi A: Chronic Myelomonocytic leukemia: 2020 update on diagnosis, risk stratification and management. Am J Hematol 95 (1): 97-115, 2020. [PUBMED Abstract]
Kongtim P, Popat U, Jimenez A, et al.: Treatment with Hypomethylating Agents before Allogeneic Stem Cell Transplant Improves Progression-Free Survival for Patients with Chronic Myelomonocytic Leukemia. Biol Blood Marrow Transplant 22 (1): 47-53, 2016. [PUBMED Abstract]
Sekeres MA, Othus M, List AF, et al.: Randomized Phase II Study of Azacitidine Alone or in Combination With Lenalidomide or With Vorinostat in Higher-Risk Myelodysplastic Syndromes and Chronic Myelomonocytic Leukemia: North American Intergroup Study SWOG S1117. J Clin Oncol 35 (24): 2745-2753, 2017. [PUBMED Abstract]
Elliott MA, Tefferi A, Hogan WJ, et al.: Allogeneic stem cell transplantation and donor lymphocyte infusions for chronic myelomonocytic leukemia. Bone Marrow Transplant 37 (11): 1003-8, 2006. [PUBMED Abstract]
Ocheni S, Kröger N, Zabelina T, et al.: Outcome of allo-SCT for chronic myelomonocytic leukemia. Bone Marrow Transplant 43 (8): 659-61, 2009. [PUBMED Abstract]
Krishnamurthy P, Lim ZY, Nagi W, et al.: Allogeneic haematopoietic SCT for chronic myelomonocytic leukaemia: a single-centre experience. Bone Marrow Transplant 45 (10): 1502-7, 2010. [PUBMED Abstract]
Eissa H, Gooley TA, Sorror ML, et al.: Allogeneic hematopoietic cell transplantation for chronic myelomonocytic leukemia: relapse-free survival is determined by karyotype and comorbidities. Biol Blood Marrow Transplant 17 (6): 908-15, 2011. [PUBMED Abstract]
Park S, Labopin M, Yakoub-Agha I, et al.: Allogeneic stem cell transplantation for chronic myelomonocytic leukemia: a report from the Societe Francaise de Greffe de Moelle et de Therapie Cellulaire. Eur J Haematol 90 (5): 355-64, 2013. [PUBMED Abstract]
Symeonidis A, van Biezen A, de Wreede L, et al.: Achievement of complete remission predicts outcome of allogeneic haematopoietic stem cell transplantation in patients with chronic myelomonocytic leukaemia. A study of the Chronic Malignancies Working Party of the European Group for Blood and Marrow Transplantation. Br J Haematol 171 (2): 239-246, 2015. [PUBMED Abstract]
Robin M, de Wreede LC, Padron E, et al.: Role of allogeneic transplantation in chronic myelomonocytic leukemia: an international collaborative analysis. Blood 140 (12): 1408-1418, 2022. [PUBMED Abstract]
Silverman LR, Demakos EP, Peterson BL, et al.: Randomized controlled trial of azacitidine in patients with the myelodysplastic syndrome: a study of the cancer and leukemia group B. J Clin Oncol 20 (10): 2429-40, 2002. [PUBMED Abstract]
Fenaux P, Mufti GJ, Hellstrom-Lindberg E, et al.: Efficacy of azacitidine compared with that of conventional care regimens in the treatment of higher-risk myelodysplastic syndromes: a randomised, open-label, phase III study. Lancet Oncol 10 (3): 223-32, 2009. [PUBMED Abstract]
Braun T, Itzykson R, Renneville A, et al.: Molecular predictors of response to decitabine in advanced chronic myelomonocytic leukemia: a phase 2 trial. Blood 118 (14): 3824-31, 2011. [PUBMED Abstract]
Drummond MW, Pocock C, Boissinot M, et al.: A multi-centre phase 2 study of azacitidine in chronic myelomonocytic leukaemia. Leukemia 28 (7): 1570-2, 2014. [PUBMED Abstract]
Tantravahi SK, Szankasi P, Khorashad JS, et al.: A phase II study of the efficacy, safety, and determinants of response to 5-azacitidine (Vidaza®) in patients with chronic myelomonocytic leukemia. Leuk Lymphoma 57 (10): 2441-4, 2016. [PUBMED Abstract]
Santini V, Allione B, Zini G, et al.: A phase II, multicentre trial of decitabine in higher-risk chronic myelomonocytic leukemia. Leukemia 32 (2): 413-418, 2018. [PUBMED Abstract]
Coston T, Pophali P, Vallapureddy R, et al.: Suboptimal response rates to hypomethylating agent therapy in chronic myelomonocytic leukemia; a single institutional study of 121 patients. Am J Hematol 94 (7): 767-779, 2019. [PUBMED Abstract]
Wattel E, Guerci A, Hecquet B, et al.: A randomized trial of hydroxyurea versus VP16 in adult chronic myelomonocytic leukemia. Groupe Français des Myélodysplasies and European CMML Group. Blood 88 (7): 2480-7, 1996. [PUBMED Abstract]
Itzykson R, Santini V, Thepot S, et al.: Decitabine Versus Hydroxyurea for Advanced Proliferative Chronic Myelomonocytic Leukemia: Results of a Randomized Phase III Trial Within the EMSCO Network. J Clin Oncol 41 (10): 1888-1897, 2023. [PUBMED Abstract]
Montalban-Bravo G, Hammond D, DiNardo CD, et al.: Activity of venetoclax-based therapy in chronic myelomonocytic leukemia. Leukemia 35 (5): 1494-1499, 2021. [PUBMED Abstract]
Bazinet A, Darbaniyan F, Kadia TM, et al.: A retrospective study of cladribine and low-dose cytarabine-based regimens for the treatment of chronic myelomonocytic leukemia and secondary acute myeloid leukemia. Cancer 129 (4): 560-568, 2023. [PUBMED Abstract]
Bazinet A, Darbaniyan F, Jabbour E, et al.: Azacitidine plus venetoclax in patients with high-risk myelodysplastic syndromes or chronic myelomonocytic leukaemia: phase 1 results of a single-centre, dose-escalation, dose-expansion, phase 1-2 study. Lancet Haematol 9 (10): e756-e765, 2022. [PUBMED Abstract]
Atypical chronic myeloid leukemia (aCML) is a leukemic disorder that exhibits both myelodysplastic and myeloproliferative features at the time of diagnosis.
Atypical CML is characterized pathologically by:[1]
Peripheral blood leukocytosis with increased numbers of mature and immature neutrophils.
Prominent dysgranulopoiesis.
No Philadelphia chromosome or BCR::ABL1 gene fusion.
Neutrophil precursors (e.g., promyelocytes, myelocytes, and metamyelocytes) accounting for more than 10% of white blood cells.
Minimal absolute basophilia with basophils accounting for less than 2% of white blood cells.
Absolute monocytosis with monocytes typically account for less than 10% of white blood cells.
Hypercellular bone marrow with granulocytic proliferation and granulocytic dysplasia.
Fewer than 20% blasts in the blood or bone marrow.
Anemia. For more information on anemia, see Fatigue.
Thrombocytopenia.
Splenomegaly (in 75% of cases).
Although cytogenetic abnormalities are found in as many as 80% of the patients with aCML, none is specific.[1–3,5] No Philadelphia chromosome or BCR::ABL1 gene fusion is present.
The exact incidence of aCML is unknown. The median age at the time of diagnosis of this rare leukemic disorder is in the seventh or eighth decade of life.[1–3]
Morphologically, aCML is characterized by myelodysplasia associated with bone marrow and peripheral blood patterns similar to chronic myeloid leukemia, but cytogenetically it lacks a Philadelphia chromosome or BCR::ABL1 gene fusion.[1] The white blood cell count in the peripheral blood is variable. Median values range from 35 × 109/L to 96 × 109/L, and some patients may have white blood cell counts greater than 300 × 109/L.[1–3,5] Blasts in the peripheral blood typically account for less than 5% of the white blood cells. Immature neutrophils usually total 10% to 20% or more.[1] The percentage of monocytes is rarely more than 10%. Minimal basophilia may be present.[1–3,5] Nuclear abnormalities, such as acquired Pelger-Huët anomaly, may be seen in the neutrophils. Moderate anemia (often showing changes indicative of dyserythropoiesis) and thrombocytopenia are common.[1–4] Bone marrow findings include: [1–3,5]
Granulocytic hypercellularity.
Blast count less than 20%.
Dysgranulopoiesis
Megakaryocytic dysplasia.
Erythroid precursors accounting for more than 30% of marrow cells with dyserythropoiesis present (in some cases).
The median survival times for aCML are reported to be less than 20 months, and thrombocytopenia and marked anemia are poor prognostic factors.[1,2] Atypical CML evolves to acute leukemia in approximately 25% to 40% of patients.[1,3] In the remaining patients, fatal complications include resistant leukocytosis, anemia, thrombocytopenia, hepatosplenomegaly, cerebral bleeding associated with thrombocytopenia, and infection.[3,4]
Treatment Overview
The optimal treatment of aCML is uncertain because of the rare incidence of this chronic leukemic disorder. Treatment with hydroxyurea may lead to short-lived partial remissions of 2 to 4 months in duration.[4] Atypical CML appears to respond poorly to treatment with interferon alfa.[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
Orazi A, Germing U: The myelodysplastic/myeloproliferative neoplasms: myeloproliferative diseases with dysplastic features. Leukemia 22 (7): 1308-19, 2008. [PUBMED Abstract]
Hernández JM, del Cañizo MC, Cuneo A, et al.: Clinical, hematological and cytogenetic characteristics of atypical chronic myeloid leukemia. Ann Oncol 11 (4): 441-4, 2000. [PUBMED Abstract]
Costello R, Sainty D, Lafage-Pochitaloff M, et al.: Clinical and biological aspects of Philadelphia-negative/BCR-negative chronic myeloid leukemia. Leuk Lymphoma 25 (3-4): 225-32, 1997. [PUBMED Abstract]
Bennett JM, Catovsky D, Daniel MT, et al.: The chronic myeloid leukaemias: guidelines for distinguishing chronic granulocytic, atypical chronic myeloid, and chronic myelomonocytic leukaemia. Proposals by the French-American-British Cooperative Leukaemia Group. Br J Haematol 87 (4): 746-54, 1994. [PUBMED Abstract]
Treatment of MDS/MPN, Unclassifiable
Disease Overview
Myelodysplastic/myeloproliferative neoplasm, unclassifiable (MDS/MPN-UC) (also known as mixed myeloproliferative/myelodysplastic syndrome, unclassifiable and overlap syndrome, unclassifiable) shows features of both myeloproliferative disease and myelodysplastic disease but does not meet the criteria for any of the other MDS/MPN entities.[1]
Diagnostic criteria for MDS/MPN-UC can be either:[1]
The combination of four sets of criteria (a–d):
Clinical, laboratory, and morphological features of myelodysplastic syndrome (MDS) (e.g., refractory anemia, refractory anemia with ringed sideroblasts, refractory cytopenia with multilineage dysplasia, and refractory anemia with excess of blasts) with fewer than 20% blasts in the blood and bone marrow. For more information on anemia, see Fatigue.
Prominent myeloproliferative features, e.g. platelet count greater than 600 × 109/L associated with megakaryocytic proliferation, or white blood cell count greater than 13.0 × 109/L with or without splenomegaly.
No history of an underlying chronic myeloproliferative disorder (CMPD), MDS, or recent cytotoxic or growth factor therapy that could cause the myelodysplastic or myeloproliferative features.
No Philadelphia chromosome or BCR::ABL1 gene fusion, del(5q), t(3;3)(q21;q26), or inv(3)(q21q26).
Mixed myeloproliferative and myelodysplastic features that cannot be assigned to any other category of MDS, CMPD, or MDS/MPN.
Clinical characteristics of MDS/MPN-UC include:
Features of both MDS and CMPD.
Hepatomegaly.
Splenomegaly.
The incidence and etiology of MDS/MPN-UC are unknown.
Laboratory features typically include anemia and dimorphic erythrocytes on the peripheral blood smear.[1] Thrombocytosis (platelet count >600 × 109/L) or leukocytosis (white blood cell count >13 × 109/L) are present. Neutrophils may exhibit dysplastic features, and giant or hypogranular platelets may be present. Blasts make up less than 20% of the white blood cells and of the nucleated cells of the bone marrow. The bone marrow is hypercellular and may exhibit proliferation in any or all of the myeloid lineages. Dysplastic features are present in at least one cell line.[1]
No cytogenetic or molecular findings are available that are specific for MDS/MPN-UC. In one small series, six of nine patients (those with ringed sideroblasts associated with marked thrombocytosis [RARS-T]) had JAK2 V617F variants, which caused constitutive activation of the JAK2 tyrosine kinase. This JAK2 pathogenic variant is also commonly observed in patients with polycythemia vera, essential thrombocythemia, and idiopathic myelofibrosis.[2] Because of its rare occurrence, the prognosis and predictive factors are unknown.[1]
Treatment Overview
Adult patients with MDS/MPN associated with platelet-derived growth factor receptor gene rearrangements are candidates for imatinib mesylate at standard dosages.[3] Because of its rare occurrence, the literature only minimally addresses other treatment options for MDS/MPN-UC. Supportive care involves treating cytopenias and infection as necessary.
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
Orazi A, Germing U: The myelodysplastic/myeloproliferative neoplasms: myeloproliferative diseases with dysplastic features. Leukemia 22 (7): 1308-19, 2008. [PUBMED Abstract]
Szpurka H, Tiu R, Murugesan G, et al.: Refractory anemia with ringed sideroblasts associated with marked thrombocytosis (RARS-T), another myeloproliferative condition characterized by JAK2 V617F mutation. Blood 108 (7): 2173-81, 2006. [PUBMED Abstract]
GLEEVEC – imatinib mesylate tablet. Novartis Pharmaceuticals Corporation, 2020. Available online. Last accessed February 18, 2025.
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.
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 myelodysplastic/myeloproliferative neoplasms. 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:
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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 Myelodysplastic/Myeloproliferative Neoplasms Treatment are:
Aaron Gerds, MD (Cleveland Clinic Taussig Cancer Institute)
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.
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The preferred citation for this PDQ summary is:
PDQ® Adult Treatment Editorial Board. PDQ Myelodysplastic/Myeloproliferative Neoplasms Treatment. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: /types/myeloproliferative/hp/mds-mpd-treatment-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389321]
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EnlargeAnatomy 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.
A blood stem cell may become a lymphoidstem cell or a myeloid stem cell. A lymphoid stem cell becomes a white blood cell. A myeloid stem cell becomes one of three types of mature blood cells:
EnlargeBlood cell development. A blood stem cell goes through several steps to become a red blood cell, platelet, or white blood cell.
In a patient with a myelodysplastic syndrome, the blood stem cells (immature cells) do not become mature red blood cells, white blood cells, or platelets in the bone marrow. These immature blood cells, called blasts, do not work the way they should and either die in the bone marrow or soon after they go into the blood. This leaves less room for healthy white blood cells, red blood cells, and platelets to form in the bone marrow. When there are fewer healthy blood cells, infection, anemia, or easy bleeding may occur.
The different types of myelodysplastic syndromes are diagnosed based on certain changes in the blood cells and bone marrow.
Refractory anemia: There are too few red blood cells in the blood and the patient has anemia. The number of white blood cells and platelets is normal.
Refractory anemia with ring sideroblasts: There are too few red blood cells in the blood and the patient has anemia. The red blood cells have too much iron inside the cell. The number of white blood cells and platelets is normal.
Refractory anemia with excess blasts: There are too few red blood cells in the blood and the patient has anemia. Five percent to 19% of the cells in the bone marrow are blasts. There also may be changes to the white blood cells and platelets. Refractory anemia with excess blasts may progress to acute myeloid leukemia (AML). For more information, see Acute Myeloid Leukemia Treatment.
Refractory cytopenia with multilineage dysplasia: There are too few of at least two types of blood cells (red blood cells, platelets, or white blood cells). Less than 5% of the cells in the bone marrow are blasts and less than 1% of the cells in the blood are blasts. If red blood cells are affected, they may have extra iron. Refractory cytopenia may progress to acute myeloid leukemia (AML).
Refractory cytopenia with unilineage dysplasia: There are too few of one type of blood cell (red blood cells, platelets, or white blood cells). There are changes in 10% or more of two other types of blood cells. Less than 5% of the cells in the bone marrow are blasts and less than 1% of the cells in the blood are blasts.
Unclassifiable myelodysplastic syndrome: The numbers of blasts in the bone marrow and blood are normal, and the disease is not one of the other myelodysplastic syndromes.
Myelodysplastic syndrome associated with an isolated del(5q) chromosome abnormality: There are too few red blood cells in the blood and the patient has anemia. Less than 5% of the cells in the bone marrow and blood are blasts. There is a specific change in the chromosome.
Age and past treatment with chemotherapy or radiation therapy affect the risk of a myelodysplastic syndrome.
Anything that increases a person’s chance of getting a disease is called a risk factor. Not every person with one or more of these risk factors will develop myelodysplastic syndromes, and they will develop in people who don’t have any known risk factors. Talk with your doctor if you think you may be at risk. Risk factors for myelodysplastic syndromes include the following:
Being exposed to heavy metals, such as mercury or lead.
The cause of myelodysplastic syndromes in most patients is not known.
Signs and symptoms of a myelodysplastic syndrome include shortness of breath and feeling tired.
Myelodysplastic syndromes often do not cause early signs or symptoms. They may be found during a routine blood test. Signs and symptoms may be caused by myelodysplastic syndromes or by other conditions. Check with your doctor if you have any of the following:
Shortness of breath.
Weakness or feeling tired.
Having skin that is paler than usual.
Easy bruising or bleeding.
Petechiae (flat, pinpoint spots under the skin caused by bleeding).
Tests that examine the blood and bone marrow are used to diagnose myelodysplastic syndromes.
The amount of hemoglobin (the protein that carries oxygen) in the red blood cells.
The portion of the blood sample made up of red blood cells.
EnlargeComplete blood count (CBC). 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 changes in the number, type, shape, and size of blood cells and for too much iron in the red blood cells.
Cytogenetic analysis: A laboratory test in which the chromosomes of cells in a sample of bone marrow or blood 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.
Blood chemistry studies: A procedure in which a blood sample is checked to measure the amounts of certain substances, such as vitamin B12 and folate, 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.
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 abnormal cells. EnlargeBone 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.
The following tests may be done on the sample of tissue that is removed:
Immunocytochemistry: A laboratory test that uses antibodies to check for certain antigens (markers) in a sample of a patient’s bone marrow. The antibodies are usually linked to an enzyme or a fluorescent dye. After the antibodies bind to the antigen in the sample of the patient’s cells, the enzyme or dye is activated, and the antigen can then be seen under a microscope. This type of test is used to help diagnose cancer and to tell the difference between myelodysplastic syndromes, leukemia, and other conditions.
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 and other blood disorders.
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.
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.
Certain factors affect prognosis (chance of recovery) and treatment options.
The prognosis and treatment options depend on the following:
The number of blast cells in the bone marrow.
Whether one or more types of blood cells are affected.
Whether the patient has signs or symptoms of anemia, bleeding, or infection.
Whether the patient has a low or high risk of leukemia.
Certain changes in the chromosomes.
Whether the myelodysplastic syndrome occurred after chemotherapy or radiation therapy for cancer.
The patient’s age and general health.
Treatment Option Overview
Key Points
There are different types of treatment for patients with myelodysplastic syndromes.
Treatment for myelodysplastic syndromes includes supportive care, drug therapy, and stem cell transplant.
The following types of treatment are used:
Supportive care
Drug therapy
Chemotherapy with stem cell transplant
New types of treatment are being tested in clinical trials.
Treatment for myelodysplastic syndromes 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 treatment.
Follow-up tests may be needed.
There are different types of treatment for patients with myelodysplastic syndromes.
Different types of treatment are available for patients with myelodysplastic syndromes. Some treatments are standard (the currently used treatment), and some are being tested in clinical trials. A treatment clinical trial is a research study meant to help improve current treatments or obtain information on new treatments for patients with cancer. When clinical trials show that a new treatment is better than the standard treatment, the new treatment may become the standard treatment. Patients may want to think about taking part in a clinical trial. Some clinical trials are open only to patients who have not started treatment.
Treatment for myelodysplastic syndromes includes supportive care, drug therapy, and stem cell transplant.
Supportive care is given to lessen the problems caused by the disease or its treatment. Supportive care may include the following:
Transfusion therapy
Transfusion therapy (blood transfusion) is a method of giving red blood cells, white blood cells, or platelets to replace blood cells destroyed by disease or treatment. A red blood cell transfusion is given when the red blood cell count is low and signs or symptoms of anemia, such as shortness of breath or feeling very tired, occur. A platelet transfusion is usually given when the patient is bleeding, is having a procedure that may cause bleeding, or when the platelet count is very low.
Patients who receive many blood cell transfusions may have tissue and organ damage caused by the buildup of extra iron. These patients may be treated with iron chelation therapy to remove the extra iron from the blood.
Patients with myelodysplastic syndrome associated with an isolated del(5q) chromosomeabnormality who need frequent red blood cell transfusions may be treated with lenalidomide. Lenalidomide is used to lessen the need for red blood cell transfusions.
Azacitidine and decitabine are used to treat myelodysplastic syndromes by killing cells that are dividing rapidly. They also help genes that are involved in cell growth to work the way they should. Treatment with azacitidine and decitabine may slow the progression of myelodysplastic syndromes to acute myeloid leukemia.
Chemotherapy used in acute myeloid leukemia (AML)
Patients with a myelodysplastic syndrome and a high number of blasts in their bone marrow have a high risk of acute leukemia. They may be treated with the same chemotherapy regimen used in patients with acute myeloid leukemia.
Chemotherapy with stem cell transplant
Chemotherapy is given to kill cancer cells. Healthy cells, including blood-forming cells, are also destroyed by the cancer treatment. Stem cell transplant is a treatment to replace the blood-forming cells. Stem cells (immature blood cells) are removed from the blood or bone marrow of the patient or a donor and are frozen and stored. After the patient completes chemotherapy, the stored stem cells are thawed and given back to the patient through an infusion. These reinfused stem cells grow into (and restore) the body’s blood cells.
This treatment may not work as well in patients whose myelodysplastic syndrome was caused by past treatment for cancer.
EnlargeDonor 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.
New types of treatment are being tested in clinical trials.
Information about clinical trials is available from the NCI website.
Treatment for myelodysplastic syndromes may cause side effects.
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 treatment.
Some clinical trials only include patients who have not yet received treatment. Other trials test treatments for patients whose cancer has not gotten better. There are also clinical trials that test new ways to stop cancer from recurring (coming back) or reduce the side effects of cancer treatment.
Clinical trials are taking place in many parts of the country. Information about clinical trials supported by NCI can be found on NCI’s clinical trials search webpage. Clinical trials supported by other organizations can be found on the ClinicalTrials.gov website.
Follow-up tests may be needed.
As you go through treatment, you will have follow-up tests or check-ups. Some tests that were done to diagnose or stage the cancer may be repeated to see how well the treatment is working. Decisions about whether to continue, change, or stop treatment may be based on the results of these tests.
Some of the tests will continue to be done from time to time after treatment has ended. The results of these tests can show if your condition has changed or if the cancer has recurred (come back).
Patients who were treated in the past with chemotherapy or radiation therapy may develop myeloidneoplasms related to that therapy. Treatment options are the same as for other myelodysplastic syndromes.
Use our clinical trial search to find NCI-supported cancer clinical trials that are accepting patients. You can search for trials based on the type of cancer, the age of the patient, and where the trials are being done. General information about clinical trials is also available.
Treatment of Relapsed or Refractory Myelodysplastic Syndromes
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.
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.
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Purpose of This Summary
This PDQ cancer information summary has current information about the treatment of myelodysplastic syndromes. 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
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The information in this patient summary was taken from the health professional version, which is reviewed regularly and updated as needed, by the PDQ Adult Treatment Editorial Board.
Clinical Trial Information
A clinical trial is a study to answer a scientific question, such as whether one treatment is better than another. Trials are based on past studies and what has been learned in the laboratory. Each trial answers certain scientific questions in order to find new and better ways to help cancer patients. During treatment clinical trials, information is collected about the effects of a new treatment and how well it works. If a clinical trial shows that a new treatment is better than one currently being used, the new treatment may become “standard.” Patients may want to think about taking part in a clinical trial. Some clinical trials are open only to patients who have not started treatment.
Clinical trials can be found online at NCI’s website. For more information, call the Cancer Information Service (CIS), NCI’s contact center, at 1-800-4-CANCER (1-800-422-6237).
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The best way to cite this PDQ summary is:
PDQ® Adult Treatment Editorial Board. PDQ Myelodysplastic Syndromes Treatment. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: /types/myeloproliferative/patient/myelodysplastic-treatment-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389239]
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The MDS are a collection of myeloid malignancies characterized by one or more peripheral blood cytopenias. MDS are diagnosed in slightly more than 10,000 people in the United States yearly, for an annual age-adjusted incidence rate of approximately 4.4 to 4.6 cases per 100,000 people.[1] They are more common in men and White individuals. The syndromes may arise de novo or secondarily after treatment with chemotherapy and/or radiation therapy for other cancers or, rarely, after environmental exposures.
Prognosis
Prognosis is directly related to the number of bone marrow blast cells, to certain cytogenetic abnormalities, and to the amount of peripheral blood cytopenias. By convention, MDS are reclassified as acute myeloid leukemia (AML) with myelodysplastic features when blood or bone marrow blasts reach or exceed 20%. Many patients succumb to complications of cytopenias before progression to this stage. For more information, see the Pathological and Prognostic Systems for MDS section. The acute leukemic phase is less responsive to chemotherapy than is de novo AML.
Pathology
MDS are characterized by abnormal bone marrow and blood cell morphology. Megaloblastoid erythroid hyperplasia with macrocytic anemia, associated with normal vitamin B12 and folate levels, is frequently observed. Circulating granulocytes are often hypogranular or hypergranular and may display the acquired pseudo-Pelger-Huët abnormality. Early, abnormal myeloid progenitors are identified in the marrow in varying percentages. Abnormally small megakaryocytes (micromegakaryocytes) may be seen in the marrow, and hypogranular or giant platelets may appear in the blood.
Clinical Features
MDS occur predominantly in older patients (usually older than 60 years), with a median age at diagnosis of approximately 70 years,[2] although patients as young as 2 years have been reported.[3] Anemia, bleeding, easy bruising, and fatigue are common initial findings. For more information, see Fatigue. Splenomegaly or hepatosplenomegaly may indicate an overlapping myeloproliferative neoplasm. Approximately 50% of patients have a detectable cytogenetic abnormality, most commonly a deletion of all or part of chromosome 5 or 7, or trisomy 8. Single-nucleotide polymorphism array technology may increase the detection of genetic abnormalities to 80%.[4,5] Although the bone marrow is usually hypercellular at diagnosis, 10% of patients present with a hypoplastic bone marrow.[6] Hypoplastic myelodysplastic patients tend to have profound cytopenias and may respond more frequently to immunosuppressive therapy.
Risk Factors
Approximately 90% of MDS cases occur de novo with no identifiable cause. Potential environmental risk factors for developing MDS include exposure to:[7,8]
Tobacco smoke.
Ionizing radiation.
Organic chemicals (e.g., benzene, toluene, xylene, and chloramphenicol).
Heavy metals.
Herbicides.
Pesticides.
Fertilizers.
Stone and cereal dusts.
Exhaust gases.
Nitro-organic explosives.
Petroleum and diesel derivatives.
References
Ma X, Does M, Raza A, et al.: Myelodysplastic syndromes: incidence and survival in the United States. Cancer 109 (8): 1536-42, 2007. [PUBMED Abstract]
Sekeres MA, Schoonen WM, Kantarjian H, et al.: Characteristics of US patients with myelodysplastic syndromes: results of six cross-sectional physician surveys. J Natl Cancer Inst 100 (21): 1542-51, 2008. [PUBMED Abstract]
Tuncer MA, Pagliuca A, Hicsonmez G, et al.: Primary myelodysplastic syndrome in children: the clinical experience in 33 cases. Br J Haematol 82 (2): 347-53, 1992. [PUBMED Abstract]
Gyger M, Infante-Rivard C, D’Angelo G, et al.: Prognostic value of clonal chromosomal abnormalities in patients with primary myelodysplastic syndromes. Am J Hematol 28 (1): 13-20, 1988. [PUBMED Abstract]
Tiu RV, Gondek LP, O’Keefe CL, et al.: Prognostic impact of SNP array karyotyping in myelodysplastic syndromes and related myeloid malignancies. Blood 117 (17): 4552-60, 2011. [PUBMED Abstract]
Du Y, Fryzek J, Sekeres MA, et al.: Smoking and alcohol intake as risk factors for myelodysplastic syndromes (MDS). Leuk Res 34 (1): 1-5, 2010. [PUBMED Abstract]
Strom SS, Gu Y, Gruschkus SK, et al.: Risk factors of myelodysplastic syndromes: a case-control study. Leukemia 19 (11): 1912-8, 2005. [PUBMED Abstract]
Pathological and Prognostic Systems for MDS
Myelodysplastic syndromes (MDS) are classified according to features of cellular morphology, etiology, and clinical presentation. The morphological classification of MDS is largely based on the percent of myeloblasts in the bone marrow and blood, the type and degree of myeloid dysplasia, and the presence of ring sideroblasts.[1] The clinical classification of the MDS depends on whether there is an identifiable etiology and whether the MDS has been treated previously.
Pathological Systems
The World Health Organization (WHO) classification [2] has supplanted the historic French-American-British (FAB) classification,[1] as shown in Table 1.
Table 1. Myelodysplastic Syndromes: Comparison of the FAB and WHO Classifications
FAB (1982)
WHO (2008)
AML = acute myeloid leukemia; FAB = French-American-British classification scheme; MDS = myelodysplastic syndromes; WHO = World Health Organization.
Myelodysplastic Syndromes
Refractory anemia.
Refractory anemia.
Refractory cytopenia with multilineage dysplasia. Refractory cytopenia with unilineage dysplasia.
Refractory anemia with ring sideroblasts.
Refractory anemia with ring sideroblasts.
Refractory anemia with excess blasts.
Refractory anemia with excess blasts -1 and -2.
Myelodysplastic syndrome, unclassifiable.
Myelodysplastic syndrome associated with del(5q).
Reclassified from MDS to:
Refractory anemia with excess blasts in transformation.
Acute myeloid leukemia identified as AML with multilineage dysplasia following a myelodysplastic syndrome.
Chronic myelomonocytic leukemia.
Myelodysplastic and myeloproliferative diseases.
MDS cellular types and subtypes in either cellular classification scheme have different degrees of disordered hematopoiesis, frequencies of transformation to acute leukemia, and prognoses.
Refractory anemia (RA)
In patients with RA, the myeloid and megakaryocytic series in the bone marrow appear normal, but megaloblastoid erythroid hyperplasia is present. Dysplasia is usually minimal. Marrow blasts are less than 5%, and no peripheral blasts are present. Macrocytic anemia with reticulocytopenia is present in the blood. Transformation to acute leukemia is rare, and median survival varies from 2 years to 5 years in most series. RA accounts for 20% to 30% of all patients with MDS.
Refractory anemia with ring sideroblasts (RARS)
In patients with RARS, the blood and marrow are identical to those in patients with RA, except that at least 15% of marrow red cell precursors are ring sideroblasts. Approximately 10% to 12% of patients present with this type, and prognosis is identical to that of RA. Approximately 1% to 2% of RARS evolve to acute myeloid leukemia (AML).
Refractory anemia with excess blasts (RAEB)
In patients with RAEB, there is significant evidence of disordered myelopoiesis and megakaryocytopoiesis in addition to abnormal erythropoiesis. Because of differences in prognosis related to progression to a frank AML, this cellular classification is composed of two categories: RAEB-1 and RAEB-2. Combined, the two categories account for approximately 40% of all patients with MDS. RAEB-1 is characterized by 5% to 9% blasts in the bone marrow and less than 5% blasts in the blood. Approximately 25% of cases of RAEB-1 progress to AML. Median survival is approximately 18 months. RAEB-2 is characterized by 10% to 19% blasts in the bone marrow. Approximately 33% of cases of RAEB-2 progress to AML. Median survival for RAEB-2 is approximately 10 months.
Refractory cytopenia with multilineage dysplasia (RCMD)
In patients with RCMD, bicytopenia or pancytopenia is present. In addition, dysplastic changes are present in 10% or more of the cells in two or more myeloid cell lines. There are less than 1% blasts in the blood and less than 5% blasts in the bone marrow. Auer rods are not present. Monocytes in the blood are less than 1 × 109. RCMD accounts for approximately 24% of cases of MDS. The frequency of evolution to acute leukemia is 11%. The overall median survival is 33 months. Refractory cytopenia with multilineage dysplasia and ring sideroblasts (RCMD-RS) represents another category of RCMD. In RCMD-RS, features of RCMD are present, and more than 15% of erythroid precursors in the bone marrow are ring sideroblasts. RCMD-RS accounts for approximately 15% of cases of MDS. Survival in RCMD-RS is similar to that in primary RCMD.
Refractory cytopenia with unilineage dysplasia (RCUD)
In patients with RCUD, a single cytopenia is present, involving either erythrocytes, neutrophils, or platelets. In addition, dysplastic changes are present in 10% or more of the cells in two or more myeloid cell lines. There are less than 1% blasts in the blood and less than 5% blasts in the bone marrow. Auer rods are not present. Monocytes in the blood are less than 1 × 109.
Unclassifiable myelodysplastic syndrome (MDS-U)
The cellular subtype MDS-U lacks findings appropriate for classification as RA, RARS, RCMD, or RAEB. Blasts in the blood and bone marrow are not increased.
Myelodysplastic syndrome associated with an isolated del(5q) chromosome abnormality
This MDS cellular subtype, the 5q- syndrome, is associated with an isolated del(5q) cytogenetic abnormality. Blasts in both blood and bone marrow are less than 5%. This subtype is associated with a long survival. Karyotypic evolution is uncommon. Additional cytogenetic abnormalities may be associated with a more aggressive MDS cellular subtype or may evolve to AML.
Therapy-related myeloid neoplasms
The latest version of the WHO pathological classification system identifies patients with therapy-related MDS or AML and places them in the same category as “therapy-related myeloid neoplasms.” This group of disorders evolves in patients who were previously treated with chemotherapy or radiation therapy for other cancers and in whom there is a clinical suspicion that the prior therapy caused the myeloid neoplasm. Classic chemotherapy agents associated with these disorders include alkylating agents, topoisomerase inhibitors, and purine nucleoside analogues.
Chronic myelomonocytic leukemia (CMML)
Although previously classified with the myelodysplastic syndromes, CMML is now assigned to a group of overlap myelodysplastic/myeloproliferative neoplasms. For more information, see Myelodysplastic/ Myeloproliferative Neoplasms Treatment.
Prognostic Scoring Systems
A variety of pathological and risk classification systems have been developed to predict the overall survival of patients with MDS and the evolution from MDS to AML. Major prognostic classification systems include the International Prognostic Scoring System (IPSS), revised as the IPSS-R;[3] the WHO Prognostic Scoring System (WPSS); and the MD Anderson Cancer Center Prognostic Scoring Systems.[4,5] Clinical variables in these systems have included bone marrow and blood myeloblast percentage, specific cytopenias, transfusion requirements, age, performance status, and bone marrow cytogenetic abnormalities.
IPSS
The IPSS incorporates bone marrow blast percentage, number of peripheral blood cytopenias, and cytogenetic risk group.
IPSS-R
Compared with the IPSS, the IPSS-R updates and gives greater weight to cytogenetic abnormalities and severity of cytopenias, while reassigning the weighting for blast percentages.[3]
WPSS
In contrast to the IPSS and IPSS-R, which should be applied only at the time of diagnosis, the WPSS is dynamic, meaning that patients can be reassigned categories as their disease progresses.
MD Anderson
The MD Anderson Cancer Center has published two prognostic scoring systems, one of which is focused on lower-risk patients.[4,5]
References
Bennett JM, Catovsky D, Daniel MT, et al.: Proposals for the classification of the myelodysplastic syndromes. Br J Haematol 51 (2): 189-99, 1982. [PUBMED Abstract]
Vardiman JW, Thiele J, Arber DA, et al.: The 2008 revision of the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia: rationale and important changes. Blood 114 (5): 937-51, 2009. [PUBMED Abstract]
Greenberg PL, Tuechler H, Schanz J, et al.: Revised international prognostic scoring system for myelodysplastic syndromes. Blood 120 (12): 2454-65, 2012. [PUBMED Abstract]
Garcia-Manero G, Shan J, Faderl S, et al.: A prognostic score for patients with lower risk myelodysplastic syndrome. Leukemia 22 (3): 538-43, 2008. [PUBMED Abstract]
Kantarjian H, O’Brien S, Ravandi F, et al.: Proposal for a new risk model in myelodysplastic syndrome that accounts for events not considered in the original International Prognostic Scoring System. Cancer 113 (6): 1351-61, 2008. [PUBMED Abstract]
Treatment of MDS
Therapies for myelodysplastic syndromes (MDS) are initiated in patients with a shorter predicted survival or in patients with clinically significant cytopenias. The impact of most MDS therapies on survival remains unproven.
The mainstay of treatment for MDS has traditionally been supportive care, particularly for patients with symptomatic cytopenias or who are at high risk of infection or bleeding.[1,2] Transfusions are reserved for the treatment of active bleeding; many centers offer prophylactic platelet transfusions for patients with platelet counts lower than 10,000/mm3. Anemia should be treated with red-cell transfusions to avoid symptoms. For more information, see Fatigue.
No prospective trials have demonstrated the benefit of prophylactic use of myeloid growth factors in asymptomatic neutropenic MDS patients. Similarly, the use of prophylactic antibiotics in such patients is of uncertain benefit. While appropriate use of antibiotics in febrile patients is standard clinical practice, the benefit of myeloid growth factors in such settings is unknown.
The use of erythropoiesis-stimulating agents (ESAs) may improve anemia. The likelihood of response to exogenous erythropoietin administration depends on the pretreatment serum erythropoietin level and baseline transfusion needs.
A meta-analysis summarized the data on erythropoietin in 205 patients with MDS from 17 studies. Responses were most likely in patients who were anemic but who did not yet require a transfusion, patients who did not have ring sideroblasts, and patients who had a serum erythropoietin level lower than 200 IU/L.[3] Effective treatment requires substantially higher doses of erythropoietin than are used for other indications; the minimum effective dose studied is 60,000 IU per week.[4] The use of high-dose darbepoetin (300 µg/dose weekly or 500 µg/dose every 2–3 weeks) has been reported to produce a major erythroid response rate of almost 50% in patients whose endogenous erythropoietin level was lower than 500 mIU/mL.[5,6] Most studies discontinued ESAs in patients who failed to show hematologic improvement after 3 to 4 months of therapy. Average response duration is approximately 2 years.[7]
One decision model found that the likelihood of responding to growth factors was higher in patients with a low serum erythropoietin level (<500 IU/L) and low transfusion needs (<2 units of packed red blood cells every month), but growth factors were rarely effective in patients with a high erythropoietin level and high transfusion needs.[8] Some patients with poor response to erythropoietin alone may have improved response with the addition of low doses of granulocyte colony-stimulating factor (G-CSF) (0.5–1.0 µg/kg/day).[9–11] Rates of response to the combination treatment vary with classification, with responses more likely in patients with refractory anemia and ring sideroblasts (RARS) and less likely in patients with excess blasts.[7] Patients with RARS are unlikely to respond to erythropoietin alone.[3]
The availability of the oral iron-chelating agent deferasirox has led to its widespread use in patients with MDS. While some consensus panels advocate prophylactic iron chelation in patients with ongoing transfusion needs and substantial transfusion history, the impact of iron chelation on survival and disease progression is unknown.[12]
Disease-Modifying Agents
Lower-risk patients (conventionally defined as International Prognostic Scoring System (IPSS) low-risk and intermediate-1–risk groups) who have failed to respond or have ceased responding to ESAs may be treated with one of several disease-modifying agents. The impact of this practice on survival in lower-risk patients is unknown. Whether these drugs should be used following an ESA failure or as up-front therapy has never been determined. In contrast, in higher-risk patients, azacitidine has been shown to improve survival. For more information, see the DNA methyltransferase inhibitors section.
Lenalidomide
The U.S. Food and Drug Administration (FDA) approved lenalidomide for the treatment of lower-risk, transfusion-dependent patients with MDS who harbor a del(5q) cytogenic abnormality. In a phase II registration study of 148 transfusion-dependent low-risk and intermediate-1–risk patients with del(5q) chromosomal abnormalities (alone, or associated with other abnormalities), lenalidomide induced transfusion independence in 67%, with a median time to response of 4 to 5 weeks.[13] The median duration of transfusion independence had not been reached after a median of 104 weeks of follow-up. Of 62 evaluable patients, 38 patients developed complete cytogenetic remission.
Lenalidomide administration is limited by dose-limiting neutropenia and thrombocytopenia.[14][Level of evidence C3] Treatment-related thrombocytopenia also correlated with cytogenetic responses, emphasizing the importance of successful suppression of the del(5q) clone with lenalidomide to achieve meaningful responses.[15]
A subsequent phase III study randomly assigned lower-risk del(5q) MDS patients to receive placebo and lenalidomide at either 5 mg daily for 28 days or 10 mg daily for 21 days of a 28-day cycle.[16] Transfusion independence responses lasting longer than 6 months occurred in 43% to 52% of subjects treated on the lenalidomide arms, compared with 6% of controls. The cytogenetic response rate was 25% to 50% on the active treatment arms, and the 3-year risk of AML transformation was 25%.
Lenalidomide has limited activity in lower-risk, red blood cell transfusion–dependent patients in MDS who do not harbor the del(5q) lesion. In a phase II study similar in design to the registration study, 56 of 215 patients (26%) achieved transfusion independence.[17] Median duration of response was 41 weeks (range, 8–136 weeks). Grade 3 or 4 myelosuppression occurred in only 20% to 25% of patients and, unlike for del(5q) patients, was not associated with subsequent attainment of a transfusion independence response to therapy.
Immunosuppressive therapy
Antithymocyte globulin (ATG) has shown activity in MDS patients in several small series. The National Heart, Lung, and Blood Institute conducted a phase II trial including 25 MDS patients with less than 20% blasts. Of all the patients studied, 11 (or 44%) responded and became transfusion-independent after ATG (three complete responses, six partial responses, and two minimal responses).[18] Multivariate analysis identified HLA-DR-15 (phenotype) expression, briefer period of red cell transfusion dependence, and younger age as predictors of response to ATG.[19] One study used alemtuzumab to treat a heavily preselected population of lower-risk MDS patients, in whom the response rate was 80%.[20]
DNA methyltransferase inhibitors
The nucleoside analogues azacitidine and decitabine are inhibitors of DNA methyltransferase. Both drugs require prolonged administration before benefits are seen. The median number of cycles required to see first hematologic response to azacitidine was 3; 90% of responders showed response by 6 cycles; and the median number of cycles of decitabine required to see first response was 2.2.[21] Azacitidine received FDA approval based on the results of a randomized trial that was not designed to study survival.[22]
A phase III randomized controlled trial (AZA PH GL 2003 CL 001 [NCT00071799]) of azacitidine versus other regimens, including low-dose cytarabine, AML-type remission induction chemotherapy, or best supportive care, was limited to patients with higher-risk MDS subtypes (IPSS intermediate-2 risk and high risk).[17] The median and 2-year overall survival (OS) favored the azacitidine arm, at 24 months versus 16 months (P = .0001) and 51% versus 26% (P < .0001), respectively.[17][Level of evidence A1] The FDA-approved azacitidine dose schedule used in this study (75 mg/m2 per day for 7 consecutive days) has proven inconvenient to some practitioners. A community-based study has suggested that alternate dosing schedules may provide similar hematologic benefits; however, the impact of such dosing schedules on survival is not known.[23]
While the azacitidine congener decitabine demonstrated similar activity in phase II trials, two randomized trials of decitabine versus supportive care failed to show a survival benefit.[21,24] Both decitabine studies used the FDA-approved dose schedule (15 mg/m2 every 8 hours for nine doses). In the European phase III study in higher-risk patients, median OS was similar for patients in both the decitabine and best supportive care arms, at 10.1 months versus 8.5 months, respectively (P = .38). A combined OS and delay in AML transformation end point was 8.8 months versus 6.1 months, respectively (P = .24).[25][Level of evidence A1]
Decitabine can be given as daily intravenous or subcutaneous infusions at doses that differ from the original labeled schedule, with hematologic response rates that appear comparable to the phase III study.[26,27]
Both of these drugs have been approved for refractory anemia, RARS (if accompanied by neutropenia or thrombocytopenia or requiring transfusions), refractory anemia with excess blasts, and refractory anemia with excess blasts in transformation. However, the highest response rates and levels of evidence have been generated in trials in which patients with higher-risk MDS (IPSS risk groups of intermediate-2 or high) were treated.[28] In lower-risk patients, response rates appear similar to those in higher-risk patients, although the survival benefit is unknown. The use of these drugs in low-risk patients may preclude their subsequent use upon disease progression.
Combinations of azacitidine with lenalidomide [29] and vorinostat [30] were compared with single-agent azacitidine in a national randomized phase II trial (S1117 [NCT01522976]).
AML induction-type chemotherapy
Induction chemotherapy typically used to treat AML may be used to treat patients with higher-risk MDS with excess blasts.[31] Low-dose cytarabine has benefitted some patients; however, this treatment was associated with a higher infection rate when compared with observation in a randomized trial. No difference in time to progression or OS was observed for patients treated with low-dose cytarabine or supportive care.
Allogeneic HSCT is the only potentially curative treatment for MDS. Retrospective data suggest cure rates in selected patients ranging from 30% to 60%; outcomes varied with IPSS score at time of transplant, with inferior survival in patients with higher IPSS scores.[32][Level of evidence C3] The role of cytoreductive therapy in reducing the blast percentage before HSCT remains uncertain. Outcomes may not be as good for patients with treatment-related MDS (5-year disease-free survival rate of 8% to 30%).[33]
Although HSCT represents the only treatment modality with curative potential, the relatively high morbidity and mortality of this approach limits its use. A decision analysis predating approval of azacitidine, in patients with a median age younger than 50 years, suggested optimal survival when transplant was delayed until disease progression for lower-risk patients but implemented at diagnosis for higher-risk patients.[34]
Allogeneic stem cell transplant with reduced-intensity conditioning (RIC) has extended transplant as a possible modality for treatment of older patients.[35] In a retrospective analysis of 1,333 patients aged 50 years or older (median, 56 years) who underwent allogeneic transplants for MDS using HLA-matched sibling and unrelated donors, 62% of the patients received RIC HSCT, and the others received standard-dose HSCT. On multivariate analysis, use of RIC and advanced disease stage at transplant were associated with increased relapse (hazard ratio [HR] of 1.44 and 1.51, respectively).[35][Level of evidence C3] The predictors of non-relapse mortality included advanced disease stage (HR, 1.43), use of an unrelated donor, and standard-dose HSCT (HR, 1.27). The 4-year OS rate was similar in both groups (30% after myeloablative conditioning vs. 32% in RIC.[35]
Therapy-Related Myeloid Neoplasms
In the absence of prospective data, therapy-related myeloid neoplasms are treated similarly to de novo MDS.
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
Tricot GJ, Lauer RC, Appelbaum FR, et al.: Management of the myelodysplastic syndromes. Semin Oncol 14 (4): 444-53, 1987. [PUBMED Abstract]
Boogaerts MA: Progress in the therapy of myelodysplastic syndromes. Blut 58 (6): 265-70, 1989. [PUBMED Abstract]
Hellström-Lindberg E: Efficacy of erythropoietin in the myelodysplastic syndromes: a meta-analysis of 205 patients from 17 studies. Br J Haematol 89 (1): 67-71, 1995. [PUBMED Abstract]
Park S, Grabar S, Kelaidi C, et al.: Predictive factors of response and survival in myelodysplastic syndrome treated with erythropoietin and G-CSF: the GFM experience. Blood 111 (2): 574-82, 2008. [PUBMED Abstract]
Mannone L, Gardin C, Quarre MC, et al.: High-dose darbepoetin alpha in the treatment of anaemia of lower risk myelodysplastic syndrome results of a phase II study. Br J Haematol 133 (5): 513-9, 2006. [PUBMED Abstract]
Gabrilove J, Paquette R, Lyons RM, et al.: Phase 2, single-arm trial to evaluate the effectiveness of darbepoetin alfa for correcting anaemia in patients with myelodysplastic syndromes. Br J Haematol 142 (3): 379-93, 2008. [PUBMED Abstract]
Jädersten M, Montgomery SM, Dybedal I, et al.: Long-term outcome of treatment of anemia in MDS with erythropoietin and G-CSF. Blood 106 (3): 803-11, 2005. [PUBMED Abstract]
Hellström-Lindberg E, Gulbrandsen N, Lindberg G, et al.: A validated decision model for treating the anaemia of myelodysplastic syndromes with erythropoietin + granulocyte colony-stimulating factor: significant effects on quality of life. Br J Haematol 120 (6): 1037-46, 2003. [PUBMED Abstract]
Hellström-Lindberg E, Ahlgren T, Beguin Y, et al.: Treatment of anemia in myelodysplastic syndromes with granulocyte colony-stimulating factor plus erythropoietin: results from a randomized phase II study and long-term follow-up of 71 patients. Blood 92 (1): 68-75, 1998. [PUBMED Abstract]
Hellström-Lindberg E, Kanter-Lewensohn L, Ost A: Morphological changes and apoptosis in bone marrow from patients with myelodysplastic syndromes treated with granulocyte-CSF and erythropoietin. Leuk Res 21 (5): 415-25, 1997. [PUBMED Abstract]
Negrin RS, Stein R, Doherty K, et al.: Maintenance treatment of the anemia of myelodysplastic syndromes with recombinant human granulocyte colony-stimulating factor and erythropoietin: evidence for in vivo synergy. Blood 87 (10): 4076-81, 1996. [PUBMED Abstract]
Greenberg PL, Rigsby CK, Stone RM, et al.: NCCN Task Force: Transfusion and iron overload in patients with myelodysplastic syndromes. J Natl Compr Canc Netw 7 (Suppl 9): S1-16, 2009. [PUBMED Abstract]
List A, Dewald G, Bennett J, et al.: Lenalidomide in the myelodysplastic syndrome with chromosome 5q deletion. N Engl J Med 355 (14): 1456-65, 2006. [PUBMED Abstract]
List A, Kurtin S, Roe DJ, et al.: Efficacy of lenalidomide in myelodysplastic syndromes. N Engl J Med 352 (6): 549-57, 2005. [PUBMED Abstract]
Sekeres MA, Maciejewski JP, Giagounidis AA, et al.: Relationship of treatment-related cytopenias and response to lenalidomide in patients with lower-risk myelodysplastic syndromes. J Clin Oncol 26 (36): 5943-9, 2008. [PUBMED Abstract]
Fenaux P, Giagounidis A, Selleslag D, et al.: RBC transfusion independence and safety profile of lenalidomide 5 or 10 mg in pts with low- or int-1-risk MDS with Del5q: results from a randomized phase III trial (MDS-004). [Abstract] Blood 114 (22): A-944, 2009.
Fenaux P, Mufti GJ, Hellstrom-Lindberg E, et al.: Efficacy of azacitidine compared with that of conventional care regimens in the treatment of higher-risk myelodysplastic syndromes: a randomised, open-label, phase III study. Lancet Oncol 10 (3): 223-32, 2009. [PUBMED Abstract]
Molldrem JJ, Caples M, Mavroudis D, et al.: Antithymocyte globulin for patients with myelodysplastic syndrome. Br J Haematol 99 (3): 699-705, 1997. [PUBMED Abstract]
Saunthararajah Y, Nakamura R, Nam JM, et al.: HLA-DR15 (DR2) is overrepresented in myelodysplastic syndrome and aplastic anemia and predicts a response to immunosuppression in myelodysplastic syndrome. Blood 100 (5): 1570-4, 2002. [PUBMED Abstract]
Sloand EM, Olnes MJ, Shenoy A, et al.: Alemtuzumab treatment of intermediate-1 myelodysplasia patients is associated with sustained improvement in blood counts and cytogenetic remissions. J Clin Oncol 28 (35): 5166-73, 2010. [PUBMED Abstract]
Kantarjian H, Issa JP, Rosenfeld CS, et al.: Decitabine improves patient outcomes in myelodysplastic syndromes: results of a phase III randomized study. Cancer 106 (8): 1794-803, 2006. [PUBMED Abstract]
Silverman LR, Demakos EP, Peterson BL, et al.: Randomized controlled trial of azacitidine in patients with the myelodysplastic syndrome: a study of the cancer and leukemia group B. J Clin Oncol 20 (10): 2429-40, 2002. [PUBMED Abstract]
Lyons RM, Cosgriff TM, Modi SS, et al.: Hematologic response to three alternative dosing schedules of azacitidine in patients with myelodysplastic syndromes. J Clin Oncol 27 (11): 1850-6, 2009. [PUBMED Abstract]
Wijermans P, Lübbert M, Verhoef G, et al.: Low-dose 5-aza-2′-deoxycytidine, a DNA hypomethylating agent, for the treatment of high-risk myelodysplastic syndrome: a multicenter phase II study in elderly patients. J Clin Oncol 18 (5): 956-62, 2000. [PUBMED Abstract]
Lübbert M, Suciu S, Baila L, et al.: Low-dose decitabine versus best supportive care in elderly patients with intermediate- or high-risk myelodysplastic syndrome (MDS) ineligible for intensive chemotherapy: final results of the randomized phase III study of the European Organisation for Research and Treatment of Cancer Leukemia Group and the German MDS Study Group. J Clin Oncol 29 (15): 1987-96, 2011. [PUBMED Abstract]
Issa JP, Garcia-Manero G, Giles FJ, et al.: Phase 1 study of low-dose prolonged exposure schedules of the hypomethylating agent 5-aza-2′-deoxycytidine (decitabine) in hematopoietic malignancies. Blood 103 (5): 1635-40, 2004. [PUBMED Abstract]
Kantarjian H, Oki Y, Garcia-Manero G, et al.: Results of a randomized study of 3 schedules of low-dose decitabine in higher-risk myelodysplastic syndrome and chronic myelomonocytic leukemia. Blood 109 (1): 52-7, 2007. [PUBMED Abstract]
Kaminskas E, Farrell A, Abraham S, et al.: Approval summary: azacitidine for treatment of myelodysplastic syndrome subtypes. Clin Cancer Res 11 (10): 3604-8, 2005. [PUBMED Abstract]
Sekeres MA, List AF, Cuthbertson D, et al.: Phase I combination trial of lenalidomide and azacitidine in patients with higher-risk myelodysplastic syndromes. J Clin Oncol 28 (13): 2253-8, 2010. [PUBMED Abstract]
Garcia-Manero G, Estey EH, Jabbour E, et al.: Final report of a phase II study of 5-azacitidine and vorinostat in patients with newly diagnosed myelodysplastic syndrome or acute myelogenous leukemia not eligible for clinical trials because poor performance and presence of other comorbidities. [Abstract] Blood 118 (21): A-608, 2011.
de Witte T, Suciu S, Verhoef G, et al.: Intensive chemotherapy followed by allogeneic or autologous stem cell transplantation for patients with myelodysplastic syndromes (MDSs) and acute myeloid leukemia following MDS. Blood 98 (8): 2326-31, 2001. [PUBMED Abstract]
Deeg HJ, Storer B, Slattery JT, et al.: Conditioning with targeted busulfan and cyclophosphamide for hemopoietic stem cell transplantation from related and unrelated donors in patients with myelodysplastic syndrome. Blood 100 (4): 1201-7, 2002. [PUBMED Abstract]
Witherspoon RP, Deeg HJ, Storer B, et al.: Hematopoietic stem-cell transplantation for treatment-related leukemia or myelodysplasia. J Clin Oncol 19 (8): 2134-41, 2001. [PUBMED Abstract]
Cutler CS, Lee SJ, Greenberg P, et al.: A decision analysis of allogeneic bone marrow transplantation for the myelodysplastic syndromes: delayed transplantation for low-risk myelodysplasia is associated with improved outcome. Blood 104 (2): 579-85, 2004. [PUBMED Abstract]
Schetelig J, van Biezen A, Brand R, et al.: Allogeneic hematopoietic stem-cell transplantation for chronic lymphocytic leukemia with 17p deletion: a retrospective European Group for Blood and Marrow Transplantation analysis. J Clin Oncol 26 (31): 5094-100, 2008. [PUBMED Abstract]
Treatment of Relapsed or Refractory MDS
Lack of response or progression after the use of erythropoiesis-stimulating agents is not considered relapsed or refractory myelodysplastic syndromes (MDS).
With the exception of the use of lenalidomide for low-risk patients with abnormalities of chromosome 5, there are no clinical trials informing the appropriate selection of therapies for patients with specific subtypes of MDS. Patients who have ceased to respond or did not respond to one therapy are frequently offered another from the therapies described in the previous sections. Retrospective data suggest that patients who do not respond or have ceased responding to DNA methyltransferase inhibitors have a median survival of only 4 to 6 months.[1,2] Patients with relapses should be considered for enrollment in clinical trials.
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
Prébet T, Gore SD, Esterni B, et al.: Outcome of high-risk myelodysplastic syndrome after azacitidine treatment failure. J Clin Oncol 29 (24): 3322-7, 2011. [PUBMED Abstract]
Jabbour E, Garcia-Manero G, Batty N, et al.: Outcome of patients with myelodysplastic syndrome after failure of decitabine therapy. Cancer 116 (16): 3830-4, 2010. [PUBMED Abstract]
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.
Latest Updates to This Summary (09/19/2024)
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 myelodysplastic syndromes. 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 Myelodysplastic Syndromes Treatment is:
Aaron Gerds, MD (Cleveland Clinic Taussig Cancer Institute)
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 Myelodysplastic Syndromes Treatment. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: /types/myeloproliferative/hp/myelodysplastic-treatment-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389450]
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.
Chronic myeloid leukemia is a disease in which the bone marrow makes too many white blood cells.
Leukemia may affect red blood cells, white blood cells, and platelets.
Signs and symptoms of chronic myeloid leukemia include weight loss and tiredness.
Most people with chronic myeloid leukemia have a gene mutation (change) called the Philadelphia (Ph) chromosome.
Tests that examine the blood and bone marrow are used to diagnose chronic myeloid leukemia.
Certain factors affect prognosis (chance of recovery) and treatment options.
Chronic myeloid leukemia is a disease in which the bone marrow makes too many white blood cells.
Chronic myeloid leukemia (also called CML or chronic myelogenous leukemia) is a slowly progressing blood and bone marrow disease that usually occurs during or after middle age and rarely occurs in children.
EnlargeAnatomy 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.
EnlargeBlood cell development. A blood stem cell goes through several steps to become a red blood cell, platelet, or white blood cell.
In CML, too many myeloblasts (a type of immature white blood cell) form in the blood and bone marrow, and the disease worsens as the number of myeloblasts increases.
pain or a feeling of fullness below the ribs on the left side
Sometimes CML does not cause any symptoms at all.
Most people with chronic myeloid leukemia have a gene mutation (change) called the Philadelphia (Ph) chromosome.
Every cell in the body contains DNA (genetic material) that determines how the cell looks and acts. DNA is contained inside chromosomes. In CML, part of the DNA from one chromosome moves to another chromosome. This change is called the “Philadelphia chromosome.” It results in the bone marrow making a protein, called tyrosine kinase, that causes too many stem cells to become white blood cells (granulocytes or blasts).
The Philadelphia chromosome is not passed from parent to child.
EnlargeThe 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.
Tests that examine the blood and bone marrow are used to diagnose chronic myeloid leukemia.
In addition to asking about your personal and family health history and doing a physical exam to check for signs of disease, such as an enlarged spleen, your doctor may perform the following tests and procedures:
the amount of hemoglobin (the protein that carries oxygen) in the red blood cells
the amount of hematocrit (whole blood that is made up of red blood cells)
EnlargeComplete blood count (CBC). Blood is collected by inserting a needle into a vein and allowing the blood to flow into a tube. The blood sample is sent to the laboratory and the red blood cells, white blood cells, and platelets are counted. The CBC is used to test for, diagnose, and monitor many different conditions.
Blood chemistry study uses a blood sample to measure the amounts of certain substances released into the blood by organs and tissues in the body. An unusual amount of a substance can be a sign of disease.
Bone marrow aspiration and biopsy is the removal of bone marrow, blood, and a small piece of bone by inserting a needle into the hipbone or breastbone. A pathologist views the bone marrow, blood, and bone under a microscope to look for abnormal cells. EnlargeBone 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.
One of the following tests may be done on the samples of blood or bone marrow tissue that are removed.
Cytogenetic analysis checks the chromosomes of cells in a sample of bone marrow, blood, tumor, or other tissue for broken, missing, rearranged, or extra chromosomes. Changes in certain chromosomes, such as the Philadelphia chromosome, may be a sign of cancer. Cytogenetic analysis is used to help diagnose cancer, plan treatment, or find out how well treatment is working.
FISH (fluorescence in situ hybridization) is 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.
Reverse transcription–polymerase chain reaction test (RT-PCR) is a laboratory test in which the amount of a genetic substance called mRNA made by a specific gene is measured. An enzyme called reverse transcriptase is used to convert a specific piece of RNA into a matching piece of DNA, which can be amplified (made in large numbers) by another enzyme called DNA polymerase. The amplified DNA copies help tell whether a specific mRNA is being made by a gene. RT-PCR can be used to check the activation of certain genes that may indicate the presence of cancer cells. This test may be used to look for certain changes in a gene or chromosome, which may help diagnose cancer.
Certain factors affect prognosis (chance of recovery) and treatment options.
After chronic myeloid leukemia has been diagnosed, tests are done to find out if the cancer has spread.
Chronic myeloid leukemia has 3 phases.
Chronic phase
Accelerated phase
Blastic phase
Chronic myeloid leukemia can relapse (return) after it has been treated.
After chronic myeloid leukemia has been diagnosed, tests are done to find out if the cancer has spread.
The extent or spread of cancer is usually described as stages. In chronic myeloid leukemia (CML), the disease is classified by phase: chronic phase, accelerated phase, or blastic phase. It is important to know the phase in order to plan treatment. The information from tests and procedures done to diagnose chronic myeloid leukemia is also used to plan treatment.
Chronic myeloid leukemia has 3 phases.
As the amount of blast cells increases in the blood and bone marrow, there is less room for healthy white blood cells, red blood cells, and platelets. This may result in infections, anemia, and easy bleeding, as well as bone pain and pain or a feeling of fullness below the ribs on the left side. The number of blast cells in the blood and bone marrow and the severity of signs or symptoms determine the phase of the disease.
Chronic phase
In chronic phase CML, fewer than 10% of the cells in the blood and bone marrow are blast cells.
Accelerated phase
In accelerated phase CML, 10% to 19% of the cells in the blood and bone marrow are blast cells.
Blastic phase
In blastic phase CML, 20% or more of the cells in the blood or bone marrow are blast cells. When tiredness, fever, and an enlarged spleen occur during the blastic phase, it is called blast crisis.
Chronic myeloid leukemia can relapse (return) after it has been treated.
There are different types of treatment for patients with chronic myeloid leukemia.
The following types of treatment are used:
Targeted therapy
Chemotherapy
Immunotherapy
High-dose chemotherapy with stem cell transplant (SCT)
Donor lymphocyte infusion (DLI)
Surgery
New types of treatment are being tested in clinical trials.
Treatment for chronic myeloid leukemia may cause side effects.
Follow-up care may be needed.
There are different types of treatment for patients with chronic myeloid leukemia.
Different types of treatments are available for chronic myeloid leukemia (CML). You and your cancer care team will work together to decide your treatment plan, which may include more than one type of treatment. Many factors will be considered, such as the stage of the cancer, your overall health, and your preferences. Your plan will include information about your cancer, the goals of treatment, your treatment options and the possible side effects, and the expected length of treatment.
Talking with your cancer care team before treatment begins about what to expect will be helpful. You’ll want to learn what you need to do before treatment begins, how you’ll feel while going through it, and what kind of help you will need. To learn more, visit Questions to Ask Your Doctor About Treatment.
The following types of treatment are used:
Targeted therapy
Targeted therapy is a type of treatment that uses drugs or other substances to identify and attack specific cancer cells.
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).
Immunotherapy is a treatment that uses the patient’s immune system to fight cancer. Substances made by the body or made in a laboratory are used to boost, direct, or restore the body’s natural defenses against cancer. Interferon is a type of immunotherapy used to treat CML. It affects the division of cancer cells and can slow tumor growth.
High-dose chemotherapy with stem cell transplant (SCT)
High doses of chemotherapy are given to kill cancer cells. Healthy cells, including blood-forming cells, are also destroyed by the cancer treatment. stem cell transplant is a treatment to replace the blood-forming cells. Stem cells (immature blood cells) are removed from the blood or bone marrow of the patient or a donor and are frozen and stored. After the patient completes chemotherapy, the stored stem cells are thawed and given back to the patient through an infusion. These reinfused stem cells grow into (and restore) the body’s blood cells.
EnlargeDonor 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.
Donor lymphocyte infusion (DLI)
Donor lymphocyte infusion (DLI) is a cancer treatment that may be used after stem cell transplant. Lymphocytes (a type of white blood cell) from the stem cell transplant donor are removed from the donor’s blood and may be frozen for storage. The donor’s lymphocytes are thawed if they were frozen and then given to the patient through one or more infusions. The lymphocytes see the patient’s cancer cells as not belonging to the body and attack them.
New types of treatment are being tested in clinical trials.
For some people, joining a clinical trial may be an option. There are different types of clinical trials for people with cancer. For example, a treatment trial tests new treatments or new ways of using current treatments. Supportive care and palliative care trials look at ways to improve quality of life, especially for those who have side effects from cancer and its treatment.
You can use the clinical trial search to find NCI-supported cancer clinical trials accepting participants. The search allows you to filter trials based on the type of cancer, your age, and where the trials are being done. Clinical trials supported by other organizations can be found on the ClinicalTrials.gov website.
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 Chronic Phase Chronic Myeloid Leukemia
Treatment of chronic phase chronic myeloid leukemia may include:
Use our clinical trial search to find NCI-supported cancer clinical trials that are accepting patients. You can search for trials based on the type of cancer, the age of the patient, and where the trials are being done. General information about clinical trials is also available.
Treatment of Accelerated Phase Chronic Myeloid Leukemia
Treatment of accelerated phase chronic myeloid leukemia may include:
targeted therapy (bosutinib)
targeted therapy (imatinib mesylate) followed by allogeneic stem cell transplant
Use our clinical trial search to find NCI-supported cancer clinical trials that are accepting patients. You can search for trials based on the type of cancer, the age of the patient, and where the trials are being done. General information about clinical trials is also available.
Treatment of Blastic Phase Chronic Myeloid Leukemia
Treatment of blastic phase chronic myeloid leukemia may include:
Use our clinical trial search to find NCI-supported cancer clinical trials that are accepting patients. You can search for trials based on the type of cancer, the age of the patient, and where the trials are being done. General information about clinical trials is also available.
Treatment of Relapsed Chronic Myeloid Leukemia
In relapsed chronic myeloid leukemia (CML), the number of blast cells increases after a remission. Treatment of relapsed CML may include targeted therapy (ponatinib or asciminib).
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.
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 chronic myeloid 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 Chronic Myeloid Leukemia Treatment. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: /types/leukemia/patient/cml-treatment-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389183]
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.
EnlargeAnatomy 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.
A blood stem cell may become a myeloidstem cell or a lymphoid stem cell. A lymphoid stem cell becomes a white blood cell. A myeloid stem cell becomes one of three types of mature blood cells:
EnlargeBlood cell development. A blood stem cell goes through several steps to become a red blood cell, platelet, or white blood cell.
In myeloproliferative neoplasms, too many blood stem cells become one or more types of blood cells. The neoplasms usually get worse slowly as the number of extra blood cells increases.
The following are types of myeloproliferative neoplasms.
The type of myeloproliferative neoplasm is based on whether too many red blood cells, white blood cells, or platelets are being made. Sometimes the body will make too many of more than one type of blood cell, but usually one type of blood cell is affected more than the others are. Myeloproliferative neoplasms include:
the amount of hemoglobin (the protein that carries oxygen) in the red blood cells
the amount of hematocrit (whole blood that is made up of red blood cells)
EnlargeComplete blood count (CBC). Blood is collected by inserting a needle into a vein and allowing the blood to flow into a tube. The blood sample is sent to the laboratory and the red blood cells, white blood cells, and platelets are counted. The CBC is used to test for, diagnose, and monitor many different conditions.
Blood chemistry study uses a blood sample to measure the amounts of certain substances released into the blood by organs and tissues in the body. An unusual amount of a substance can be a sign of disease.
Bone marrow aspiration and biopsy is 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 abnormal cells. EnlargeBone 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.
Cytogenetic analysis checks the chromosomes of cells in a sample of bone marrow, blood, tumor, or other tissue for 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.
Genetic testing is done on a bone marrow or blood sample to check for mutations in JAK2, MPL, or CALR genes. A JAK2 gene mutation is often found in patients with polycythemia vera, essential thrombocythemia, or primary myelofibrosis. MPL or CALR gene mutations are found in patients with essential thrombocythemia or primary myelofibrosis.
Polycythemia vera is a disease in which too many red blood cells are made in the bone marrow.
Symptoms of polycythemia vera include headaches and a feeling of fullness below the ribs on the left side.
Special blood tests are used to diagnose polycythemia vera.
Polycythemia vera is a disease in which too many red blood cells are made in the bone marrow.
In polycythemia vera, the blood becomes thickened with too many red blood cells. The number of white blood cells and platelets may also increase. These extra blood cells may collect in the spleen and cause it to swell. The increased number of red blood cells, white blood cells, or platelets in the blood can cause bleeding problems and make clots form in blood vessels. This can increase the risk of stroke or heart attack. In patients who are older than 65 years or who have a history of blood clots, the risk of stroke or heart attack is higher. Patients also have an increased risk of acute myeloid leukemia or primary myelofibrosis.
Symptoms of polycythemia vera include headaches and a feeling of fullness below the ribs on the left side.
Polycythemia vera often does not cause early signs or symptoms. It may be found during a routine blood test. Signs and symptoms may occur as the number of blood cells increases. Other conditions may cause the same signs and symptoms. Check with your doctor if you have:
a feeling of pressure or fullness below the ribs on the left side
headaches
double vision or seeing dark or blind spots that come and go
itching all over the body, especially after being in warm or hot water
reddened face that looks like a blush or sunburn
weakness
dizziness
weight loss for no known reason
Special blood tests are used to diagnose polycythemia vera.
In addition to a complete blood count, bone marrow aspiration and biopsy, and cytogenetic analysis, a serumerythropoietin test is used to diagnose polycythemia vera. In this test, a sample of blood is checked for the level of erythropoietin (a hormone that stimulates new red blood cells to be made). In polycythemia vera, the erythropoietin level would be lower than normal because the body does not need to make more red blood cells.
Essential Thrombocythemia
Key Points
Essential thrombocythemia is a disease in which too many platelets are made in the bone marrow.
Patients with essential thrombocythemia may have no signs or symptoms.
Certain factors affect prognosis (chance of recovery) and treatment options for essential thrombocythemia.
Essential thrombocythemia is a disease in which too many platelets are made in the bone marrow.
Patients with essential thrombocythemia may have no signs or symptoms.
Essential thrombocythemia often does not cause early signs or symptoms. It may be found during a routine blood test. Signs and symptoms may be caused by essential thrombocythemia or by other conditions. Check with your doctor if you have:
headaches
burning or tingling in the hands or feet
redness and warmth of the hands or feet
vision or hearing problems
Platelets are sticky. When there are too many platelets, they may clump together and make it hard for the blood to flow. Clots may form in blood vessels and there may also be increased bleeding. These can cause serious health problems such as stroke and heart attack, or pulmonary embolism and deep vein thrombosis in people older than 60 years, who have had blood clots or high white blood cell counts in the past. In some people, essential thrombocythemia may become acute leukemia.
Certain factors affect prognosis (chance of recovery) and treatment options for essential thrombocythemia.
whether the patient has signs or symptoms or other problems related to essential thrombocythemia
Overt and Prefibrotic Primary Myelofibrosis
Key Points
Primary myelofibrosis is a disease in which abnormal blood cells and fibers build up inside the bone marrow.
Symptoms of primary myelofibrosis include pain below the ribs on the left side and feeling very tired.
Certain factors affect prognosis (chance of recovery) and treatment options for primary myelofibrosis.
Primary myelofibrosis is a disease in which abnormal blood cells and fibers build up inside the bone marrow.
The bone marrow is made of tissues that make blood cells (red blood cells, white blood cells, and platelets) and a web of fibers that support the blood-forming tissues. In primary myelofibrosis (also called chronic idiopathic myelofibrosis), large numbers of blood stem cells become blood cells that do not mature properly (blasts). The web of fibers inside the bone marrow also becomes very thick (like scar tissue) and slows the blood-forming tissue’s ability to make blood cells. This causes the blood-forming tissues to make fewer and fewer blood cells. In order to make up for the low number of blood cells made in the bone marrow, the liver and spleen begin to make the blood cells.
Symptoms of primary myelofibrosis include pain below the ribs on the left side and feeling very tired.
Primary myelofibrosis often does not cause early signs or symptoms. It may be found during a routine blood test. Signs and symptoms may be caused by primary myelofibrosis or by other conditions. Check with your doctor if you have:
pain or a feeling of fullness below the ribs on the left side
early satiety (feeling full sooner than normal when eating)
Signs and symptoms of chronic eosinophilic leukemia include fever and feeling very tired.
Chronic eosinophilic leukemia may not cause early signs or symptoms. It may be found during a routine blood test. Signs and symptoms may be caused by chronic eosinophilic leukemia or by other conditions. Check with your doctor if you have:
There is no standard staging system for myeloproliferative neoplasms.
There is no standard staging system for myeloproliferative neoplasms.
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 myeloproliferative neoplasms. It is important to know the type of myeloproliferative neoplasm in order to plan treatment.
Treatment Option Overview
Key Points
There are different types of treatment for patients with myeloproliferative neoplasms.
The following types of treatment are used:
Watchful waiting
Phlebotomy
Platelet apheresis
Transfusion therapy
Chemotherapy
Radiation therapy
Other drug therapy
Surgery
Immunotherapy
Targeted therapy
High-dose chemotherapy with stem cell transplant
New types of treatment are being tested in clinical trials.
Treatment for myeloproliferative neoplasms may cause side effects.
Follow-up care may be needed.
There are different types of treatment for patients with myeloproliferative neoplasms.
Different types of treatments are available for patients with myeloproliferative neoplasms. 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. 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.
Phlebotomy is a procedure in which blood is taken from a vein. A sample of blood may be taken for tests such as a CBC or blood chemistry. Sometimes phlebotomy is used as a treatment and blood is taken from the body to remove extra red blood cells. Phlebotomy is used in this way to treat some myeloproliferative neoplasms.
Platelet apheresis
Platelet apheresis is a treatment that uses a special machine to remove platelets from the blood. Blood is taken from the patient and put through a blood cell separator where the platelets are removed. The rest of the blood is then returned to the patient’s bloodstream.
Transfusion therapy
Blood transfusion is a method of giving red blood cells, white blood cells, or platelets to replace blood cells destroyed by disease or cancer treatment.
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).
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, such as the spleen, with cancer.
Anagrelide therapy is used to reduce the risk of blood clots in patients who have too many platelets in their blood. Low-dose aspirin may also be used to reduce the risk of blood clots.
Splenectomy (surgery to remove the spleen) may be done if the spleen is enlarged.
Immunotherapy
Immunotherapy is a treatment that uses the patient’s immune system to fight cancer. Substances made by the body or made in a laboratory are used to boost, direct, or restore the body’s natural defenses against cancer.
Interferon: Interferon affects the division of cancer cells and can slow tumor growth. Interferon alfa and pegylated interferon alpha are commonly used to treat certain myeloproliferative neoplasms.
Targeted therapy
Targeted therapy is a type of treatment that uses drugs or other substances to identify and attack specific cancer cells.
Other types of targeted therapies are being studied in clinical trials.
High-dose chemotherapy with stem cell transplant
High doses of chemotherapy are given to kill cancer cells. Healthy cells, including blood-forming cells, are also destroyed by the cancer treatment. Stem cell transplant is a treatment to replace the blood-forming cells. Stem cells (immature blood cells) are removed from the blood or bone marrow of the patient or a donor and are frozen and stored. After the patient completes chemotherapy, the stored stem cells are thawed and given back to the patient through an infusion. These reinfused stem cells grow into (and restore) the body’s blood cells.
EnlargeDonor 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.
New types of treatment are being tested in clinical trials.
For some people, joining a clinical trial may be an option. There are different types of clinical trials for people with cancer. For example, a treatment trial tests new treatments or new ways of using current treatments. Supportive care and palliative care trials look at ways to improve quality of life, especially for those who have side effects from cancer and its treatment.
You can use the clinical trial search to find NCI-supported cancer clinical trials accepting participants. The search allows you to filter trials based on the type of cancer, your age, and where the trials are being done. Clinical trials supported by other organizations can be found on the ClinicalTrials.gov website.
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).
Use our clinical trial search to find NCI-supported cancer clinical trials that are accepting patients. You can search for trials based on the type of cancer, the age of the patient, and where the trials are being done. General information about clinical trials is also available.
Treatment of Polycythemia Vera
The purpose of treatment for polycythemia vera is to reduce the number of extra blood cells. Treatment of polycythemia vera may include:
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.
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.
Patients with primary myelofibrosis may have signs or symptoms of anemia. Anemia is usually treated with transfusion of red blood cells to relieve symptoms and improve quality of life. In addition, anemia may be treated with:
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.
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.
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.
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 myeloproliferative neoplasms. It is meant to inform and help patients, families, and caregivers. It does not give formal guidelines or recommendations for making decisions about health care.
Reviewers and Updates
Editorial Boards write the PDQ cancer information summaries and keep them up to date. These Boards are made up of experts in cancer treatment and other specialties related to cancer. The summaries are reviewed regularly and changes are made when there is new information. The date on each summary (“Updated”) is the date of the most recent change.
The information in this patient summary was taken from the health professional version, which is reviewed regularly and updated as needed, by the PDQ Adult Treatment Editorial Board.
Clinical Trial Information
A clinical trial is a study to answer a scientific question, such as whether one treatment is better than another. Trials are based on past studies and what has been learned in the laboratory. Each trial answers certain scientific questions in order to find new and better ways to help cancer patients. During treatment clinical trials, information is collected about the effects of a new treatment and how well it works. If a clinical trial shows that a new treatment is better than one currently being used, the new treatment may become “standard.” Patients may want to think about taking part in a clinical trial. Some clinical trials are open only to patients who have not started treatment.
Clinical trials can be found online at NCI’s website. For more information, call the Cancer Information Service (CIS), NCI’s contact center, at 1-800-4-CANCER (1-800-422-6237).
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The best way to cite this PDQ summary is:
PDQ® Adult Treatment Editorial Board. PDQ Myeloproliferative Neoplasms Treatment. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: /types/myeloproliferative/patient/chronic-treatment-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389435]
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AML is also called acute myelogenous leukemia and acute nonlymphocytic leukemia.
Incidence and Mortality
Estimated new cases and deaths from AML in the United States in 2025:[1]
New cases: 22,010.
Deaths: 11,090.
Based on Surveillance, Epidemiology, and End Results (SEER) Program data from 2014 to 2020, 31.9% of patients with AML were alive 5 years after diagnosis.[2]
Anatomy
EnlargeBlood cell development. A blood stem cell goes through several steps to become a red blood cell, platelet, or white blood cell.
AML is a heterogenous group of blood cancers that result from clonal expansion of myeloid hematopoietic precursors in the bone marrow. Not only are circulating leukemia cells (also called blasts) seen in the peripheral blood, but granulocytopenia, anemia, and thrombocytopenia are also common as proliferating leukemia cells interfere with normal hematopoiesis.[3]
Clinical Presentation
The diagnosis of AML is uncommon before age 45 years; the median age at diagnosis is 69 years.[2] Patients may present with symptoms that include:
Weakness.
Fever.
Infection.
Pallor.
Bleeding.
The hampered production of normal blood cells due to leukemic infiltration of the bone marrow can also cause other symptoms and complications. Less commonly, patients have signs or symptoms related to the collection of leukemia cells in certain anatomical locations, such as central nervous system (CNS) or testicular involvement, or the presence of a myeloid sarcoma (also called chloroma). The symptoms of acute leukemia often arise over a 4- to 6-week period before diagnosis.[3]
Diagnostic Evaluation
The differentiation of AML from other forms of leukemia, in particular chronic myeloid leukemia and acute lymphocytic leukemia, has vital therapeutic implications. The primary diagnostic tool in this determination is flow cytometry to evaluate surface antigens on the leukemia cells. Simple morphology is not adequate in determining lineage and, at a minimum, special histochemical stains are needed. While a diagnosis can be made by evaluating peripheral blood, a bone marrow biopsy is used to evaluate morphology and cell surface markers, as well as provide material for cytogenetic and molecular analysis. A peripheral blood or bone marrow blast count of 20% or greater is required to make the diagnosis, except for cases with certain chromosomal abnormalities (i.e., t(15;17), t(8;21), inv(16), or t(16;16)).[4]
Prognosis and Prognostic Factors
While the rates of new cases of AML have not changed significantly over the last decade, age-adjusted death rates have dropped.[2] Treatment should be sufficiently aggressive to achieve complete remission (CR) because partial remission offers no substantial survival benefit. Approximately 60% to 70% of adults with AML can be expected to attain CR status after appropriate induction therapy. More than 25% of adults with AML (about 45% of those who attain CR) can be expected to survive 3 or more years and may be cured.
Approximately half of patients with AML will harbor chromosomal abnormalities; therefore, conventional cytogenetic analysis remains mandatory in the evaluation of suspected AML.[5,6] With the routine use of molecular diagnostics, the identification of recurrent somatic pathogenic variants in NPM1, FLT3, CEPBA, RUNX1, and other genes has become a routine part of determining prognosis. Cytogenetic and molecular analyses provide the strongest prognostic information available, predicting outcome of both remission induction and consolidation therapy.[7] Cytogenic and molecular information has been combined to form distinct prognostic groups.
Additional adverse prognostic factors for AML include:
Age at diagnosis. Remission rates in adult AML are inversely related to age, with an expected remission rate of more than 65% for those younger than 60 years. Data suggest that once attained, duration of remission may be shorter in older patients. Increased morbidity and mortality during induction appear to be directly related to age.
CNS involvement with leukemia.
Systemic infection at diagnosis.
Elevated white blood cell count (>100,000/mm3) at diagnosis.
History of myelodysplastic syndrome or another antecedent hematologic disorder.
Long-Term Effects of Cancer Treatment
The risk of developing any long-term effects depends on the type and dose of treatment that was used and the age at which the patient underwent treatment.
A study of 30 patients who had AML that was in remission for at least 10 years demonstrated a 13% incidence of secondary malignancies.[8] Of 31 female long-term survivors of AML or acute lymphoblastic leukemia (ALL) diagnosed before age 40 years, 26 resumed normal menstruation after completion of therapy. Among 36 live offspring of survivors, two congenital problems occurred.[8]
Most patients with AML who undergo intensive therapy are treated with an anthracycline. Anthracyclines have been associated with increased risk of congestive heart failure (CHF).[9] Anthracycline cardiotoxicity is dose-dependent. In one study, doxorubicin-related CHF was 5% at a lifetime cumulative dose of 400 mg/m2, rising to 26% at a cumulative dose of 550 mg/m2.[10] In many cases, heart failure can manifest as a late effect.[11] In an analysis of children who underwent treatment for acute leukemia, the cumulative incidence of CHF at 10 years was 1.7% in ALL and 7.5% in AML.[12]
Patients who undergo allogeneic hematopoietic stem cell transplant can experience a large number of long-term or late side effects of treatment as a result of high-dose chemotherapy and/or radiation, and as an effect of chronic graft-versus-host disease and immunosuppression. These side effects may include chronic fatigue, thyroid and gonadal dysfunction, infertility, chronic infection, accelerated coronary heart disease, osteopenia, cataracts, iron overload, adverse psychological outcomes, and second cancers.[13–15]
In the Bone Marrow Transplant Survivor Study, hematopoietic cell transplant survivors had accelerated aging and were 8.4 times more likely to be frail than their siblings (95% confidence interval [CI], 2.0−34.5; P = .003). In a multivariable analysis, frailty was associated with a 2.76-fold increase in the risk of death, compared with a nonfrail state (95% CI, 1.7−4.4; P < .001).[16]
References
American Cancer Society: Cancer Facts and Figures 2025. American Cancer Society, 2025. Available online. Last accessed January 16, 2025.
Surveillance, Epidemiology, and End Results Program: Cancer Stat Facts: Leukemia — Acute Myeloid Leukemia (AML). Bethesda, Md: National Cancer Institute, DCCPS, Surveillance Research Program, 2020. Available online. Last accessed January 24, 2025.
Sekeres MA, Gerds AT: Mitigating Fear and Loathing in Managing Acute Myeloid Leukemia. Semin Hematol 52 (3): 249-55, 2015. [PUBMED Abstract]
Swerdlow SH, Campo E, Harris NL, et al., eds.: WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. 4th rev. ed. International Agency for Research on Cancer, 2017.
Slovak ML, Kopecky KJ, Cassileth PA, et al.: Karyotypic analysis predicts outcome of preremission and postremission therapy in adult acute myeloid leukemia: a Southwest Oncology Group/Eastern Cooperative Oncology Group Study. Blood 96 (13): 4075-83, 2000. [PUBMED Abstract]
Grimwade D, Walker H, Harrison G, et al.: The predictive value of hierarchical cytogenetic classification in older adults with acute myeloid leukemia (AML): analysis of 1065 patients entered into the United Kingdom Medical Research Council AML11 trial. Blood 98 (5): 1312-20, 2001. [PUBMED Abstract]
Döhner H, Estey E, Grimwade D, et al.: Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel. Blood 129 (4): 424-447, 2017. [PUBMED Abstract]
Micallef IN, Rohatiner AZ, Carter M, et al.: Long-term outcome of patients surviving for more than ten years following treatment for acute leukaemia. Br J Haematol 113 (2): 443-5, 2001. [PUBMED Abstract]
Steinherz LJ, Steinherz PG, Tan CT, et al.: Cardiac toxicity 4 to 20 years after completing anthracycline therapy. JAMA 266 (12): 1672-7, 1991. [PUBMED Abstract]
Swain SM, Whaley FS, Ewer MS: Congestive heart failure in patients treated with doxorubicin: a retrospective analysis of three trials. Cancer 97 (11): 2869-79, 2003. [PUBMED Abstract]
Hequet O, Le QH, Moullet I, et al.: Subclinical late cardiomyopathy after doxorubicin therapy for lymphoma in adults. J Clin Oncol 22 (10): 1864-71, 2004. [PUBMED Abstract]
Chellapandian D, Pole JD, Nathan PC, et al.: Congestive heart failure among children with acute leukemia: a population-based matched cohort study. Leuk Lymphoma 60 (2): 385-394, 2019. [PUBMED Abstract]
Inamoto Y, Lee SJ: Late effects of blood and marrow transplantation. Haematologica 102 (4): 614-625, 2017. [PUBMED Abstract]
Sun CL, Francisco L, Baker KS, et al.: Adverse psychological outcomes in long-term survivors of hematopoietic cell transplantation: a report from the Bone Marrow Transplant Survivor Study (BMTSS). Blood 118 (17): 4723-31, 2011. [PUBMED Abstract]
Armenian SH, Sun CL, Kawashima T, et al.: Long-term health-related outcomes in survivors of childhood cancer treated with HSCT versus conventional therapy: a report from the Bone Marrow Transplant Survivor Study (BMTSS) and Childhood Cancer Survivor Study (CCSS). Blood 118 (5): 1413-20, 2011. [PUBMED Abstract]
Arora M, Sun CL, Ness KK, et al.: Physiologic Frailty in Nonelderly Hematopoietic Cell Transplantation Patients: Results From the Bone Marrow Transplant Survivor Study. JAMA Oncol 2 (10): 1277-1286, 2016. [PUBMED Abstract]
Classification of AML
World Health Organization (WHO) Classification
The classification of acute myeloid leukemia (AML) has been revised by a group of pathologists and clinicians under the auspices of the WHO.[1] While elements of the French-American-British (FAB) classification have been retained (i.e., morphology, immunophenotype, cytogenetics, and clinical features),[2,3] the WHO classification incorporates and interrelates morphology, cytogenetics, molecular genetics, and immunologic markers, which construct a classification that is universally applicable and has prognostic and therapeutic relevance.[1,3,4] Each criterion has prognostic and treatment implications but, for practical purposes, initial antileukemic therapy is similar for all subtypes.
In 2001, the WHO proposed a new classification system that incorporated diagnostic cytogenetic information and that more reliably correlated with outcome. This classification system also decreased the bone marrow percentage of leukemic blast requirement for the diagnosis of AML from 30% to 20%. An additional clarification was made so patients with recurrent cytogenetic abnormalities did not need to meet the minimum blast requirement to be considered as having an AML diagnosis.[5–7]
In 2008, the WHO expanded the number of cytogenetic abnormalities linked to AML classification and, for the first time, included specific pathogenic variants (CEBPA and NPM) in its classification system.[5,8] With the addition of these gene variants, FAB subclassification no longer provided prognostic information for patients with a diagnosis of AML, not otherwise specified (NOS).[9]
In 2016, the WHO classification underwent revisions to incorporate the expanding knowledge of leukemia biomarkers that are significantly important to the diagnosis, prognosis, and treatment of leukemia.[10] With emerging technologies aimed at genetic, epigenetic, proteomic, and immunophenotypic classification, AML classification will continue to evolve and provide informative prognostic and biological guidelines to clinicians and researchers.
2016 WHO classification of AML and related neoplasms
AML with well-defined genetic abnormalities is characterized by recurrent genetic abnormalities.[10] The reciprocal translocations t(8;21), inv(16) or t(16;16), t(15;17), and translocations involving the 11q23 breakpoint are the most commonly identified chromosomal abnormalities. These structural chromosome rearrangements result in the formation of fusion genes that encode chimeric proteins that may contribute to the initiation or progression of leukemogenesis. Many of these translocations are detected by either reverse transcriptase–polymerase chain reaction (RT–PCR) or fluorescence in situ hybridization (FISH), which has a higher sensitivity than metaphase cytogenetics. Other recurring cytogenetic abnormalities are less common.
Molecular diagnostic platforms such as next-generation sequencing along with RT-PCR are used to identify recurrent molecular abnormalities in AML, helping to further refine diagnostic categories in the 2016 WHO classification system.[10]
AML with t(8;21)(q22;q22), RUNX1–RUNX1T1
The translocation t(8;21)(q22;q22) is one of the most common chromosomal aberrations in AML and accounts for 5% to 12% of cases.[11] Myeloid sarcomas (chloromas) may be present and may be associated with a bone marrow blast percentage of less than 20%.
Common morphological features include:
Large blasts with abundant basophilic cytoplasm, often containing numerous azurophilic granules.
A few blasts in some cases show very large granules (pseudo Chediak-Higashi granules).
Auer rods, which may be detected in mature neutrophils.
Smaller blasts, predominantly in the peripheral blood.
Promyelocytes, myelocytes, and mature neutrophils with variable dysplasia in the bone marrow.
Rarely, AML with this translocation presents with a bone marrow blast percentage of less than 20%.[5] Along with inv(16)(p13;q22) or t(16;16)(p13;q22), AML with t(8;21) makes up a category known as core binding factor AML. This category of AML is associated with long-term survival when treated with high-dose cytarabine.[12–15]
The translocation t(8;21)(q22;q22) involves the RUNX1 gene, which encodes CBF-alpha, and the RUNX1T1 (8;21) gene.[5,16] The RUNX1::RUNX1T1 fusion transcript is consistently detected in patients with t(8;21) AML. This translocation is usually associated with a good response to chemotherapy and a high complete remission (CR) rate with long-term survival when treated with high-dose cytarabine in the consolidation phase, as demonstrated in the Cancer and Leukemia Group B (CLB-9022 and CLB-8525) trials.[12–15] Additional chromosome abnormalities are common, for example, loss of a sex chromosome and del(9)(q22). Leukocytosis (i.e., white blood count >25 × 109/L) is associated with an inferior outcome,[17] as is the presence of a KIT pathogenic variant.[18]
AML with inv(16)(p13.1;q22) or t(16;16)(p13.1;q22), CBFB::MYH11
The inv(16)(p13;q22) abnormality or t(16;16)(p13;q22) translocation is found in approximately 10% to 12% of all cases of AML, predominantly in younger patients.[5,19] Myeloid sarcomas may be present at initial diagnosis or at relapse.
Common morphological features include:
Monocytic and granulocytic differentiation.
A characteristically abnormal eosinophil component with immature purple-violet eosinophil granules that may obscure cell morphology if present in great numbers.
Auer rods in myeloblasts.
Decreased neutrophils in bone marrow.
As is found in rare cases of AML with t(8;21), the bone marrow blast percentage in this AML is occasionally less than 20%.
Both inv(16)(p13;q22) and t(16;16)(p13;q22) result in the fusion of the CBFB gene at 16q22 to the smooth muscle MYH11 gene at 16p13, thereby forming the CBFB::MYH11 fusion gene .[11] The use of FISH and RT–PCR methods is sometimes necessary to document this fusion gene because its presence is not always documented by traditional cytogenetics banding techniques.[20] Similar to AML with t(8;21), patients with the CBFB::MYH11 fusion gene achieve higher CR rates and long-term survival when treated with high-dose cytarabine in the consolidation setting.[12,13,15] Unlike AML with t(8;21), the prognostic relevance of KIT pathogenic variants is unclear.[21]
APL with PML::RARA
APL is defined by the presence of the PML::RARA fusion protein, typically a result of t(15;17)(q22;q12), but can be cryptic or result from complex cytogenetic rearrangements other than t(15;17)(q22;q12). It is also an AML in which promyelocytes are the dominant leukemic cell type. APL exists as two subtypes, hypergranular or typical APL and microgranular or hypogranular APL. APL comprises 5% to 8% of cases of AML and occurs predominately in adults in midlife.[5] Both typical and microgranular APL are commonly associated with disseminated intravascular coagulation (DIC).[22,23] In microgranular APL, unlike typical APL, the leukocyte count can be very high with a rapid doubling time.[5]
Common morphological features of typical APL include:
Kidney-shaped or bilobed nuclei.
Cytoplasm densely packed with large granules (bright pink, red, or purple in Romanowsky stains).
Bundles of Auer rods within the cytoplasm (faggot cells).
Larger Auer rods than in other types of AML.
Strongly positive myeloperoxidase (MPO) reaction in all leukemic promyelocytes.
Only occasional leukemic promyelocytes in the blood.
Common morphological features of microgranular APL include:
Bilobed nuclear shape.
Apparent scarce or absent granules (submicroscopic azurophilic granules).
Small number of abnormal promyelocytes with visible granules and/or bundles of Auer rods (faggot cells).
High leukocyte count in the peripheral blood.
Strongly positive MPO reaction in all leukemic promyelocytes.
In APL, the RARA gene on 17q12 fuses with a nuclear regulatory factor on 15q22 (PML gene) resulting in a PML::RARA gene fusion transcript.[24–26] Rare cases of cryptic or masked t(15;17) lack typical cytogenetic findings and involve complex variant translocations or submicroscopic insertion of the RARA gene into the PML gene, leading to the expression of the PML::RARA fusion transcript.[5] FISH and/or RT–PCR methods may be required to unmask these cryptic genetic rearrangements.[27,28] In approximately 1% of the patients with APL, variant chromosomal aberrations may be found in which the RARA gene is fused with other genes.[29] Variant translocations involving the RARA gene include t(11;17)(q23;q21), t(5;17)(q32;q12), and t(11;17)(q13;q21).[5]
APL has a specific sensitivity to treatment with all-trans retinoic acid (ATRA, tretinoin), which acts as a differentiating agent.[30–32] High CR rates and long-term disease-free survival in APL may be obtained by combining ATRA treatment with chemotherapy,[33] or in a chemotherapy-free regimen with arsenic trioxide.[34]
AML with t(9;11)(p21.3;q23.3), MLLT3::KMT2A
AML with 11q23 abnormalities comprises 5% to 6% of cases of AML and is typically associated with monocytic features. This type of AML is more common in children. Two clinical subgroups who have a high frequency of AML with 11q23 abnormalities are infants with AML and patients with therapy-related AML, usually occurring after treatment with DNA topoisomerase inhibitors. Patients may present with DIC and extramedullary monocytic sarcomas and/or tissue infiltration (gingiva, skin).[5]
Common morphological features include:
Monoblasts and promonocytes predominate in the bone marrow.
Monoblasts and promonocytes with strong, positive nonspecific-esterase reactions.
The MLLT3 gene on 11q23, an epigenetic regulator, is involved in translocations with approximately 135 different rearrangements that have been identified.[35] Genes other than MLLT3 may be involved in 11q23 abnormalities.[36] FISH may be required to detect genetic abnormalities involving the KMT2A gene (also known as MLL).[36–38] In general, risk categories and prognoses for individual 11q23 translocations are difficult to determine because of the lack of studies involving significant numbers of patients; however, patients with t(11;19)(q23;p13.1) have been reported to have poor outcomes.[13]
AML with t(6;9)(p23;q34.1), DEK::NUP214
The t(6;9) translocation leads to the formation of a leukemia-associated DEK::NUP214 fusion protein and accounts for approximately 1% of AML cases.[39–41] NUP214 is a component of the nuclear pore complex. This subgroup of AML has been associated with a poor prognosis.[39,42,43]
AML with inv(3)(q21.3;q26.2) or t(3;3)(q21.3;q26.2), GATA2, MECOM
The inv(3) abnormality or t(3;3) translocation occur infrequently and account for approximately 1% of all AML cases.[41] MECOM at chromosome 3q26 codes for two proteins, EVI1 and MDS1-EVI1, both of which are transcription regulators. The inv(3) and t(3;3) abnormalities do not lead to a fusion gene, rather they reposition the distal GATA2 enhancer, resulting in overexpression of EVI1, and simultaneously confer GATA2 haploinsufficiency.[44,45] These abnormalities are associated with poor prognosis.[15,46,47] Abnormalities involving MECOM can be detected in some AML cases with other 3q abnormalities and are also associated with poor prognosis.
AML (megakaryoblastic) with t(1;22)(p13.3;q13.3), RBM15::MKL1
The t(1;22)(p13;q13) translocation that produces the RBM15::MKL1 fusion gene is an uncommon driver of pediatric AML (<1% of pediatric AML) and is restricted to acute megakaryocytic leukemia. For more information, see Childhood Acute Myeloid Leukemia Treatment.
AML with BCR::ABL1 (provisional entity)
This provisional entity was added by the WHO in 2016 in an effort to recognize that patients with the BCR::ABL1 fusion protein should be treated with a tyrosine kinase inhibitor.[10] However, this entity is very difficult to distinguish from chronic myeloid leukemia (CML) in blast phase (BP-CML). Loss of IKZF1 and/or CDKN2A may help distinguish true cases of AML with BCR::ABL1 from BP-CML.[48] For more information, see Chronic Myeloid Leukemia Treatment.
AML with NPM1 pathogenic variants
NPM1 is a protein that has been linked to ribosomal protein assembly and transport and is also a molecular chaperone involved in preventing protein aggregation in the nucleolus. Immunohistochemical methods can be used to accurately identify patients with NPM1 pathogenic variants by the demonstration of cytoplasmic localization of NPM.[49] Abnormal NPM1 protein diminishes its nuclear localization and lead to impaired hematopoietic differentiation. They are primarily associated with a normal karyotype (50%), and less commonly seen in conjunction with an abnormal karyotype (<10%), or complex karyotype (<3%).[50–52] An NPM1 pathogenic variant confers improved prognosis in the absence of FLT3–internal tandem duplication (ITD) variants.[50,53,54]
AML with biallelic CEBPA pathogenic variants
In adults younger than 60 years, 10% to 15% of cytogenetically normal AML cases have CEBPA pathogenic variants.[53,55] The CEBPA gene is located on chromosome 19 and encodes a transcription factor that coordinates myeloid differentiation and cellular growth arrest.[56]
Outcomes for patients with AML and CEBPA pathogenic variants are relatively favorable and similar to that of patients with core-binding factor leukemias.[53,57] Studies have demonstrated that AML with biallelic CEBPA variants is independently associated with a favorable prognosis, while AML with monoallelic CEBPA variants is not.[55,58–60] These findings led to the WHO 2016 revision of this subtype definition to require biallelic variants.[10]
AML with RUNX1 pathogenic variants (provisional entity)
AML with RUNX1 pathogenic variants, which is a provisional entity in the 2016 WHO classification of AML and related neoplasms, denotes a distinct population of de novo AML without myelodysplastic syndrome (MDS)-related features.[61] Variants in RUNX1 are associated with a high risk of treatment failure.[62–64]
AML With Myelodysplasia-Related Features
AML with myelodysplasia-related features is characterized by 20% or more blasts in the blood or bone marrow and dysplasia in two or more myeloid cell lines, generally including megakaryocytes.[5] To make the diagnosis, dysplasia must be present in 50% or more of the cells of at least two lineages and must be present in a pretreatment bone marrow specimen or must have the presence of an MDS-related cytogenetic abnormality.[5] AML with myelodysplasia-related features may occur de novo or after MDS or a myelodysplastic/myeloproliferative neoplasm overlap. The diagnostic terminology AML with myelodysplasia-related features evolving from a myelodysplastic syndrome should be used when an MDS precedes AML.[5] When NPM1 variants or biallelic CEBPA variants are present, multilineage dysplasia alone will not classify a case as AML with myelodysplasia-related changes.[5] For more information, see Myelodysplastic Syndromes Treatment and Myelodysplastic/Myeloproliferative Neoplasms Treatment.
AML with myelodysplasia-related features occurs primarily in older patients.[5] Patients with AML with myelodysplasia-related features frequently present with severe pancytopenia.
Common morphological features include:
Multilineage dysplasia in the blood or bone marrow.
Dysplasia in 50% or more of the cells of two or more cell lines.
Dysgranulopoiesis (neutrophils with hypogranular cytoplasm, hyposegmented nuclei or bizarrely segmented nuclei).
Dyserythropoiesis (megaloblastic nuclei, karyorrhexis, or multinucleation of erythroid precursors and ringed sideroblasts).
Dysmegakaryopoiesis (micromegakaryocytes and normal size or large megakaryocytes with monolobed or multiple separated nuclei).
Chromosome abnormalities observed in AML with myelodysplasia-related features are similar to those found in MDS and frequently involve gain or loss of major segments of certain chromosomes, predominately chromosomes 5 and/or 7. The probability of achieving a CR has been reported to be affected adversely by a diagnosis of AML with myelodysplasia-related features.[65–67]
Therapy-Related Myeloid Neoplasms
Therapy-related myeloid neoplasms (t-MN) include AML (t-AML) and MDS (t-MDS) that arise secondary to cytotoxic chemotherapy and/or radiation therapy.[5] The therapy-related (or secondary) MDS are included because of their close clinicopathological relationships to therapy-related AML. Although these therapy-related disorders can be distinguished by the specific mutagenic agents involved, this distinction may be difficult to make because of the frequent overlapping use of multiple potentially mutagenic agents in treating cancer.[68] Because the associated cytogenetic abnormality, not the mutagenetic agent, determines prognosis and treatment it should be noted in the diagnosis.[10]
Since t-MN have been associated with germline pathogenic variants in cancer susceptibility genes, considering germline genetic testing or genetic counseling is warranted in those with strong family histories of cancer.[69]
Alkylating agent-related t-MN
The alkylating agent/radiation-related acute leukemias and myelodysplastic syndromes typically occur 5 to 6 years after exposure to the mutagenic agent, with a reported range of approximately 10 to 192 months.[70,71] The risk of occurrence is related to both the total cumulative dose of the alkylating agent and the age of the patient.
Cytogenetic abnormalities have been observed in more than 90% of cases of t-MN and commonly include chromosomes 5 and/or 7.[70,72,73] Complex chromosomal abnormalities (≥3 distinct abnormalities) are the most common finding.[68,72–74]
Topoisomerase II inhibitor-related t-MN
Topoisomerase II inhibitor-related t-MN occurs in patients treated with topoisomerase II inhibitors. The agents implicated are the epipodophyllotoxins etoposide and teniposide and the anthracyclines doxorubicin and 4-epi-doxorubicin.[70] The mean latency period from the time of institution of the causative therapy to the development of t-MN is approximately 2 years.[75]
As with alkylating agent/radiation-related t-MN, the cytogenetic abnormalities are often complex.[68,72–74] The predominant cytogenetic finding involves chromosome 11q23 abnormalities and KMT2A pathogenic variants.[68,76]
AML, Not Otherwise Specified (NOS)
Cases of AML that do not fulfill the criteria for AML with recurrent genetic abnormalities, AML with myelodysplasia-related features, or t-MN fall within the category of AML, NOS.[10] As mentioned before, the subcategories of AML, NOS lack prognostic significance when it is unclear if NPM1 and CEBPA pathogenic variants are present.[9] Classification in this subset of AML is based on leukemic cell features of morphology, cytochemistry, and maturation (i.e., the FAB classification system) and include:[5]
AML with minimal differentiation.
AML without maturation.
AML with maturation.
Acute myelomonocytic leukemia.
Acute monoblastic/monocytic leukemia.
Pure erythroid leukemia.
Acute megakaryoblastic leukemia.
Acute basophilic leukemia.
Acute panmyelosis with myelofibrosis.
Myeloid Sarcoma
Myeloid sarcoma (also known as extramedullary myeloid tumor, granulocytic sarcoma, and chloroma) is a tumor mass that consists of myeloblasts or immature myeloid cells, occurring in an extramedullary site.[5] Development of myeloid sarcoma has been reported in 2% to 8% of patients with AML.[77] Clinical features include occurrence common in subperiosteal bone structures of the skull, paranasal sinuses, sternum, ribs, vertebrae, and pelvis; lymph nodes, skin, mediastinum, small intestine, and the epidural space; and occurrence de novo or concomitant with AML or a myeloproliferative disorder.[10,77,78]
Morphological and cytochemical features include:
Granulocytic sarcoma composed of myeloblasts, neutrophils, and neutrophil precursors with three subtypes based on degree of maturation (i.e., blastic, immature, and differentiated).
Monoblastic sarcoma preceding or occurring simultaneously with acute monoblastic leukemia.
Tumors with trilineage hematopoiesis occurring with transformation of chronic myeloproliferative disorders.
Myeloblasts and neutrophils that are positive for MPO.
Neutrophils that are positive for naphthol ASD chloroacetate esterase.
Immunophenotyping with antibodies to MPO, lysozyme, and chloroacetate is critical to the diagnosis of these lesions.[5] The myeloblasts in granulocytic sarcomas express myeloid-associated antigens (CD13, CD33, CD117, and MPO). The monoblasts in monoblastic sarcomas express acute monoblastic leukemia antigens (CD14, CD116, and CD11c) and usually react with antibodies to lysozyme and CD68. The main differential diagnosis includes non-Hodgkin lymphoma of the lymphoblastic type, Burkitt lymphoma, large-cell lymphoma, and small, round-cell tumors, especially in children (e.g., neuroblastoma, rhabdomyosarcoma, Ewing/primitive neuroectodermal tumors, and medulloblastoma). When able, FISH for common chromosomal abnormalities should be completed, as well as molecular studies to refine diagnosis and aid in prognosis.
No unique chromosomal abnormalities are associated with myeloid sarcoma.[77,79] The presence of myeloid sarcoma in patients with the otherwise good-risk t(8;21) AML may be associated with a lower CR rate and decreased remission duration.[80] Myeloid sarcoma occurring in the setting of MDS or myeloproliferative disorder is equivalent to blast transformation (progression to AML). In the case of AML, the prognosis is that of the underlying leukemia.[10] Although the initial presentation of myeloid sarcoma may appear to be isolated, it is a partial manifestation of a systemic disease and should be treated with intensive chemotherapy.[77,78,81,82]
Acute leukemias of ambiguous lineage are rare types of acute leukemia in which the morphological, cytochemical, and immunophenotypic features of the blast population do not allow classification in myeloid or lymphoid categories; or the types have morphological and/or immunophenotypic features of both myeloid and lymphoid cells or both B and T lineages (i.e., acute bilineal leukemia and acute biphenotypic leukemia).[10,83,84]
MPO (flow cytometry, immunohistochemistry, or cytochemistry) or monocytic differentiation (≥ 2 of the following: nonspecific esterase cytochemistry, CD11c, CD14, CD64, lysozyme).
T-cell Lineage
Strong cytoplasmic CD3 (with antibodies to CD3 epsilon chain) or surface CD3.
B-cell Lineage
Strong CD19 with ≥1 of the following strongly expressed: cytoplasmic CD79a, cCD22, or CD10; or weak CD19 with at least two of the following strongly expressed: CD79a, cCD22, or CD10.
Cytogenetic abnormalities are observed in a high percentage of acute leukemias of ambiguous lineage.[85–88] Approximately 33% of cases have the Philadelphia chromosome, and some cases are associated with t(4;11)(q21;q23) or other 11q23 abnormalities. In general, the prognosis appears to be unfavorable. The occurrence of 11q23 abnormalities or BCR::ABL1 are especially unfavorable prognostic indicators;[86,89,90] however, preliminary results indicate that tyrosine kinase inhibitors can be used successfully.[91,92]
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Rozman M, Navarro JT, Arenillas L, et al.: Multilineage dysplasia is associated with a poorer prognosis in patients with de novo acute myeloid leukemia with intermediate-risk cytogenetics and wild-type NPM1. Ann Hematol 93 (10): 1695-703, 2014. [PUBMED Abstract]
Weinberg OK, Seetharam M, Ren L, et al.: Clinical characterization of acute myeloid leukemia with myelodysplasia-related changes as defined by the 2008 WHO classification system. Blood 113 (9): 1906-8, 2009. [PUBMED Abstract]
Smith SM, Le Beau MM, Huo D, et al.: Clinical-cytogenetic associations in 306 patients with therapy-related myelodysplasia and myeloid leukemia: the University of Chicago series. Blood 102 (1): 43-52, 2003. [PUBMED Abstract]
Churpek JE, Marquez R, Neistadt B, et al.: Inherited mutations in cancer susceptibility genes are common among survivors of breast cancer who develop therapy-related leukemia. Cancer 122 (2): 304-11, 2016. [PUBMED Abstract]
Brunning RD, Matutes E, Flandrin G, et al.: Acute myeloid leukaemias and myelodysplastic syndromes, therapy related. In: Jaffe ES, Harris NL, Stein H, et al., eds.: Pathology and Genetics of Tumours of Haematopoietic and Lymphoid Tissues. IARC Press, 2001. World Health Organization Classification of Tumours, 3, pp 89-91.
Ellis M, Ravid M, Lishner M: A comparative analysis of alkylating agent and epipodophyllotoxin-related leukemias. Leuk Lymphoma 11 (1-2): 9-13, 1993. [PUBMED Abstract]
Olney HJ, Mitelman F, Johansson B, et al.: Unique balanced chromosome abnormalities in treatment-related myelodysplastic syndromes and acute myeloid leukemia: report from an international workshop. Genes Chromosomes Cancer 33 (4): 413-23, 2002. [PUBMED Abstract]
Mauritzson N, Albin M, Rylander L, et al.: Pooled analysis of clinical and cytogenetic features in treatment-related and de novo adult acute myeloid leukemia and myelodysplastic syndromes based on a consecutive series of 761 patients analyzed 1976-1993 and on 5098 unselected cases reported in the literature 1974-2001. Leukemia 16 (12): 2366-78, 2002. [PUBMED Abstract]
Pedersen-Bjergaard J, Andersen MK, Christiansen DH, et al.: Genetic pathways in therapy-related myelodysplasia and acute myeloid leukemia. Blood 99 (6): 1909-12, 2002. [PUBMED Abstract]
Leone G, Voso MT, Sica S, et al.: Therapy related leukemias: susceptibility, prevention and treatment. Leuk Lymphoma 41 (3-4): 255-76, 2001. [PUBMED Abstract]
Bloomfield CD, Archer KJ, Mrózek K, et al.: 11q23 balanced chromosome aberrations in treatment-related myelodysplastic syndromes and acute leukemia: report from an international workshop. Genes Chromosomes Cancer 33 (4): 362-78, 2002. [PUBMED Abstract]
Yamauchi K, Yasuda M: Comparison in treatments of nonleukemic granulocytic sarcoma: report of two cases and a review of 72 cases in the literature. Cancer 94 (6): 1739-46, 2002. [PUBMED Abstract]
Yilmaz AF, Saydam G, Sahin F, et al.: Granulocytic sarcoma: a systematic review. Am J Blood Res 3 (4): 265-70, 2013. [PUBMED Abstract]
Brunning RD, Matutes E, Flandrin G, et al.: Acute myeloid leukaemia not otherwise categorised. In: Jaffe ES, Harris NL, Stein H, et al., eds.: Pathology and Genetics of Tumours of Haematopoietic and Lymphoid Tissues. IARC Press, 2001. World Health Organization Classification of Tumours, 3, pp 91-105.
Byrd JC, Weiss RB, Arthur DC, et al.: Extramedullary leukemia adversely affects hematologic complete remission rate and overall survival in patients with t(8;21)(q22;q22): results from Cancer and Leukemia Group B 8461. J Clin Oncol 15 (2): 466-75, 1997. [PUBMED Abstract]
Hayashi T, Kimura M, Satoh S, et al.: Early detection of AML1/MTG8 fusion mRNA by RT-PCR in the bone marrow cells from a patient with isolated granulocytic sarcoma. Leukemia 12 (9): 1501-3, 1998. [PUBMED Abstract]
Imrie KR, Kovacs MJ, Selby D, et al.: Isolated chloroma: the effect of early antileukemic therapy. Ann Intern Med 123 (5): 351-3, 1995. [PUBMED Abstract]
Matutes E, Pickl WF, Van’t Veer M, et al.: Mixed-phenotype acute leukemia: clinical and laboratory features and outcome in 100 patients defined according to the WHO 2008 classification. Blood 117 (11): 3163-71, 2011. [PUBMED Abstract]
van den Ancker W, Terwijn M, Westers TM, et al.: Acute leukemias of ambiguous lineage: diagnostic consequences of the WHO2008 classification. Leukemia 24 (7): 1392-6, 2010. [PUBMED Abstract]
Hanson CA, Abaza M, Sheldon S, et al.: Acute biphenotypic leukaemia: immunophenotypic and cytogenetic analysis. Br J Haematol 84 (1): 49-60, 1993. [PUBMED Abstract]
Legrand O, Perrot JY, Simonin G, et al.: Adult biphenotypic acute leukaemia: an entity with poor prognosis which is related to unfavourable cytogenetics and P-glycoprotein over-expression. Br J Haematol 100 (1): 147-55, 1998. [PUBMED Abstract]
Carbonell F, Swansbury J, Min T, et al.: Cytogenetic findings in acute biphenotypic leukaemia. Leukemia 10 (8): 1283-7, 1996. [PUBMED Abstract]
Pane F, Frigeri F, Camera A, et al.: Complete phenotypic and genotypic lineage switch in a Philadelphia chromosome-positive acute lymphoblastic leukemia. Leukemia 10 (4): 741-5, 1996. [PUBMED Abstract]
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Kawajiri C, Tanaka H, Hashimoto S, et al.: Successful treatment of Philadelphia chromosome-positive mixed phenotype acute leukemia by appropriate alternation of second-generation tyrosine kinase inhibitors according to BCR-ABL1 mutation status. Int J Hematol 99 (4): 513-8, 2014. [PUBMED Abstract]
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Treatment Option Overview for AML
Phases of Therapy
The treatment of patients with acute myeloid leukemia (AML) is based on whether the disease is newly diagnosed (previously untreated), in remission, or recurrent. Also, the intensity of the treatment and the patient’s overall health status are considered when choosing a treatment approach. Successful treatment of AML requires the control of bone marrow and systemic disease, and specific treatment of central nervous system (CNS) disease, if present. The cornerstone of this strategy includes systemically administered combination chemotherapy. Because only 5% or fewer of patients with AML develop CNS disease, prophylactic treatment is not indicated.[1,2]
Newly diagnosed (untreated): Untreated AML is defined as newly diagnosed leukemia that has not been previously treated. The initial treatment for patients with newly diagnosed AML is often induction therapy that aims to induce a remission. In patients with AML, a complete remission (CR) is defined as a normal peripheral blood cell count (absolute neutrophil count >1,000/mm3 and platelet count >100,000/mm3) and normocellular marrow with less than 5% blasts in the marrow and no signs or symptoms of the disease. In addition, no signs or symptoms are evident of CNS leukemia or other extramedullary infiltration.[3]
Modifications to the definition of CR have been proposed because some responses are deeper than a CR, and others may not meet all the criteria for a complete response. In addition, most AML patients meeting the criteria for CR have residual leukemia.[3]
If studied pretreatment, CR with negativity for a genetic marker by RT–qPCR, or CR with negativity by multicolor flow cytometry.
CR
Bone marrow blasts <5%; absence of circulating blasts and blasts with Auer rods; absence of extramedullary disease; ANC ≥1.0 × 109/L (1,000/microL); platelet count ≥100 × 109/L (100,000/microL).
CRh
ANC ≥0.5 x 109/L (500/microL) and platelet count ≥50 x 109/L (100,000/microL); otherwise all other CR criteria met.[4]
CRi
All CR criteria except for residual neutropenia (<1.0 × 109/L [1,000/microL]) or thrombocytopenia (<100 × 109/L [100,000/microL]).
MLFS
Bone marrow blasts <5%; absence of blasts with Auer rods; absence of extramedullary disease; no hematologic recovery required.
PR
All hematologic criteria of CR; decrease of bone marrow blast percentage to 5 to 25%; and decrease of pretreatment bone marrow blast percentage by at least 50%.
No response
Patients evaluable for response but not meeting criteria for CR, CRh, CRi, MLFS, or PR are categorized as having no response prior to the response landmark. Patients failing to achieve response by the designated landmark are designated as having refractory disease.
In remission: When patients are in a remission after induction chemotherapy, consolidation chemotherapy is given, with the aim of deepening the response and consolidating the remission. Maintenance therapy is not included in most current treatment protocols and clinical trials. Consolidation therapy appears to be effective when given immediately after remission is achieved.[5]
Persistent/recurrent disease: Despite intensive chemotherapy, some patients with newly diagnosed AML will not go into remission and have primary refractory disease. Also, some patients who are in a remission after induction and consolidation chemotherapy may have a return of their disease.[3] The rates of primary refractory disease and relapse vary with the age of the patient, genomic variants seen in the leukemia cells, and initial treatment given.
Table 3. Treatment Response Categories for Persistent/Recurrent Acute Myeloid Leukemia
Response Category
Definition
CR = complete remission; CRh = CR with partial hematologic recovery; CRhMRD-LL = CR with partial hematologic recovery and measurable residual disease at a low level; CRi = CR with incomplete hematologic recovery; CRiMRD-LL = CR with incomplete hematologic recovery and measurable residual disease at a low level; CRMRD- = CR without measurable residual disease; CRMRD-LL = CR with measurable residual disease detection at a low level; MRD = measurable residual disease; MRD- = absence of measurable residual disease; MRD+ = presence of measurable residual disease; MLFS = morphological leukemia-free state; PR = partial response; RT–qPCR = reverse transcription–quantitative polymerase chain reaction.
Primary refractory disease
No CR, CRh, or CRi at the response landmark (i.e., after two courses of intensive induction treatment) or a defined landmark (e.g., 180 days after commencing less-intensive therapy).
Relapsed disease (after CR, CRh, or CRi)
Bone marrow blasts ≥5%; or reappearance of blasts in the blood in at least two peripheral blood samples obtained at least 1 week apart; or development of extramedullary disease.
MRD relapse (after CR, CRh, or CRi without MRD-)
Defined by one of the following:
Conversion from MRD- to MRD+, independent of method; or
Increase of MRD copy numbers ≥1 log10 between any two positive samples in patients with CRMRD-LL, CRhMRD-LL, or CRiMRD-LL by qPCR.
Either result should be rapidly confirmed in a second consecutive sample from the same tissue source.
Stable disease
Absence of CRMRD-, CR, CRi, PR, MLFS; and criteria for progressive disease not met.
Progressive disease
Evidence for an increase in bone marrow blast percentage and/or increase of absolute blast counts in the blood:
>50% increase in marrow blasts; or
>50% increase in peripheral blasts in the absence of differentiation syndrome; or
New extramedullary disease.
Supportive Care During Therapy
Because myelosuppression is an anticipated consequence of both the leukemia and its treatment with chemotherapy, patients must be closely monitored during therapy. Facilities must be available for hematologic support with multiple blood fractions, including platelet transfusions, and for the treatment of related infectious complications.[6]
Transfusion therapy
Supportive care during remission induction treatment should routinely include red blood cell and platelet transfusions, when appropriate.[7,8] Rapid marrow ablation with consequent earlier marrow regeneration decreases morbidity and mortality. Randomized trials have shown similar outcomes for patients who received prophylactic platelet transfusions at a level of 10,000/mm3 rather than 20,000/mm3.[9] The incidence of platelet alloimmunization was similar among groups randomly assigned to receive pooled platelet concentrates from random donors; filtered, pooled platelet concentrates from random donors; ultraviolet B-irradiated, pooled platelet concentrates from random donors; or filtered platelets obtained by apheresis from single random donors.[10]
No good evidence exists to support granulocyte transfusions in the treatment of AML. A multicenter randomized trial (RING [NCT00627393]) was conducted to address the utility of granulocyte transfusions in the setting of infections.[11] There was no difference between the granulocyte and control arms for the composite primary end point of survival plus microbial response at 42 days after randomization. However, the power to detect a true beneficial effect was low because enrollment was half that of the planned study size.
Growth factors
The following growth factors have been studied in the treatment of AML:
Colony-stimulating factors: Granulocyte colony–stimulating factor and granulocyte-macrophage colony–stimulating factor have been studied in an effort to shorten the period of granulocytopenia associated with leukemia treatment.[12] If used, these agents are administered after administration of chemotherapy. Although the use of growth factors decreases the time to neutrophil recovery by 2 to 5 days, and decreases rates of febrile neutropenia and duration of hospitalization, randomized clinical trials have not shown an impact of growth factors on overall survival and their cost-effectiveness has been inconsistently reported.[13,14] Use of growth factors is not routinely recommended in the remission induction setting.
Erythropoiesis-stimulating agents: Anemia associated with the diagnosis of AML and induction chemotherapy is managed primarily with red blood transfusions. Unlike myelodysplastic syndromes, there is no role for the use of erythropoiesis stimulating agents (e.g., epoetin alfa and darbepoetin) during the treatment of AML.
Thrombopoietin mimetics: Clinical trials have assessed the use of thrombopoietin mimetics in the treatment of AML. Eltrombopag as a single agent was tested in a multicenter, randomized, placebo-controlled, double-blind, phase I/II trial of 98 patients with platelet counts less than 30 × 109/L as a result of AML or MDS. No significant improvements in platelet counts were recorded. Significant hemorrhage was reported in ten (16%) patients given eltrombopag and nine (26%) patients given placebo. No difference in disease progression or overall survival was observed.[15]
Eltrombopag appeared to hasten platelet recovery and reduce the number of platelet transfusions needed when added in an unblinded fashion to induction chemotherapy in older FLT3-negative AML patients.[16] However, in a separate, randomized double-blind study of 148 patients, eltrombopag or placebo was added to high-dose induction chemotherapy.[17] The results of this study did not indicate any clinical benefit of eltrombopag over placebo. Given the minimal efficacy signal at this point, eltrombopag is not routinely recommended in the supportive care or remission induction setting.
Antimicrobial therapy
Empiric broad spectrum antimicrobial therapy is an absolute necessity for febrile patients who are profoundly neutropenic.[18,19] Careful instruction in personal hand hygiene, dental care, and recognition of early signs of infection are appropriate in all patients. Elaborate isolation facilities (including filtered air, sterile food, and gut flora sterilization) are not indicated.[20,21] Likewise, there are no advantages to eating a cooked neutropenic diet, as demonstrated in randomized trials.[22]
Antibiotic prophylaxis with a fluoroquinolone and antifungal prophylaxis with an oral triazole or parenteral echinocandin is appropriate for patients with expected prolonged, profound neutropenia (<100/mm3 for 2 weeks for profound neutropenia lasting >7 days).[23] Unlike patients undergoing treatment for acute lymphoblastic lymphoma, Pneumocystis jirovecii prophylaxis is not routinely employed.
Nucleoside analog-based antiviral prophylaxis, such as acyclovir, is appropriate for patients who are seropositive for herpes simplex virus undergoing induction chemotherapy.[23]
References
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Treatment of Newly Diagnosed AML
Treatment Options for Newly Diagnosed (Untreated; Remission Induction) AML
Intrathecal cytarabine or methotrexate may be used to treat central nervous system (CNS) leukemia, if present.
The two-drug regimen of cytarabine given as a continuous infusion for 7 days and a 3-day course of anthracycline (the so-called 7 + 3 induction therapy) results in a complete response rate of approximately 65%. In most instances, there is no further clinical benefit when adding potentially non-cross−resistant drugs (such as fludarabine, topoisomerase inhibitors, thioguanine, mitoxantrone, histone deacetylases inhibitors, or clofarabine) to a 7 + 3 regimen. Cladribine, when added to 7 + 3 induction chemotherapy, showed improved remission rates [11] and survival rates [12] across two randomized controlled trials, but this regimen has not been widely adopted in the absence of confirmatory trials. The addition of midostaurin and gemtuzumab ozogamicin to intensive induction chemotherapy is discussed below.
The choice of anthracycline and the dose-intensity of anthracycline may influence the survival of patients with AML. Idarubicin appeared to be more effective than daunorubicin, particularly in younger adults, although the doses of idarubicin and daunorubicin may not have been equivalent.[3–6] No significant survival difference between daunorubicin and mitoxantrone has been reported.[13]
Selection of an anthracycline
At present, there is no conclusive evidence to recommend one anthracycline over another.
Evidence (anthracyclines):
In a systematic review and meta-analysis, 18 randomized controlled trials that included 6,755 patients assessed the use of idarubicin versus daunorubicin as part of induction chemotherapy.[14]
The use of idarubicin led to improved outcomes, including overall survival (OS), when compared with daunorubicin (12 studies, 5,976 patients; hazard ratio [HR], 0.90; 95% confidence interval [CI], 0.84−0.96; P = .0008). However, there was an increased risk of death during induction (14 studies, 6,349 patients; relative risk [RR], 1.18; 95% CI, 1.01−1.36; P = .03) and mucositis (five studies, 2,000 patients; RR, 1.22; 95% CI, 1.04−1.44; P = .02) with idarubicin as compared with daunorubicin. Moreover, the survival benefit for idarubicin was no longer present if a daunorubicin dose of at least 180 mg/m2 was used (four studies, 2,867 patients; HR, 0.91; 95% CI, 0.82−1.00; P = .06).
In patients aged 60 years and younger, outcomes for those who received daunorubicin (90 mg/m2/dose, total induction dosing at 270 mg/m2) were superior to those who received more traditional dosing (45 mg/m2/dose; total dose = 135 mg/m2). The complete remission (CR) rate was 71% versus 57% (P < .001), and the median survival was 24 months versus 16 months (P = .003).[15]
No randomized comparison data between daunorubicin at 270 mg/m2 and daunorubicin at 180 mg/m2, or between daunorubicin at 270 mg/m2 and idarubicin, are available.
Addition of an FLT3 inhibitor
Variants in the tyrosine kinase domain (TKD) and internal tandem duplications (ITD) of the FLT3 gene are frequent in AML and are often associated with an inferior outcome.
Midostaurin
Evidence (midostaurin):
A multicenter, randomized, phase III trial (NCT00651261) included patients with FLT3-altered AML. Patients received either the FLT3/multikinase inhibitor, midostaurin, or placebo in addition to cytarabine and daunorubicin induction chemotherapy. The addition of midostaurin led to improved survival (median, 75 vs. 26 months; HR for death, 0.78; one-sided P = .009).[8]
The event-free survival (defined as the time from randomization to relapse, death from any cause, or failure to achieve protocol-specified CR) was improved for patients in the midostaurin arm (HR for event or death, 0.78; one-sided P = .002), and the survival benefit was consistent across all FLT3 variant subtypes. The rates of CR (59% vs. 54%) and time to neutrophil count recovery were similar between the two arms.[8][Level of evidence A1]
The U.S. Food and Drug Administration (FDA) approved midostaurin in combination with induction therapy for patients with AML and any FLT3 variant.
Quizartinib
Evidence (quizartinib):
A multicenter, randomized, phase III trial (NCT02668653) included patients with FLT3-ITD–altered AML. Patients received either the selective ITD-specific FLT3 inhibitor, quizartinib, or placebo in addition to cytarabine and daunorubicin induction chemotherapy. The addition of quizartinib led to improved survival (median, 31.9 vs. 15.1 months; HR for death, 0.78; P = .032).[16]
The EFS (defined as the time from randomization to lack of CR within 42 days from the start of the last induction cycle, relapse, or death from any cause, whichever occurred first) was similar for patients in the quizartinib and placebo arms (HR for event or death, 0.92; 95% CI, 0.75–1.11; P = .24). The rates of CR and time to neutrophil count recovery were similar between the two arms.[16][Level of evidence A1]
The FDA approved quizartinib in combination with induction therapy for patients with AML and an FLT3-ITD variant but not for patients with other FLT3 variants, such as FLT3-TKD.
The addition of an FLT3 inhibitor to induction chemotherapy is the standard of care for patients with FLT3-altered AML who are eligible for intensive chemotherapy. An ongoing study (NCT03836209) is evaluating which FLT3 inhibitor is best for patients with FLT3-ITD AML receiving up-front chemotherapy. Additional studies are evaluating FLT3 inhibitors in combination with hypomethylating agents and venetoclax in patients who are not candidates for intensive therapy.
Addition of gemtuzumab ozogamicin
Evidence (gemtuzumab ozogamicin):
In a meta-analysis of more than 3,000 patients, the addition of the CD33-directed immunotoxin gemtuzumab ozogamicin to cytarabine plus anthracycline or clofarabine plus anthracycline led to a small increase in the OS rate at 5 years (30.7% vs. 34.6%; HR, 0.90; 95% CI, 0.82−0.98; P = .01).[9]
The improvement in the 5-year OS rate was seen across all ages, but this effect was greatest in patients with favorable-risk cytogenetics (55.2% vs. 76.3%; HR, 0.47; 95% CI, 0.31−0.73; P = .0005), and to a lesser extent with intermediate-risk cytogenetics (34.1% vs. 39.4%; HR, 0.84; 95% CI, 0.75−0.95; P = .007). It was not seen in patients with an adverse-risk karyotype.[9][Level of evidence A1]
In contrast, gemtuzumab ozogamicin did not improve the 1-year survival rate of older patients who received low-dose cytarabine, although the CR rate increased from 17% to 30% (odds ratio [OR], 0.48; 95% CI, 0.32–0.73; P = .006).[17]
The FDA label for gemtuzumab ozogamicin includes a boxed warning about the risk of hepatotoxicity, including severe or fatal hepatic sinusoidal obstruction syndrome.
Liposomal daunorubicin-cytarabine (CPX-351)
CPX-351 is a two-drug liposomal encapsulation that delivers cytarabine and daunorubicin at a fixed 5:1 synergistic molar ratio.
Evidence (CPX-351):
A multicenter trial investigated CPX-351 in patients aged 60 to 75 years with therapy-related AML, AML with a history of myelodysplastic syndrome (MDS), or AML with myelodysplasia-related changes.[10]
Compared with 7 + 3 induction chemotherapy, CPX-351 resulted in a better overall remission rate (47.7% vs. 33.3%; P = .016), and improved median OS (9.56 vs. 5.95 months; HR, 0.69; 95% CI, 0.52−0.90; P = .003).[10][Level of evidence A1]
The rates of early mortality and toxicities were similar between the two arms. However, the median time to recovery of neutrophils and platelets was longer for CPX-351 (35.0 and 36.5 days, respectively) as compared with 7 + 3 induction chemotherapy (29 and 29 days, respectively).
Older adults or adults with significant comorbid conditions
Some patients may decline or be too frail for intensive induction chemotherapy. Low-dose cytarabine, decitabine, azacitidine, or best supportive care can be considered equivalently effective treatment approaches for older patients with AML who decline traditional 7 + 3 induction chemotherapy. Unlike a succinct course of 7 + 3 induction, these less-intensive therapies are continued indefinitely, as long as the patient is deriving benefit (i.e., until disease progression or significant toxicity occurs).
One of the following chemotherapy regimens may be used as less-intensive therapy:
Hypomethylating agents (azacitidine and decitabine).
Low-dose cytarabine.
Venetoclax plus hypomethylating agents or low-dose cytarabine.
Glasdegib plus low-dose cytarabine.
Ivosidenib with or without azacitidine.
Enasidenib.
Intrathecal cytarabine or methotrexate may be used to treat CNS leukemia, if present.
Evidence (chemotherapy for patients who decline intensive remission induction therapy):
Hypomethylating agents: The hypomethylating agents azacitidine and decitabine are used commonly in this population of older patients, particularly in the United States. Although approval of the drugs by the FDA is for an MDS indication, the registration studies leading to approval included patients with 20% to 30% myeloblasts, or what would now be considered oligoblastic AML.[18,19]
Azacitidine: An international phase III trial (NCT01074047) randomly assigned patients with AML who were 65 years or older to receive either azacitidine or conventional regimens (7 + 3 induction, low-dose cytarabine, or best supportive care alone).[20]
Azacitidine led to a median OS of 10.4 months (95% CI, 8.0−12.7) as compared with 6.5 months (95% CI, 5.0−8.6) with conventional regimens (HR, 0.85; 95% CI, 0.69−1.03; P = .1009).[20][Level of evidence A1]
Decitabine: One phase III trial randomly assigned 485 patients with AML who were older than 65 years to receive either decitabine (n = 242) or their preferred choice (n = 243) of either supportive care (n = 28) or low-dose cytarabine (n = 215).[21]
Although rates of CR + CRp (CR with incomplete platelet recovery) were more than double in the decitabine arm (17.8%) compared with the treatment-choice arm (7.8%) (P = .001), median OS was not significantly improved for patients receiving decitabine (7.7 months) compared with the treatment of choice (5.0 months) (HR for death for decitabine, 0.85; 95% CI, .69–1.04; P = .11).
Compared with treatment for 5 consecutive days, treatment for 10 consecutive days may lead to higher response rates, particularly in those with TP53 variants and/or unfavorable cytogenetic features.[22][Level of evidence C3]
Low-dose cytarabine: Older adults who decline intensive remission-induction therapy or are considered ineligible for intensive remission-induction therapy may derive benefit from low-dose cytarabine, administered twice daily for 10 days in cycles repeated every 4 to 6 weeks.[23]
The CR rate using this regimen was 18% compared with 1% for patients treated with hydroxyurea (P = .006).
Survival with low-dose cytarabine was better than was survival with hydroxyurea (OR, 0.60; 95% CI, 0.44–0.81; P = .009).[23][Level of evidence A1]
Venetoclax plus hypomethylating agents or low-dose cytarabine: The FDA approved venetoclax, an inhibitor of the anti-apoptotic protein BCL2, in combination with low-dose cytarabine or a hypomethylating agent for the treatment of AML in patients aged 75 years or older, and those who cannot undergo 7 + 3 induction chemotherapy because of comorbidities. Approval was granted based on the results of two studies.
The first study (NCT02203773) was a nonrandomized, open-label, phase Ib clinical trial of venetoclax in combination with azacitidine or decitabine.[24]
In this study, 35 (61%; 95% CI, 47.6%−74.0%) of 57 patients had CR or CR with incomplete hematologic recovery (CRi). The median duration of response for all patients with a response (CR + CRi + partial remission [PR]) was 8.4 months (range, 4.7−11.7; n = 36).
The second study (NCT02287233) was a phase I/IIb study of venetoclax in combination with low-dose cytarabine in 82 patients with newly diagnosed AML, including patients with previous exposure to a hypomethylating agent for an antecedent hematologic disorder such as MDS.[25]
In the 82 patients enrolled in the study, the CR/CRi rate was 54% (95% CI, 42%−65%), with a median duration of remission of 8.1 months (95% CI, 5.3−14.9 months). The median OS for all patients, irrespective of response, was 10.1 months (95% CI, 5.7−14.2 months).
The most common adverse events with venetoclax combinations are gastrointestinal symptoms and myelosuppression, which may require delays between cycles, growth factor support, or decreased duration of venetoclax administration per cycle. Additionally, appropriate prophylactic measures are typically taken to prevent tumor lysis syndrome.[25][Level of evidence C3]
Glasdegib plus low-dose cytarabine: Glasdegib, an oral inhibitor of the hedgehog pathway, combined with low-dose cytarabine was compared with low-dose cytarabine alone in a randomized, phase II open-label study that included 116 patients with AML who were aged 75 years or older or who had severe comorbid conditions (cardiac disease, renal impairment, or Eastern Cooperative Oncology Group performance status 2).[26]
Of the 78 patients with AML who received glasdegib plus low-dose cytarabine, 24% (n = 19) of patients had a CR or CRi compared with 5% (2 of 38) of patients who received low-dose cytarabine alone. The median OS was 8.3 months (80%; CI, 6.6–9.5) for patients who received glasdegib/low-dose cytarabine and 4.3 months (80%; CI, 2.9–4.9) for patients who received low-dose cytarabine alone in patients with AML (HR, 0.46; 80% CI, 0.35–0.62; P = .0002).[26][Level of evidence A1]
Similar to venetoclax, the FDA approved glasdegib in combination with low-dose cytarabine for the treatment of AML in patients aged 75 years or older or who are unable to receive intensive induction chemotherapy.
Ivosidenib: For older or frail patients with AML and IDH1 variants, the IDH1 inhibitor ivosidenib is an option. The FDA approved ivosidenib alone or in combination with azacitidine for the treatment of AML that has a susceptible IDH1 variant (detected by an FDA-approved diagnostic test) in adults aged 75 years or older with newly diagnosed AML or who have comorbidities that preclude the use of intensive induction chemotherapy. Within the context of a phase I study, 34 patients with newly diagnosed IDH1-altered AML who were not candidates for intensive induction chemotherapy were treated with single-agent ivosidenib.[27]
Differentiation syndrome was reported in 6 patients (18%), but did not require treatment discontinuation.
The rate of CR plus CRi was 42.4% (95% CI, 25.5%−60.8%), with a median duration of response that was not reached (lower bound of the 95% CI was 4.6 months).
For all 34 patients on the study, the median OS was 12.6 months (95% CI, 4.5−25.7).[27][Level of evidence C3]
The combination of azacitidine and ivosidenib was evaluated in a double-blind, randomized, placebo-controlled, phase III trial in patients with newly diagnosed AML who were not eligible for intensive induction chemotherapy. The intention-to-treat analysis included 72 patients treated with azacitidine and ivosidenib and 74 patients treated with azacitidine and placebo. A supplemental new drug application for ivosidenib in combination with azacitidine for patients with untreated IDH1-altered AML is under priority review with the FDA.[28]
At a median follow-up of 12.4 months, the primary end point of EFS was improved in patients who received azacitidine and ivosidenib, compared with patients who received azacitidine and placebo (HR, 0.33; 95% CI, 0.16–0.69).
The median OS was 24 months for patients who received azacitidine and ivosidenib and 7.9 months for patients who received azacitidine and placebo (HR for death, 0.44; 95% CI, 0.27–0.73).
Differentiation syndrome occurred in 14% of patients who received azacitidine and ivosidenib and 8% of patients who received azacitidine and placebo. The incidence of bleeding events was 41% with azacitidine and ivosidenib and 29% with azacitidine and placebo. Infection of any grade was seen in 28% of patients who received azacitidine and ivosidenib and 49% of patients who received azacitidine and placebo. For more information about differentiation syndrome, see the Treatment of Newly Diagnosed Acute Promyelocytic Leukemia section.[28][Level of evidence A1]
Enasidenib: For patients with AML and IDH2 variants, the IDH2 inhibitor enasidenib is an option for older or frail patients. Although it does not have approval in this setting, enasidenib monotherapy was evaluated in a phase I/II trial in patients with newly diagnosed AML who were not eligible for standard chemotherapy.[29]
Of the 39 patients enrolled, seven (18%) had CR, one (3%) had CRi, and two (5%) had a PR.
Median OS for all patients was 11.3 months (95% CI, 5.7−15.1), and was not reached for patients who had a response.[29][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
Yates J, Glidewell O, Wiernik P, et al.: Cytosine arabinoside with daunorubicin or adriamycin for therapy of acute myelocytic leukemia: a CALGB study. Blood 60 (2): 454-62, 1982. [PUBMED Abstract]
Dillman RO, Davis RB, Green MR, et al.: A comparative study of two different doses of cytarabine for acute myeloid leukemia: a phase III trial of Cancer and Leukemia Group B. Blood 78 (10): 2520-6, 1991. [PUBMED Abstract]
Wiernik PH, Banks PL, Case DC, et al.: Cytarabine plus idarubicin or daunorubicin as induction and consolidation therapy for previously untreated adult patients with acute myeloid leukemia. Blood 79 (2): 313-9, 1992. [PUBMED Abstract]
Vogler WR, Velez-Garcia E, Weiner RS, et al.: A phase III trial comparing idarubicin and daunorubicin in combination with cytarabine in acute myelogenous leukemia: a Southeastern Cancer Study Group Study. J Clin Oncol 10 (7): 1103-11, 1992. [PUBMED Abstract]
Berman E, Heller G, Santorsa J, et al.: Results of a randomized trial comparing idarubicin and cytosine arabinoside with daunorubicin and cytosine arabinoside in adult patients with newly diagnosed acute myelogenous leukemia. Blood 77 (8): 1666-74, 1991. [PUBMED Abstract]
Mandelli F, Petti MC, Ardia A, et al.: A randomised clinical trial comparing idarubicin and cytarabine to daunorubicin and cytarabine in the treatment of acute non-lymphoid leukaemia. A multicentric study from the Italian Co-operative Group GIMEMA. Eur J Cancer 27 (6): 750-5, 1991. [PUBMED Abstract]
Löwenberg B, Suciu S, Archimbaud E, et al.: Mitoxantrone versus daunorubicin in induction-consolidation chemotherapy–the value of low-dose cytarabine for maintenance of remission, and an assessment of prognostic factors in acute myeloid leukemia in the elderly: final report. European Organization for the Research and Treatment of Cancer and the Dutch-Belgian Hemato-Oncology Cooperative Hovon Group. J Clin Oncol 16 (3): 872-81, 1998. [PUBMED Abstract]
Stone RM, Mandrekar SJ, Sanford BL, et al.: Midostaurin plus Chemotherapy for Acute Myeloid Leukemia with a FLT3 Mutation. N Engl J Med 377 (5): 454-464, 2017. [PUBMED Abstract]
Hills RK, Castaigne S, Appelbaum FR, et al.: Addition of gemtuzumab ozogamicin to induction chemotherapy in adult patients with acute myeloid leukaemia: a meta-analysis of individual patient data from randomised controlled trials. Lancet Oncol 15 (9): 986-96, 2014. [PUBMED Abstract]
Lancet JE, Uy GL, Cortes JE, et al.: CPX-351 (cytarabine and daunorubicin) Liposome for Injection Versus Conventional Cytarabine Plus Daunorubicin in Older Patients With Newly Diagnosed Secondary Acute Myeloid Leukemia. J Clin Oncol 36 (26): 2684-2692, 2018. [PUBMED Abstract]
Holowiecki J, Grosicki S, Robak T, et al.: Addition of cladribine to daunorubicin and cytarabine increases complete remission rate after a single course of induction treatment in acute myeloid leukemia. Multicenter, phase III study. Leukemia 18 (5): 989-97, 2004. [PUBMED Abstract]
Holowiecki J, Grosicki S, Giebel S, et al.: Cladribine, but not fludarabine, added to daunorubicin and cytarabine during induction prolongs survival of patients with acute myeloid leukemia: a multicenter, randomized phase III study. J Clin Oncol 30 (20): 2441-8, 2012. [PUBMED Abstract]
Arlin Z, Case DC, Moore J, et al.: Randomized multicenter trial of cytosine arabinoside with mitoxantrone or daunorubicin in previously untreated adult patients with acute nonlymphocytic leukemia (ANLL). Lederle Cooperative Group. Leukemia 4 (3): 177-83, 1990. [PUBMED Abstract]
Li X, Xu S, Tan Y, et al.: The effects of idarubicin versus other anthracyclines for induction therapy of patients with newly diagnosed leukaemia. Cochrane Database Syst Rev (6): CD010432, 2015. [PUBMED Abstract]
Fernandez HF, Sun Z, Yao X, et al.: Anthracycline dose intensification in acute myeloid leukemia. N Engl J Med 361 (13): 1249-59, 2009. [PUBMED Abstract]
Erba HP, Montesinos P, Kim HJ, et al.: Quizartinib plus chemotherapy in newly diagnosed patients with FLT3-internal-tandem-duplication-positive acute myeloid leukaemia (QuANTUM-First): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet 401 (10388): 1571-1583, 2023. [PUBMED Abstract]
Burnett AK, Hills RK, Hunter AE, et al.: The addition of gemtuzumab ozogamicin to low-dose Ara-C improves remission rate but does not significantly prolong survival in older patients with acute myeloid leukaemia: results from the LRF AML14 and NCRI AML16 pick-a-winner comparison. Leukemia 27 (1): 75-81, 2013. [PUBMED Abstract]
Silverman LR, Demakos EP, Peterson BL, et al.: Randomized controlled trial of azacitidine in patients with the myelodysplastic syndrome: a study of the cancer and leukemia group B. J Clin Oncol 20 (10): 2429-40, 2002. [PUBMED Abstract]
Kantarjian H, O’brien S, Cortes J, et al.: Results of intensive chemotherapy in 998 patients age 65 years or older with acute myeloid leukemia or high-risk myelodysplastic syndrome: predictive prognostic models for outcome. Cancer 106 (5): 1090-8, 2006. [PUBMED Abstract]
Dombret H, Seymour JF, Butrym A, et al.: International phase 3 study of azacitidine vs conventional care regimens in older patients with newly diagnosed AML with >30% blasts. Blood 126 (3): 291-9, 2015. [PUBMED Abstract]
Kantarjian HM, Thomas XG, Dmoszynska A, et al.: Multicenter, randomized, open-label, phase III trial of decitabine versus patient choice, with physician advice, of either supportive care or low-dose cytarabine for the treatment of older patients with newly diagnosed acute myeloid leukemia. J Clin Oncol 30 (21): 2670-7, 2012. [PUBMED Abstract]
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Burnett AK, Milligan D, Prentice AG, et al.: A comparison of low-dose cytarabine and hydroxyurea with or without all-trans retinoic acid for acute myeloid leukemia and high-risk myelodysplastic syndrome in patients not considered fit for intensive treatment. Cancer 109 (6): 1114-24, 2007. [PUBMED Abstract]
DiNardo CD, Pratz KW, Letai A, et al.: Safety and preliminary efficacy of venetoclax with decitabine or azacitidine in elderly patients with previously untreated acute myeloid leukaemia: a non-randomised, open-label, phase 1b study. Lancet Oncol 19 (2): 216-228, 2018. [PUBMED Abstract]
Wei AH, Strickland SA, Hou JZ, et al.: Venetoclax Combined With Low-Dose Cytarabine for Previously Untreated Patients With Acute Myeloid Leukemia: Results From a Phase Ib/II Study. J Clin Oncol 37 (15): 1277-1284, 2019. [PUBMED Abstract]
Cortes JE, Heidel FH, Hellmann A, et al.: Randomized comparison of low dose cytarabine with or without glasdegib in patients with newly diagnosed acute myeloid leukemia or high-risk myelodysplastic syndrome. Leukemia 33 (2): 379-389, 2019. [PUBMED Abstract]
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Treatment of AML in Remission
Although individual patients with acute myeloid leukemia (AML) have been reported to have long disease-free survival (DFS) or cure with a single cycle of chemotherapy,[1] consolidation therapy is always indicated in therapy that is planned with curative intent. In a small randomized study conducted by the Eastern Cooperative Oncology Group, all patients who did not receive consolidation therapy experienced a relapse after a short median complete remission (CR) duration.[2]
Treatment options for AML in remission (consolidation phase) include:
Chemotherapy with short-term (3−4 cycles), relatively intensive chemotherapy with cytarabine-based regimens similar to standard induction clinical trials (consolidation chemotherapy) and consolidation chemotherapy with more dose-intensive cytarabine-based treatment.
Maintenance therapy (longer-term therapy at lower doses) has not been shown to benefit AML patients in a number of studies, but two strategies have shown a benefit:
High-dose chemotherapy with autologous peripheral blood stem cell rescue.
High-dose marrow-ablative or reduced-intensity therapy followed by allogeneic hematopoietic cell transplant (HCT).
Chemotherapy
Nontransplant consolidation therapy using cytarabine-containing regimens has treatment-related death rates that are usually less than 10% to 20% and has reported long-term DFS rates from 20% to 50%.[3–6] The optimal doses, schedules, and duration of consolidation chemotherapy have not been determined.
The standard consolidation therapy for AML patients in remission is high-dose cytarabine; however, there exists some controversy about whether it benefits all younger AML patients in first complete response versus selected subgroups, such as those with core-binding factor abnormalities.[7–11] The duration of consolidation therapy has ranged from one cycle [4,6] to four or more cycles.[3,5]
Evidence (chemotherapy):
A large, randomized trial that compared three different cytarabine-containing consolidation therapy regimens showed a clear benefit in survival to patients younger than 60 years who received high-dose cytarabine.[3]
Intensification of cytarabine dose or duration of consolidation chemotherapy with conventionally dosed cytarabine did not improve DFS or overall survival (OS) in patients aged 60 years or older, as evidenced in the Medical Research Council (MRC-LEUK-AML11) trial.[12,13]
Dose-intensive cytarabine-based chemotherapy can be complicated by severe neurological [14] and/or pulmonary toxic effects [15] and should be administered by physicians experienced in these regimens at centers that are equipped to treat potential complications. In a retrospective analysis of 256 patients who received high-dose bolus cytarabine at a single institution, the most powerful predictor of cytarabine neurotoxicity was renal insufficiency. The incidence of neurotoxicity was significantly greater in patients treated with twice daily doses of 3 g/m2/dose when compared with 2 g/m2/dose.
Maintenance Therapy
While a number of older studies have included longer-term therapy at lower doses (maintenance), there has been no convincing evidence that maintenance therapy provides prolonged DFS or OS. However, maintenance therapy with midostaurin or oral azacitidine may improve outcomes.
Midostaurin
Evidence (midostaurin):
Variants in the tyrosine kinase domain and internal tandem duplications of the FLT3 gene are frequent in AML and are often associated with an inferior outcome.
In the multicenter, randomized, phase III RATIFY trial (NCT00651261), the FLT3/multikinase inhibitor midostaurin plus cytarabine and daunorubicin induction chemotherapy was compared with placebo in patients with FLT3-altered AML.[16][Level of evidence A1]
The addition of the FLT3/multikinase inhibitor midostaurin to cytarabine and daunorubicin induction chemotherapy led to improved survival (median, 75 vs. 26 months; hazard ratio [HR] for death, 0.78; one-sided P = .009).
Patients who remained in remission after completion of consolidation therapy entered a maintenance phase in which they received midostaurin or placebo, administered at a dose of 50 mg orally twice daily, for twelve 28-day cycles. A maintenance regimen was administered for the full 12 cycles in 120 patients (69 in the midostaurin group, and 51 in the placebo group).
An ad-hoc landmark analysis from the end of maintenance revealed no difference in DFS between the two arms. Moreover, from the start of maintenance therapy there was no difference in OS between the two arms.[17]
While maintenance was well tolerated in the RATIFY study, only a small subset of patients tolerated midostaurin as maintenance therapy after chemotherapy or transplant in a separate phase II study.[18]
In the multicenter, randomized phase II RADIUS trial (NCT01883362), the addition of midostaurin to standard of care was compared with standard of care alone after allogeneic HCT.[19] Similar to the RATIFY trial, midostaurin was administered at a dose of 50 mg orally twice daily, for twelve 28-day cycles. Thirty patients were enrolled in each arm, but only half were able to complete the entire 12 cycles of therapy.
The estimated 18-month relapse-free survival (RFS) rate was 89% in the midostaurin arm and 76% in the standard of care arm (HR, 0.46; 95% confidence interval [CI], 0.12−1.86; P = 0.27). The predicted relative reduction in the risk of relapse with the addition of midostaurin was 54%.[19][Level of evidence B1]
Oral azacitidine
Evidence (oral azacitidine):
The randomized, double-blind, placebo-controlled phase III QUAZAR AML-001 trial (NCT01757535) provided the basis for regulatory approval of oral azacitidine as maintenance therapy for AML.[20] The study included 472 patients with AML who were aged 55 years or older, were within 4 months of first CR or CR with incomplete hematologic recovery after induction chemotherapy with or without consolidation treatment, and were not candidates for allogeneic HCT. Oral azacitidine or placebo was administered at 300 mg daily for 14 days every 28 days. Treatment was continued until disease progression or unacceptable toxicity.
For patients who received azacitidine, the median OS from randomization was 24.7 months (95% CI, 18.7−30.5) compared with 14.8 months (95% CI, 11.7−17.6) for patients receiving placebo (HR, 0.69; 95% CI, 0.55−0.86; P = .0009).[20][Level of evidence A1]
Hematopoietic Cell (Bone Marrow or Stem Cell) Transplant
Allogeneic HCT
Allogeneic HCT, even with minimal conditioning chemotherapy, results in the lowest incidence of leukemic relapse, even when compared with HCT from an identical twin (syngeneic HCT). This finding led to the concept of an immunologic graft-versus-leukemia effect, similar to (and related to) graft-versus-host disease. The improvement in freedom from relapse using allogeneic HCT as the primary consolidation therapy is offset, at least in part, by the increased morbidity and mortality caused by graft-versus-host disease, veno-occlusive disease of the liver, and infection. The DFS rates using allogeneic transplant in first complete remission have ranged from 45% to 60%.[21–24]
The use of allogeneic HCT in adults requires either a HLA-matched sibling donor, an HLA-matched unrelated donor, a haploidentical donor (“half HLA-matched”), or two well-matched umbilical cord blood units. Including patients who underwent HCT from 2007 to 2017, the 3-year probabilities of survival after HLA-matched sibling transplant were 59% (±1%) for patients with early disease, 53% (±1%) for patients with intermediate disease, and 29% (±1%) for patients with advanced disease, according to the Center for International Blood and Marrow Transplant Research registry.[24] The probabilities of survival after an unrelated donor transplant were 53% (±1%) for patients with early disease, 50% (±1%) for intermediate disease, and 27% (±1%) for patients with advanced disease. [Level of evidence C1]
Because HCT can cure more than 30% of patients who experience relapse after chemotherapy, some investigators suggested that allogeneic bone marrow transplant (BMT) can be reserved for early first relapse or second CR without compromising the number of patients who are ultimately cured.[25] Clinical and cytogenetic information can define certain subsets of patients with predictable better or worse prognoses according to favorable- and adverse-risk factors in those using consolidation chemotherapy.[26]
Favorable-risk AML: Favorable-risk factors include t(8;21), inv(16), normal karyotype with an NPM1 variant (in absence of an FLT3 variant), and normal karyotype with double cytosine-cytosine-adenosine-adenosine-thymidine (CCAAT)-enhancer binding protein (C/EBP)-alpha variants. Patients in the favorable-risk group have a reasonable chance of cure with intensive consolidation chemotherapy, and it may be reasonable to defer transplant in that group until early first relapse.
Adverse-risk AML: Adverse-risk factors include deletion of 5q, 7q, 17p, inversion of 3 or t(3;3), abnormality of (17p), trisomy 8, t(6;9), t(9;22), most translocations involving chromosome 11q23, KMT2A variants, a complex or monosomal karyotype, a history of myelodysplasia or antecedent hematologic disorder, TP53 variants, RUNX1 variants, ASXL1 variants, and normal karyotype with FLT3 variants. The adverse-risk group is highly unlikely to be cured with consolidation chemotherapy, and allogeneic BMT in first CR is a reasonable option for patients. However, even with allogeneic stem cell transplant, the outcome for patients with high-risk AML is poor (5-year DFS rate of 8% to 30% for patients with treatment-related leukemia or myelodysplasia).[27]
Normal cytogenetics: Patients with normal cytogenetics are in an intermediate-risk group, and consolidation management should be individualized based on additional molecular markers, patient comorbid factors, and patient preference or, preferably, managed according to a clinical trial.
A common clinical trial design used to evaluate the benefit of allogeneic transplant as consolidation therapy for AML in first remission is the so-called donor-no donor comparison. In this design, newly diagnosed AML patients who achieve a CR are deemed medically eligible for allogeneic transplant and undergo HLA typing. If a matched sibling or matched unrelated donor is identified, the patient is allocated to the transplant arm. Analysis of outcome is by intention to treat; that is, patients assigned to the donor arm who do not receive a transplant are grouped in the analysis with the patients who did actually receive a transplant. RFS is the usual end point for this type of trial. OS from the time of diagnosis is less frequently reported in these trials.
Investigators attempted to address this issue with a meta-analysis using data from 18 separate prospective trials of AML patients using the donor-no donor design, with data from an additional six trials included for sensitivity analysis.[28] The trials included in this meta-analysis enrolled adult patients aged 60 years and younger from 1982 to 2006. Median follow-up ranged from 42 months to 142 months. Preparative regimens were similar among the different trials. Allogeneic transplant was compared with autologous transplant (six trials) or with a variety of consolidation chemotherapy regimens, with high-dose cytarabine being the most common.
Treatment-related mortality ranged from 5% to 42% in the donor groups compared with 3% to 27% in the no-donor group.
Of 18 trials reporting RFS across all cytogenetic risk groups, the combined HR for overall RFS benefit with allogeneic transplant was 0.80, indicating a statistically significant reduction in death or relapse in a first CR.
Of the 15 trials reporting OS across all cytogenetic risk groups, the combined HR for OS was 0.90, again indicating a statistically significant reduction in death or relapse in a first CR.
In subgroup analysis according to cytogenetic risk , there was no RFS or OS benefit of allogeneic transplant for patients with favorable-risk AML (RFS: HR, 1.07; 95% CI, 0.83–1.38; P = .59; OS: HR, 1.06; 95% CI, 0.64–1.76; P = .81). However, a transplant benefit was seen for patients with intermediate (RFS: HR, 0.83; 95% CI, 0.74–0.93; P < .01; OS: HR, 0.84; 95% CI, 0.71–0.99; P = .03) or adverse-risk cytogenetics (RFS: HR, 0.73; 95% CI, 0.59–0.90; P < .01; OS: HR, 0.60; 95% CI, 0.40–0.90; P = .01).[28][Level of evidence B4] The conclusion from this meta-analysis was that allogeneic transplant from a sibling donor in a first CR is justified on the basis of improved RFS and OS for patients with intermediate- or adverse-risk, but not favorable-risk, cytogenetics.
An important caveat to this analysis is that induction and consolidation strategies for AML among studies included in the meta-analysis were not uniform; nor were definitions of cytogenetic risk groups uniform. This may have resulted in inferior survival rates among chemotherapy-only treated patients.
Most physicians who treat patients with leukemia agree that transplant should be offered to AML patients in first CR in the setting of adverse-risk cytogenetics and should not be offered to patients in first CR with favorable-risk cytogenetics.[26] However, older patients with favorable-risk AML who are unlikely to tolerate intensive cytarabine-based consolidation therapy can be considered for allogeneic HCT as consolidation therapy.[29]
Autologous hematopoietic stem cell transplant
The role of autologous transplant for AML patients has diminished over time because of the improvements in the nonrelapse mortality associated with allogeneic HCT, as well as the advent of haploidentical and umbilical cord transplant expanding the potential donor pool so that nearly every patient has a donor.[30–33] Autologous HCT can yield DFS rates between 35% and 50% in patients with AML in first remission. Autologous HCT has also cured a smaller proportion of patients in second remission.[34–40] Treatment-related mortality rates of patients who have had autologous peripheral blood or marrow transplant range from 10% to 20%.
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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Schaich M, Röllig C, Soucek S, et al.: Cytarabine dose of 36 g/m² compared with 12 g/m² within first consolidation in acute myeloid leukemia: results of patients enrolled onto the prospective randomized AML96 study. J Clin Oncol 29 (19): 2696-702, 2011. [PUBMED Abstract]
Miyawaki S, Ohtake S, Fujisawa S, et al.: A randomized comparison of 4 courses of standard-dose multiagent chemotherapy versus 3 courses of high-dose cytarabine alone in postremission therapy for acute myeloid leukemia in adults: the JALSG AML201 Study. Blood 117 (8): 2366-72, 2011. [PUBMED Abstract]
Stone RM, Berg DT, George SL, et al.: Postremission therapy in older patients with de novo acute myeloid leukemia: a randomized trial comparing mitoxantrone and intermediate-dose cytarabine with standard-dose cytarabine. Blood 98 (3): 548-53, 2001. [PUBMED Abstract]
Goldstone AH, Burnett AK, Wheatley K, et al.: Attempts to improve treatment outcomes in acute myeloid leukemia (AML) in older patients: the results of the United Kingdom Medical Research Council AML11 trial. Blood 98 (5): 1302-11, 2001. [PUBMED Abstract]
Haupt HM, Hutchins GM, Moore GW: Ara-C lung: noncardiogenic pulmonary edema complicating cytosine arabinoside therapy of leukemia. Am J Med 70 (2): 256-61, 1981. [PUBMED Abstract]
Stone RM, Mandrekar SJ, Sanford BL, et al.: Midostaurin plus Chemotherapy for Acute Myeloid Leukemia with a FLT3 Mutation. N Engl J Med 377 (5): 454-464, 2017. [PUBMED Abstract]
Larson RA, Mandrekar SJ, Sanford BL: An Analysis of Maintenance Therapy and Post-Midostaurin Outcomes in the International Prospective Randomized, Placebo-Controlled, Double-Blind Trial (CALGB 10603/RATIFY [Alliance]) for Newly Diagnosed Acute Myeloid Leukemia (AML) Patients with FLT3 Mutations. [Abstract] Blood 130 (Suppl 1):145, 2017.
Schlenk RF, Weber D, Fiedler W, et al.: Midostaurin added to chemotherapy and continued single-agent maintenance therapy in acute myeloid leukemia with FLT3-ITD. Blood 133 (8): 840-851, 2019. [PUBMED Abstract]
Maziarz RT, Levis M, Patnaik MM, et al.: Midostaurin after allogeneic stem cell transplant in patients with FLT3-internal tandem duplication-positive acute myeloid leukemia. Bone Marrow Transplant 56 (5): 1180-1189, 2021. [PUBMED Abstract]
Wei AH, Döhner H, Pocock C, et al.: Oral Azacitidine Maintenance Therapy for Acute Myeloid Leukemia in First Remission. N Engl J Med 383 (26): 2526-2537, 2020. [PUBMED Abstract]
Clift RA, Buckner CD, Thomas ED, et al.: The treatment of acute non-lymphoblastic leukemia by allogeneic marrow transplantation. Bone Marrow Transplant 2 (3): 243-58, 1987. [PUBMED Abstract]
Reiffers J, Gaspard MH, Maraninchi D, et al.: Comparison of allogeneic or autologous bone marrow transplantation and chemotherapy in patients with acute myeloid leukaemia in first remission: a prospective controlled trial. Br J Haematol 72 (1): 57-63, 1989. [PUBMED Abstract]
Bostrom B, Brunning RD, McGlave P, et al.: Bone marrow transplantation for acute nonlymphocytic leukemia in first remission: analysis of prognostic factors. Blood 65 (5): 1191-6, 1985. [PUBMED Abstract]
D’Souza A, Fretham C, Lee SJ, et al.: Current Use of and Trends in Hematopoietic Cell Transplantation in the United States. Biol Blood Marrow Transplant 26 (8): e177-e182, 2020. [PUBMED Abstract]
Schiller GJ, Nimer SD, Territo MC, et al.: Bone marrow transplantation versus high-dose cytarabine-based consolidation chemotherapy for acute myelogenous leukemia in first remission. J Clin Oncol 10 (1): 41-6, 1992. [PUBMED Abstract]
Döhner H, Estey E, Grimwade D, et al.: Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel. Blood 129 (4): 424-447, 2017. [PUBMED Abstract]
Witherspoon RP, Deeg HJ, Storer B, et al.: Hematopoietic stem-cell transplantation for treatment-related leukemia or myelodysplasia. J Clin Oncol 19 (8): 2134-41, 2001. [PUBMED Abstract]
Koreth J, Schlenk R, Kopecky KJ, et al.: Allogeneic stem cell transplantation for acute myeloid leukemia in first complete remission: systematic review and meta-analysis of prospective clinical trials. JAMA 301 (22): 2349-61, 2009. [PUBMED Abstract]
Tallman MS, Wang ES, Altman JK, et al.: Acute Myeloid Leukemia, Version 3.2019, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw 17 (6): 721-749, 2019. [PUBMED Abstract]
Gerds AT, Appelbaum FR: To transplant or not to transplant for adult acute myeloid leukemia: an ever-evolving decision. Clin Adv Hematol Oncol 10 (10): 655-62, 2012. [PUBMED Abstract]
Gooley TA, Chien JW, Pergam SA, et al.: Reduced mortality after allogeneic hematopoietic-cell transplantation. N Engl J Med 363 (22): 2091-101, 2010. [PUBMED Abstract]
Ciurea SO, Zhang MJ, Bacigalupo AA, et al.: Haploidentical transplant with posttransplant cyclophosphamide vs matched unrelated donor transplant for acute myeloid leukemia. Blood 126 (8): 1033-40, 2015. [PUBMED Abstract]
Chao NJ, Stein AS, Long GD, et al.: Busulfan/etoposide–initial experience with a new preparatory regimen for autologous bone marrow transplantation in patients with acute nonlymphoblastic leukemia. Blood 81 (2): 319-23, 1993. [PUBMED Abstract]
Linker CA, Ries CA, Damon LE, et al.: Autologous bone marrow transplantation for acute myeloid leukemia using busulfan plus etoposide as a preparative regimen. Blood 81 (2): 311-8, 1993. [PUBMED Abstract]
Sanz MA, de la Rubia J, Sanz GF, et al.: Busulfan plus cyclophosphamide followed by autologous blood stem-cell transplantation for patients with acute myeloblastic leukemia in first complete remission: a report from a single institution. J Clin Oncol 11 (9): 1661-7, 1993. [PUBMED Abstract]
Cassileth PA, Andersen J, Lazarus HM, et al.: Autologous bone marrow transplant in acute myeloid leukemia in first remission. J Clin Oncol 11 (2): 314-9, 1993. [PUBMED Abstract]
Jones RJ, Santos GW: Autologous bone marrow transplantation with 4-hydroperoxycyclophosphamide purging. In: Gale RP, ed.: Acute Myelogenous Leukemia: Progress and Controversies: Proceedings of a Wyeth-Ayerst-UCLA Symposia Western Workshop Held at Lake Lanier, Georgia, November 28-December 1, 1989. Wiley-Liss, 1990, pp 411-419.
Gorin NC, Aegerter P, Auvert B, et al.: Autologous bone marrow transplantation for acute myelocytic leukemia in first remission: a European survey of the role of marrow purging. Blood 75 (8): 1606-14, 1990. [PUBMED Abstract]
Robertson MJ, Soiffer RJ, Freedman AS, et al.: Human bone marrow depleted of CD33-positive cells mediates delayed but durable reconstitution of hematopoiesis: clinical trial of MY9 monoclonal antibody-purged autografts for the treatment of acute myeloid leukemia. Blood 79 (9): 2229-36, 1992. [PUBMED Abstract]
Treatment of Refractory or Recurrent AML
No standard treatment regimen exists for patients with refractory or recurrent acute myeloid leukemia (AML).[1,2]
Treatment options for refractory or recurrent AML include:
A number of intensive salvage chemotherapy regimens have demonstrated efficacy in recurrent AML, including:
Fludarabine, cytarabine, and filgrastim (FLAG)
FLAG has shown antileukemic activity in patients with relapsed and refractory AML.
Evidence (FLAG):
A multicenter phase II study included 83 patients with relapsed or refractory AML or de novo refractory anemia with excess blasts in transformation. The primary end point was the rate of complete remission (CR) achieved after one or two courses of FLAG induction chemotherapy.[3]
In patients with relapsed leukemia whose first remission lasted for 6 months or more, the CR rate was 81% (17 of 21 patients).
In patients with AML whose first remission lasted less than 6 months, or in patients with primary refractory disease, the CR rate was 30% (13 of 44 patients).[3][Level of evidence C3]
Myelosuppression and mucositis were common therapy-related toxicities.
Idarubicin has been added to this regimen as well (FLAG-Ida).[4]
Mitoxantrone, etoposide, and cytarabine (MEC)
Evidence (MEC):
A study evaluated one course of MEC chemotherapy in 74 patients with AML and a poor prognosis. The population included 30 patients with relapsed AML, 28 patients with primary refractory AML, and 16 patients with secondary AML.[5]
A phase III randomized Eastern Cooperative Oncology Group (ECOG) trial (E-2995) assessed 129 patients with one of the following disease statuses: relapsed AML less than 6 months after first CR; relapsed AML after allogeneic or autologous bone marrow transplant; second or greater AML relapse; primary induction failure; secondary AML; or high-risk myelodysplastic syndromes. Patients were randomly assigned to receive MEC with or without valspodar, a multidrug resistance modulator.
The complete response rate was only 17% to 25% in both arms.[6][Level of evidence B3]
Standard or high-dose cytarabine and mitoxantrone
Evidence (standard or high-dose cytarabine and mitoxantrone):
A study of cytarabine and mitoxantrone included 49 patients with relapsed or refractory AML.[7]
Treatment was successful in 50% to 60% of patients who experienced relapse after initially obtaining a CR, with 62.5% of patients with AML in first relapse achieving M1 marrow.[7,8]
High-dose etoposide and cyclophosphamide
Evidence (high-dose etoposide and cyclophosphamide):
Reported results have been similar to those for the combination of cytarabine and mitoxantrone.[9]
Idarubicin and cytarabine
Evidence (idarubicin and cytarabine):
Reported results have been similar to those for the combination of cytarabine and mitoxantrone.[10,11]
Cytarabine, daunorubicin, and etoposide (ADE).[13]
Clofarabine plus cytarabine with or without filgrastim (CLAG).[14,15]
Reduced-intensity therapy, including targeted therapy
Patients who are unable or unwilling to undergo intensive therapy can be treated with reduced-intensity therapies.
Gilteritinib
Gilteritinib is an oral FLT3 inhibitor with activity in both internal tandem duplication (ITD) and tyrosine kinase domain (TKD) subtypes.
Evidence (gilteritinib):
In a phase III trial, 371 patients were randomly assigned in a 2:1 ratio to receive either gilteritinib or preselected salvage chemotherapy (MEC, FLAG-Ida, azacitidine, or low-dose cytarabine).[16,17]
With a median follow-up of 37.1 months, the median overall survival (OS) was 9.3 months for patients who received gilteritinib versus 5.6 months for patients who received chemotherapy (hazard ratio [HR] for death, 0.665; 95% confidence interval [CI], 0.52–0.85). The estimated OS rate at 2 years was 20.6% (95% CI, 15.8%–26.0%) for patients who received gilteritinib and 14.2% (95% CI, 8.3%–21.6%) for patients who received chemotherapy.[16] Among those treated with gilteritinib, the median duration of complete response or complete response with partial hematologic recovery was 10 months (interquartile range [IQR], 2.08–not evaluable), and 23 months (IQR, 4.9–not evaluable) for just those achieving a complete response.[17]
The rates of complete response and complete response with partial hematologic recovery were higher in patients who received gilteritinib than in patients who received chemotherapy (34% vs. 15.3%; HR, 18.6; 95% CI, 9.8–27.4).
Adverse events of grade 3 or higher were less common in patients who received gilteritinib when adjusted for exposure time.[16][Level of evidence A1] The most common adverse event of interest was increased liver transaminases for patients who received gilteritinib therapy. If liver transaminase levels (considered related to treatment) increase to more than 5 times the upper limit of normal, gilteritinib therapy is paused. When the enzymes return to less than 2.5 times the upper limit of normal, therapy can resume at a reduced dose of 80 mg once daily.[17][Level of evidence A1]
Enasidenib
Enasidenib is an oral small molecule inhibitor with activity against the altered IDH2 enzyme.
Evidence (enasidenib):
In a phase I/II study, 214 patients with relapsed or refractory AML were treated with enasidenib.[18]
The overall response rate was 40.3% (95% CI, 33.0%–48.0%), with a median response duration of 5.8 months.
This included 46 patients (26.1%) with a CR or a CR with incomplete hematologic recovery (CRi).
Grade 3 or 4 treatment-related adverse events included indirect hyperbilirubinemia (12%) and differentiation syndrome (7%). As a result, the U.S. Food and Drug Administration (FDA) added a boxed warning to enasidenib, which alerts prescribers that differentiation syndrome can occur.[18][Level of evidence C3]
Ivosidenib
Ivosidenib is an oral small molecule inhibitor with activity against the altered IDH1 enzyme.
Evidence (ivosidenib):
In a phase I/II study, 179 patients with relapsed or refractory AML were treated with ivosidenib.[19]
The overall response rate was 39.1% (95% CI, 31.9%–46.7%) with a median duration response of 6.5 months (range, 4.6–9.3). This included 54 patients (30.2%) with a CR or a CRi.
Over one-third of patients who initially required transfusions became transfusion independent.
Grade 3 or higher prolongation of the QT interval was seen in 14 patients (7.8%), and grade 3 or higher differentiation was seen in 7 patients (3.9%). The FDA added a boxed warning to ivosidenib, which alerts prescribers that differentiation syndrome can occur.[19][Level of evidence C3]
Revumenib
Revumenib is an oral menin inhibitor that is approved by the FDA for the treatment of relapsed or refractory acute leukemia with a KMT2A translocation in adult and pediatric patients aged 1 year and older.
In the phase I/II AUGMENT-101 study (NCT04065399), 104 patients with relapsed or refractory acute leukemia with a KMT2A rearrangement received revumenib. Patients had to have a corrected QT interval (QTc) using Fridericia’s formula of less than 450 milliseconds at baseline.[20]
The overall rate of CR plus CRh (complete remission with partial hematologic recovery) was 21.2% (95% CI, 13.8%–30.3%). The median duration of CR plus CRh was 6.4 months (95% CI, 2.7–not reached).[20][Level of evidence C3]
Of the 83 patients who were dependent on red blood cell and/or platelet transfusions, 14% became independent of transfusions during a 56-day postbaseline period.
Revumenib has a boxed warning for differentiation syndrome, which was observed in 29% of patients. Grade 3 or 4 differentiation syndrome was observed in 13% of patients, and one patient died (0.7%).
Grade 3 or higher QTc prolongation was observed in 12% of patients.
Because revumenib is metabolized by CYP3A4, the dose must be reduced in patients receiving strong CYP3A4 inhibitors. The standard dose for patients who weigh more than 40 kg is 270 mg orally twice daily, with a dose reduction to 160 mg orally twice daily for patients receiving a strong CYP3A4 inhibitor. Furthermore, the dose is adjusted according to body surface area in patients who weigh less than 40 kg.
Hypomethylating agents
Evidence (hypomethylating agents):
In a retrospective analysis, 655 patients with relapsed or primary treatment-refractory AML received either azacitidine (57%) or decitabine (43%).[21]
Overall, 16% of patients achieved a CR or a CRi and experienced a median OS of 21 months.[21][Level of evidence C3]
Gemtuzumab ozogamicin
The antibody-targeted chemotherapy agent gemtuzumab ozogamicin has been evaluated in patients who had relapsed AML and expressed CD33.
Evidence (gemtuzumab ozogamicin):
A pooled analysis of three open-label, single-arm, phase II studies included 277 patients.[22]
The overall response rate was 26%. Thirty-five patients (13%) achieved a CR and 36 patients (13%) achieved a CR without platelet recovery. It is unclear whether the inadequate platelet recovery was the result of megakaryocyte toxic effects of gemtuzumab or subclinical residual leukemia. [22]
The long-term outcomes of patients who receive gemtuzumab and achieve CR without platelet recovery are unclear. Gemtuzumab induces profound bone marrow aplasia similar to leukemia induction chemotherapy and also has substantial hepatic toxic effects, including hepatic veno-occlusive disease.[22][Level of evidence C3]
Clofarabine with or without cytarabine
Evidence (clofarabine with or without cytarabine):
Clofarabine, a purine nucleoside analogue, was studied as a single agent in 62 patients with relapsed or refractory AML.[23]
Eight of 19 patients who received treatment for their first relapse experienced a complete response.
Clofarabine was administered in combination with intermediate-dose cytarabine in patients with relapsed or refractory AML.[24]
Seven of 29 patients with AML or myelodysplastic syndrome who received treatment for their first relapse had a CR.[24][Level of evidence C3]
Allogeneic Hematopoietic Cell Transplant
When patients with relapsed disease are treated aggressively, they may have extended disease-free survival (DFS); however, patients with relapsed disease can only be cured with HCT.[25][Level of evidence C2] Allogeneic HCT for patients in their second CR provides better DFS rates than transplant for patients in relapse.[26][Level of evidence C1]
Evidence (allogeneic HCT):
Current transplant outcomes are reported by the Center for International Blood and Marrow Transplantation Registry. The group reported the following outcomes for transplants done in the United States between 2008 and 2018:[27][Level of evidence C2]
The 3-year survival rate was 53% for patients with AML in second or subsequent CR versus 31% for patients with relapsed disease (or never in a CR) who underwent a matched sibling donor transplant.
The 3-year survival rate was 50% for patients with AML in second or subsequent CR versus 30% for patients with relapsed disease (or who never achieved CR) who underwent a matched unrelated donor transplant.
Allogeneic HCT can be effective salvage therapy in some patients whose disease fails to go into remission with intensive chemotherapy (primary refractory leukemia). A number of retrospective studies have demonstrated the ability of allogeneic HCT to induce remission in primary refractory disease.[28]
Evidence (allogeneic HCT to induce remission):
In one retrospective analysis of 168 patients with AML and primary refractory disease who underwent allogeneic HCT, the 5-year OS rate was 22%.[29]
Another analysis was conducted among patients enrolled in a prospective cooperative group trial, SWOG S0106 (NCT00085709).[30]
Of the 589 patients treated in the cooperative group trial, 150 (25%) had primary refractory disease.
Among the 64 patients with primary refractory disease who received an allogeneic HCT, the 4-year survival rate was 48% compared with 4% among the 86 patients who did not undergo transplant.[30][Level of evidence C3]
Randomized trials testing the efficacy of this approach are not available.
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
Döhner H, Estey E, Grimwade D, et al.: Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel. Blood 129 (4): 424-447, 2017. [PUBMED Abstract]
Sekeres MA, Guyatt G, Abel G, et al.: American Society of Hematology 2020 guidelines for treating newly diagnosed acute myeloid leukemia in older adults. Blood Adv 4 (15): 3528-3549, 2020. [PUBMED Abstract]
Jackson G, Taylor P, Smith GM, et al.: A multicentre, open, non-comparative phase II study of a combination of fludarabine phosphate, cytarabine and granulocyte colony-stimulating factor in relapsed and refractory acute myeloid leukaemia and de novo refractory anaemia with excess of blasts in transformation. Br J Haematol 112 (1): 127-37, 2001. [PUBMED Abstract]
Pastore D, Specchia G, Carluccio P, et al.: FLAG-IDA in the treatment of refractory/relapsed acute myeloid leukemia: single-center experience. Ann Hematol 82 (4): 231-5, 2003. [PUBMED Abstract]
Spadea A, Petti MC, Fazi P, et al.: Mitoxantrone, etoposide and intermediate-dose Ara-C (MEC): an effective regimen for poor risk acute myeloid leukemia. Leukemia 7 (4): 549-52, 1993. [PUBMED Abstract]
Greenberg PL, Lee SJ, Advani R, et al.: Mitoxantrone, etoposide, and cytarabine with or without valspodar in patients with relapsed or refractory acute myeloid leukemia and high-risk myelodysplastic syndrome: a phase III trial (E2995). J Clin Oncol 22 (6): 1078-86, 2004. [PUBMED Abstract]
Paciucci PA, Dutcher JP, Cuttner J, et al.: Mitoxantrone and ara-C in previously treated patients with acute myelogenous leukemia. Leukemia 1 (7): 565-7, 1987. [PUBMED Abstract]
Hiddemann W, Kreutzmann H, Straif K, et al.: High-dose cytosine arabinoside and mitoxantrone: a highly effective regimen in refractory acute myeloid leukemia. Blood 69 (3): 744-9, 1987. [PUBMED Abstract]
Brown RA, Herzig RH, Wolff SN, et al.: High-dose etoposide and cyclophosphamide without bone marrow transplantation for resistant hematologic malignancy. Blood 76 (3): 473-9, 1990. [PUBMED Abstract]
Lambertenghi-Deliliers G, Maiolo AT, Annaloro C, et al.: Idarubicin in sequential combination with cytosine arabinoside in the treatment of relapsed and refractory patients with acute non-lymphoblastic leukemia. Eur J Cancer Clin Oncol 23 (7): 1041-5, 1987. [PUBMED Abstract]
Harousseau JL, Reiffers J, Hurteloup P, et al.: Treatment of relapsed acute myeloid leukemia with idarubicin and intermediate-dose cytarabine. J Clin Oncol 7 (1): 45-9, 1989. [PUBMED Abstract]
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Liu Yin JA, Wheatley K, Rees JK, et al.: Comparison of ‘sequential’ versus ‘standard’ chemotherapy as re-induction treatment, with or without cyclosporine, in refractory/relapsed acute myeloid leukaemia (AML): results of the UK Medical Research Council AML-R trial. Br J Haematol 113 (3): 713-26, 2001. [PUBMED Abstract]
Becker PS, Kantarjian HM, Appelbaum FR, et al.: Clofarabine with high dose cytarabine and granulocyte colony-stimulating factor (G-CSF) priming for relapsed and refractory acute myeloid leukaemia. Br J Haematol 155 (2): 182-9, 2011. [PUBMED Abstract]
Scappini B, Gianfaldoni G, Caracciolo F, et al.: Cytarabine and clofarabine after high-dose cytarabine in relapsed or refractory AML patients. Am J Hematol 87 (12): 1047-51, 2012. [PUBMED Abstract]
Perl AE, Martinelli G, Cortes JE, et al.: Gilteritinib or Chemotherapy for Relapsed or Refractory FLT3-Mutated AML. N Engl J Med 381 (18): 1728-1740, 2019. [PUBMED Abstract]
Perl AE, Larson RA, Podoltsev NA, et al.: Follow-up of patients with R/R FLT3-mutation-positive AML treated with gilteritinib in the phase 3 ADMIRAL trial. Blood 139 (23): 3366-3375, 2022. [PUBMED Abstract]
Stein EM, DiNardo CD, Pollyea DA, et al.: Enasidenib in mutant IDH2 relapsed or refractory acute myeloid leukemia. Blood 130 (6): 722-731, 2017. [PUBMED Abstract]
DiNardo CD, Stein EM, de Botton S, et al.: Durable Remissions with Ivosidenib in IDH1-Mutated Relapsed or Refractory AML. N Engl J Med 378 (25): 2386-2398, 2018. [PUBMED Abstract]
Issa GC, Aldoss I, Thirman MJ, et al.: Menin Inhibition With Revumenib for KMT2A-Rearranged Relapsed or Refractory Acute Leukemia (AUGMENT-101). J Clin Oncol 43 (1): 75-84, 2025. [PUBMED Abstract]
Stahl M, DeVeaux M, Montesinos P, et al.: Hypomethylating agents in relapsed and refractory AML: outcomes and their predictors in a large international patient cohort. Blood Adv 2 (8): 923-932, 2018. [PUBMED Abstract]
Larson RA, Sievers EL, Stadtmauer EA, et al.: Final report of the efficacy and safety of gemtuzumab ozogamicin (Mylotarg) in patients with CD33-positive acute myeloid leukemia in first recurrence. Cancer 104 (7): 1442-52, 2005. [PUBMED Abstract]
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Faderl S, Gandhi V, O’Brien S, et al.: Results of a phase 1-2 study of clofarabine in combination with cytarabine (ara-C) in relapsed and refractory acute leukemias. Blood 105 (3): 940-7, 2005. [PUBMED Abstract]
Forman SJ, Schmidt GM, Nademanee AP, et al.: Allogeneic bone marrow transplantation as therapy for primary induction failure for patients with acute leukemia. J Clin Oncol 9 (9): 1570-4, 1991. [PUBMED Abstract]
Clift RA, Buckner CD, Thomas ED, et al.: The treatment of acute non-lymphoblastic leukemia by allogeneic marrow transplantation. Bone Marrow Transplant 2 (3): 243-58, 1987. [PUBMED Abstract]
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Treatment of Acute Promyelocytic Leukemia (APL)
Special consideration must be given to induction therapy for APL. Treatment is centered around the use of differentiating agents to clear the leukemic cells. Early mortality is related to bleeding, differentiation syndrome, or infection. High complete remission (CR) rates are very common across treatment regimens, and persistent disease or relapse is rare.
Treatment of Newly Diagnosed APL
Treatment options for newly diagnosed APL include:
ATRA induces terminal differentiation of the leukemic cells followed by restoration of nonclonal hematopoiesis. Administration of ATRA leads to rapid resolution of coagulopathy in most patients, and heparin administration is not required in patients receiving ATRA. However, randomized trials have not shown a reduction in morbidity and mortality during ATRA induction when compared with chemotherapy. ATRA administration may result in the following conditions:
Differentiation syndrome: Administration of ATRA can lead to a syndrome of respiratory distress, known as differentiation syndrome. Prompt recognition of the syndrome and aggressive administration of steroids can prevent severe respiratory distress.[1]
Hyperleukocytosis: The optimal management of ATRA-induced hyperleukocytosis has not been established. Hyperleukocytosis in APL is typically treated with the addition of cytotoxic chemotherapy. Leukopheresis is not recommended because of an increased risk of complications such as bleeding events and disseminated intravascular coagulation.
Studies performed in the 1990s demonstrated that overall survival (OS) rates improved in patients receiving ATRA in addition to chemotherapy.[2,3] ATO, an agent with both differentiation-inducing and apoptosis-inducing properties against APL cells, is also used in the treatment of APL. Induction remission therapy for APL is determined by disease risk. Low- to intermediate-risk APL (white blood cell [WBC] count ≤10 × 109/L) is treated without chemotherapy (ATRA and ATO), and high-risk is treated with a combination of ATRA and ATO plus chemotherapy.
ATRA plus ATO for low- to intermediate-risk disease
Evidence (ATRA plus ATO for low- to intermediate-risk disease):
In a phase III, randomized controlled, multicenter trial in patients with APL classified as low-to-intermediate risk (WBC count, ≤10 × 109/L) ATRA plus chemotherapy was compared with ATRA plus ATO.[4]
CR rates were equally high for both groups. CR occurred in all 77 patients (100%) who could be evaluated in the ATRA plus ATO group and in 75 of 79 patients (95%) in the ATRA plus chemotherapy group (P = .12).
With a median follow-up of 34.4 months, the 2-year OS rate was 99% (95% confidence interval [CI], 96%−100%) in the ATRA plus ATO group, and 91% (95% CI, 85%−97%) in the ATRA plus chemotherapy group (P = .02).
The 2-year cumulative incidence of relapse was similarly low in both groups, 1% (95% CI, 0%−4%) in the ATRA plus ATO group and 6% (95% CI, 0%−11%) in the ATRA plus chemotherapy group (P = .24).
The primary end point was event-free survival (EFS) (defined as no achievement of hematologic CR after induction therapy, no achievement of molecular CR after three consolidation courses, molecular relapse, hematologic relapse, or death). The 2-year EFS rate was 97% for the ATRA plus ATO group and 85% in the ATRA plus chemotherapy group (P < .001 for noninferiority).
The results of this chemotherapy-free regimen for low- to intermediate-risk APL were confirmed in a second, phase III, randomized controlled trial.[5][Level of evidence A1]
ATRA plus chemotherapy, followed by ATO-based consolidation therapy for high-risk disease
Remission induction with a combination of anthracycline and ATRA is used for remission induction in patients with high-risk disease (WBC count, >10 × 109/L).
Evidence (ATRA plus chemotherapy, followed by ATO-based consolidation therapy for high-risk disease):
The AIDA-2000 study (NCT00180128) combined oral ATRA until CR or for a maximum of 45 days and four doses of intravenous idarubicin (12 mg/m2) on days 2, 4, 6, and 8. Consolidation was then risk stratified so low- to intermediate-risk patients received additional cycles of anthracycline and ATRA, and high-risk patients also received cytarabine, etoposide, 6-thioguanine, and CHT chemotherapy (6-mercaptopurine plus methotrexate) as consolidation.[6]
After induction, 420 of 445 patients (94.4%) treated on the AIDA-2000 protocol were in CR. The 6-year OS rate was 87.4% and the cumulative incidence of relapse rate was 10.7%.[6][Level of evidence B4]
In the phase II APML4 study, ATO was added to the ATRA-and-idarubicin remission−induction backbone.[7]
Of the 124 patients who could be evaluated, there were 4 (3.2%) early deaths and 118 (95%) hematologic CRs.
The 2-year freedom-from-relapse rate was 97.5% (95% CI, 90.4%−99.4%), the failure-free survival rate was 88.1% (95% CI, 80.7%−92.8%), and the OS rate was 93.2% (95% CI, 85.8%−96.8%).[7][Level of evidence B4]
An ATO-based regimen, which includes gemtuzumab ozogamicin as the only cytotoxic drug, has been developed.
In a single-institution study, patients received ATRA plus ATO induction. They also received a dose of gemtuzumab ozogamicin (or idarubicin) if the WBC was greater than 10 × 109/L on presentation or rose to more than 30 × 109/L during induction.[8] Patients in remission received ATO and ATRA in alternating months for a total of seven cycles as consolidation; gemtuzumab ozogamicin was substituted if either ATO or ATRA were discontinued because of toxicity.
Of the 54 patients with high-risk disease treated on the protocol, one patient received both gemtuzumab ozogamicin and idarubicin (12 mg/m2 daily for 3 days) because of persistent leukocytosis despite receiving gemtuzumab ozogamicin.
The CR rate was 96%, and five (9%) patients relapsed.
The 5-year rates were 81% for EFS, 89% for disease-free survival (DFS), and 86% for OS, indicating that the responses are durable.
Across the entire study population, the 5-year OS rate was similar among the 45 high-risk patients who received gemtuzumab ozogamicin (84%) compared with the seven patients who received a dose of idarubicin (100%, P = .453).[8][Level of evidence B4]
Long-term follow up from this study has been published.[9]
It is important to note that most current regimens for the treatment of APL include some form of maintenance therapy. A meta-analysis of randomized trials has indicated that maintenance clearly improves DFS but not OS; however, these trials did not include ATO-containing regimens.
ATO has high rates of second remission in patients with relapsed APL.[10] As a single agent, ATO can lead to complete response rates of 80% to 90% in patients with hematologic relapse, and 70% to 80% in patients with molecular remission.[11–14] The choice of salvage therapy is based on the previous therapy and interval of time between first remission and relapse.
In patients with early relapse less than 6 months after ATRA and ATO, anthracycline-based regimens and ATRA as given for initial remission induction for high-risk disease should be considered.
In patients who relapse less than 6 months after ATRA and anthracycline-based regimens (no previous ATO exposure), ATO-based regimens should be considered.
In all patients with late relapse (>6 months), ATO-based regimens with or without anthracycline or gemtuzumab ozogamicin should be considered.
For patients receiving ATO as salvage therapy, a small randomized trial suggested that the addition of ATRA does not confer any benefit over ATO alone in patients who previously received ATRA.[14] In this 20-patient study, the complete response rate after one cycle of ATO with or without ATRA was 80%.
HCT
Some patients in second remission with ATO have experienced long-term DFS after autologous stem cell transplant,[15,16] and it can be considered in patients who are in molecular remission (negative quantitative polymerase chain reaction [PCR] on a marrow sample). Patients who do not go into remission or have evidence of measurable residual disease by quantitative PCR on a marrow sample after salvage therapy are considered for an allogeneic HCT.[17] A registry study reported a 3-year OS rate after transplant in second CR of 80% compared with 59% in patients without transplant (P = .03).[10]
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
Frankel SR, Eardley A, Lauwers G, et al.: The “retinoic acid syndrome” in acute promyelocytic leukemia. Ann Intern Med 117 (4): 292-6, 1992. [PUBMED Abstract]
Adès L, Guerci A, Raffoux E, et al.: Very long-term outcome of acute promyelocytic leukemia after treatment with all-trans retinoic acid and chemotherapy: the European APL Group experience. Blood 115 (9): 1690-6, 2010. [PUBMED Abstract]
Sanz MA, Montesinos P, Vellenga E, et al.: Risk-adapted treatment of acute promyelocytic leukemia with all-trans retinoic acid and anthracycline monochemotherapy: long-term outcome of the LPA 99 multicenter study by the PETHEMA Group. Blood 112 (8): 3130-4, 2008. [PUBMED Abstract]
Lo-Coco F, Avvisati G, Vignetti M, et al.: Retinoic acid and arsenic trioxide for acute promyelocytic leukemia. N Engl J Med 369 (2): 111-21, 2013. [PUBMED Abstract]
Burnett AK, Russell NH, Hills RK, et al.: Arsenic trioxide and all-trans retinoic acid treatment for acute promyelocytic leukaemia in all risk groups (AML17): results of a randomised, controlled, phase 3 trial. Lancet Oncol 16 (13): 1295-305, 2015. [PUBMED Abstract]
Lo-Coco F, Avvisati G, Vignetti M, et al.: Front-line treatment of acute promyelocytic leukemia with AIDA induction followed by risk-adapted consolidation for adults younger than 61 years: results of the AIDA-2000 trial of the GIMEMA Group. Blood 116 (17): 3171-9, 2010. [PUBMED Abstract]
Iland HJ, Bradstock K, Supple SG, et al.: All-trans-retinoic acid, idarubicin, and IV arsenic trioxide as initial therapy in acute promyelocytic leukemia (APML4). Blood 120 (8): 1570-80; quiz 1752, 2012. [PUBMED Abstract]
Ravandi F, Estey E, Jones D, et al.: Effective treatment of acute promyelocytic leukemia with all-trans-retinoic acid, arsenic trioxide, and gemtuzumab ozogamicin. J Clin Oncol 27 (4): 504-10, 2009. [PUBMED Abstract]
Abaza Y, Kantarjian H, Garcia-Manero G, et al.: Long-term outcome of acute promyelocytic leukemia treated with all-trans-retinoic acid, arsenic trioxide, and gemtuzumab. Blood 129 (10): 1275-1283, 2017. [PUBMED Abstract]
Lengfelder E, Lo-Coco F, Ades L, et al.: Arsenic trioxide-based therapy of relapsed acute promyelocytic leukemia: registry results from the European LeukemiaNet. Leukemia 29 (5): 1084-91, 2015. [PUBMED Abstract]
Leoni F, Gianfaldoni G, Annunziata M, et al.: Arsenic trioxide therapy for relapsed acute promyelocytic leukemia: a bridge to transplantation. Haematologica 87 (5): 485-9, 2002. [PUBMED Abstract]
Soignet SL, Frankel SR, Douer D, et al.: United States multicenter study of arsenic trioxide in relapsed acute promyelocytic leukemia. J Clin Oncol 19 (18): 3852-60, 2001. [PUBMED Abstract]
Thirugnanam R, George B, Chendamarai E, et al.: Comparison of clinical outcomes of patients with relapsed acute promyelocytic leukemia induced with arsenic trioxide and consolidated with either an autologous stem cell transplant or an arsenic trioxide-based regimen. Biol Blood Marrow Transplant 15 (11): 1479-84, 2009. [PUBMED Abstract]
Raffoux E, Rousselot P, Poupon J, et al.: Combined treatment with arsenic trioxide and all-trans-retinoic acid in patients with relapsed acute promyelocytic leukemia. J Clin Oncol 21 (12): 2326-34, 2003. [PUBMED Abstract]
Yanada M, Tsuzuki M, Fujita H, et al.: Phase 2 study of arsenic trioxide followed by autologous hematopoietic cell transplantation for relapsed acute promyelocytic leukemia. Blood 121 (16): 3095-102, 2013. [PUBMED Abstract]
Holter Chakrabarty JL, Rubinger M, Le-Rademacher J, et al.: Autologous is superior to allogeneic hematopoietic cell transplantation for acute promyelocytic leukemia in second complete remission. Biol Blood Marrow Transplant 20 (7): 1021-5, 2014. [PUBMED Abstract]
de Botton S, Fawaz A, Chevret S, et al.: Autologous and allogeneic stem-cell transplantation as salvage treatment of acute promyelocytic leukemia initially treated with all-trans-retinoic acid: a retrospective analysis of the European acute promyelocytic leukemia group. J Clin Oncol 23 (1): 120-6, 2005. [PUBMED Abstract]
Latest Updates to This Summary (03/14/2025)
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.
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 acute myeloid leukemia. It is intended as a resource to inform and assist clinicians in the care of their patients. It does not provide formal guidelines or recommendations for making health care decisions.
Reviewers and Updates
This summary is reviewed regularly and updated as necessary by the PDQ Adult Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).
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be cited with text, or
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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 Acute Myeloid Leukemia Treatment are:
Alexander Ambinder, MD, MPH (Johns Hopkins University )
Aaron Gerds, MD (Cleveland Clinic Taussig Cancer Institute)
Any comments or questions about the summary content should be submitted to Cancer.gov through the NCI website’s Email Us. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.
Levels of Evidence
Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Adult Treatment Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.
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The preferred citation for this PDQ summary is:
PDQ® Adult Treatment Editorial Board. PDQ Acute Myeloid Leukemia Treatment. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: /types/leukemia/hp/adult-aml-treatment-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389432]
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BCC and SCC are the most common forms of skin cancer and together are referred to as nonmelanoma skin cancers. This summary addresses the treatment of BCC and SCC of the skin and the related noninvasive lesion actinic keratosis. For more information about the treatment of melanoma, see Melanoma Treatment.
Incidence and Mortality
Nonmelanoma skin cancer is the most common cancer in the United States. BCC is the more common type, accounting for about three-quarters of nonmelanoma skin cancers.[1] The incidence of nonmelanoma skin cancer appears to be increasing in some,[2] but not all,[3] areas of the United States. Overall U.S. incidence rates have likely been increasing for a number of years.[4] At least some of this increase may be attributable to increasing skin cancer awareness and the resulting examination and biopsy of skin lesions.
The total number and incidence rate of nonmelanoma skin cancers cannot be estimated precisely because reporting to cancer registries is not required. However, based on extrapolation of Medicare fee-for-service data to the U.S. population, it has been estimated that the total number of people treated for nonmelanoma skin cancers in 2012 was about 3.3 million.[5,6] That number exceeds all other annual new cases of cancer estimated by the American Cancer Society, which total about 2 million.[6] Although nonmelanoma skin cancer is the most common of all malignancies, it accounts for less than 0.1% of patient deaths caused by cancer.
Anatomy
EnlargeAnatomy of the skin showing the epidermis (including the squamous cell and basal cell layers), dermis, subcutaneous tissue, and other parts of the skin.
Risk Factors
Risk factors for nonmelanoma skin cancer include:
Sun and UV radiation exposure (including tanning beds). Epidemiological evidence suggests that cumulative exposure to UV radiation and the sensitivity of an individual’s skin to UV radiation are risk factors for skin cancer, though the type of exposure (i.e., high-intensity exposure and short-duration exposure vs. chronic exposure) and pattern of exposure (i.e., continuous pattern vs. intermittent pattern) may differ among the three main skin cancer types.[7–9] Skin cancers are more common in the southern latitudes of the Northern hemisphere.
History of sunburns. People who have had sunburns are predisposed to the development of SCC.
Light complexion and eye color. Individuals with a light complexion (fair skin that freckles and burns easily), light-colored eyes (blue, green, or other light-colored eyes), and light-colored hair (red or blond) who have had substantial exposure to sunlight are at an increased risk of developing nonmelanoma skin cancer.
Family history or personal history of BCC, SCC, actinic keratosis, familial dysplastic nevus syndrome, or atypical nevi.
Chronic cutaneous inflammation. People with chronic cutaneous inflammation, as seen in long-standing skin ulcers, are predisposed to the development of SCC.
Immune suppression. Organ transplant recipients receiving immunosuppressive drugs and individuals with immunosuppressive diseases are at an elevated risk of developing skin cancers, particularly SCC.[1]
Other environmental exposure. Arsenic exposure and therapeutic radiation increase the risk of cutaneous SCC.[1]
Types of Skin Cancer
This evidence-based summary covers basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) of the skin and the related noninvasive lesion actinic keratosis (viewed by some pathologists as a variant of in situ SCC).[1] BCC and SCC are both of epithelial origin. Although BCC and SCC are by far the most frequent types of nonmelanoma skin cancers, approximately 82 types of skin malignancies, with a wide range of clinical behaviors, fall into the category of nonmelanoma skin cancer.[10]
Other types of malignant disease of the skin include:
BCC is at least three times more common than SCC in nonimmunocompromised patients. It usually occurs in sun-exposed areas of skin, with the nose being the most common site. Although there are many different clinical presentations for BCC, the most characteristic type is the asymptomatic nodular or nodular ulcerative lesion that is elevated from the surrounding skin, has a pearly quality, and contains telangiectatic vessels.
BCCs are composed of nonkeratinizing cells derived from the basal cell layer of the epidermis. They are slow growing and rarely metastasize. BCC tends to be locally destructive and can result in serious deforming damage if left untreated or if local recurrences cannot be completely excised. High-risk areas for tumor recurrence after initial treatment include the central face (e.g., periorbital region, eyelids, nasolabial fold, or nose-cheek angle), postauricular region, pinna, ear canal, forehead, and scalp.[11]
Morpheaform type is a specific BCC subtype. This subtype typically appears as a scar-like, firm plaque. Because of indistinct clinical tumor margins, morpheaform type is difficult to treat adequately with traditional treatments.[12]
BCCs often have a characteristic variant in the PTCH1 tumor suppressor gene, although the mechanism of carcinogenesis is not clear.[1]
Squamous cell carcinoma
People with chronic sun damage, history of sunburns, arsenic exposure, chronic cutaneous inflammation (as seen in long-standing skin ulcers), and previous radiation therapy are predisposed to the development of SCC. SCCs tend to occur on sun-exposed portions of the skin, such as the ears, lower lip, and dorsa of the hands. SCCs that develop from actinic keratosis on sun-exposed skin are less likely to metastasize and these patients have a better prognosis than those who develop de novo SCCs or SCCs on non–sun-exposed skin.[12]
SCCs are composed of keratinizing cells. These tumors are more aggressive than BCCs and have a range of growth, invasive, and metastatic potential. Prognosis is associated with the degree of differentiation, and tumor grade is reported as part of the staging system.[10] A four-grade system (G1–G4) is most common, but two- and three-grade systems may also be used.
Variants in the PTCH1 tumor suppressor gene have been reported in SCCs removed from patients with a prior history of multiple BCCs.[13]
SCC in situ (also called Bowen disease) is a noninvasive lesion. Distinguishing SCC in situ pathologically from a benign inflammatory process may be difficult.[1] The risk of development into invasive SCC is low, reportedly in the range of 3% to 4%.[14]
Actinic keratosis
Actinic keratoses are potential precursors of SCC, but the rate of progression is extremely low, and most do not become SCCs. These typically red, scaly patches usually arise on areas of chronically sun-exposed skin and are likely to be found on the face and dorsal aspects of the hand.
Diagnostic and Staging Evaluation
BCC and SCC are usually diagnosed based on routine histopathology obtained from a shave, punch, incisional, or excisional biopsy.[1]
Other tests and procedures that may be used to diagnose and stage BCC and SCC of the skin include:
Physical examination, including skin examination and history.
Chest x-ray.
Computed tomography (CT) scan or positron emission tomography (PET)–CT scan of the head and neck or chest.
Ultrasonography of the regional lymph nodes.
Lymph node biopsy.
Ophthalmic examination or evaluation is performed to diagnose and stage eyelid carcinoma.
References
Reszko A, Aasi SZ, Wilson LD, et al.: Cancer of the skin. In: DeVita VT Jr, Lawrence TS, Rosenberg SA: Cancer: Principles and Practice of Oncology. 9th ed. Lippincott Williams & Wilkins, 2011, pp 1610-33.
Athas WF, Hunt WC, Key CR: Changes in nonmelanoma skin cancer incidence between 1977-1978 and 1998-1999 in Northcentral New Mexico. Cancer Epidemiol Biomarkers Prev 12 (10): 1105-8, 2003. [PUBMED Abstract]
Harris RB, Griffith K, Moon TE: Trends in the incidence of nonmelanoma skin cancers in southeastern Arizona, 1985-1996. J Am Acad Dermatol 45 (4): 528-36, 2001. [PUBMED Abstract]
Rogers HW, Weinstock MA, Harris AR, et al.: Incidence estimate of nonmelanoma skin cancer in the United States, 2006. Arch Dermatol 146 (3): 283-7, 2010. [PUBMED Abstract]
Rogers HW, Weinstock MA, Feldman SR, et al.: Incidence Estimate of Nonmelanoma Skin Cancer (Keratinocyte Carcinomas) in the U.S. Population, 2012. JAMA Dermatol 151 (10): 1081-6, 2015. [PUBMED Abstract]
American Cancer Society: Cancer Facts and Figures 2025. American Cancer Society, 2025. Available online. Last accessed January 16, 2025.
Koh HK: Cutaneous melanoma. N Engl J Med 325 (3): 171-82, 1991. [PUBMED Abstract]
Preston DS, Stern RS: Nonmelanoma cancers of the skin. N Engl J Med 327 (23): 1649-62, 1992. [PUBMED Abstract]
English DR, Armstrong BK, Kricker A, et al.: Case-control study of sun exposure and squamous cell carcinoma of the skin. Int J Cancer 77 (3): 347-53, 1998. [PUBMED Abstract]
Cutaneous carcinoma of the head and neck. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. Springer; 2017, pp 171–81.
Dubin N, Kopf AW: Multivariate risk score for recurrence of cutaneous basal cell carcinomas. Arch Dermatol 119 (5): 373-7, 1983. [PUBMED Abstract]
Wagner RF, Casciato DA: Skin cancers. In: Casciato DA, Lowitz BB, eds.: Manual of Clinical Oncology. 4th ed. Lippincott, Williams, and Wilkins, 2000, pp 336-373.
Ping XL, Ratner D, Zhang H, et al.: PTCH mutations in squamous cell carcinoma of the skin. J Invest Dermatol 116 (4): 614-6, 2001. [PUBMED Abstract]
Kao GF: Carcinoma arising in Bowen’s disease. Arch Dermatol 122 (10): 1124-6, 1986. [PUBMED Abstract]
Stage Information for Skin Cancer
There are separate staging systems in the 8th edition of the American Joint Committee on Cancer’s (AJCC’s) AJCC Cancer Staging Manual for carcinoma of the eyelid and for cutaneous carcinoma of the head and neck. The cutaneous carcinoma staging system addresses cutaneous squamous cell carcinoma (SCC) and cutaneous basal cell carcinoma (BCC).[1,2] The staging system for carcinomas of the eyelid addresses carcinomas of all histologies.
Regional lymph nodes should be routinely examined in all cases of SCC, especially for the following cases:
High-risk tumors appearing on the lips, on the ears, and in the perianal and perigenital regions.
High-risk areas of the hand.
Sites of chronic ulceration or inflammation, or burn scars.
Sites of previous radiation therapy treatment.
BCC rarely metastasizes, so a metastatic workup is usually not necessary.
There are several factors that correlate with poor prognosis for recurrence and metastasis. They apply primarily to patients with SCC and an aggressive subset of nonmelanoma skin carcinoma, but rarely to patients with BCC, and include:[1]
Extranodal extension.
Tumor diameter.
Depth of tumor.
Anatomical site.
Perineural invasion.
Histopathological grade or differentiation and desmoplasia.
Extension to bony structures.
Nodal disease.
Immunosuppression and advanced disease.
Overall health.
Comorbidity.
Lifestyle factors.
Tobacco use.
Even with relatively small tumor sizes, SCCs that occur in immunosuppressed patients tend to behave more aggressively than SCCs in nonimmunosuppressed patients. Although immunosuppression is not a formal part of the AJCC staging system, it is recommended that centers prospectively studying SCCs record the presence and type of immunosuppression.
Staging for Cutaneous Carcinoma of the Head and Neck (Excluding Carcinomas of the Eyelid)
The AJCC has designated staging by TNM (tumor, node, metastasis) classification for cutaneous carcinoma of the head and neck, excluding carcinomas of the eyelid.[1]
Table 1. Definitions of Primary Tumor (T) for Cutaneous Carcinoma of the Head and Necka
T Category
T Criteria
aReprinted with permission from AJCC: Cutaneous carcinoma of the head and neck. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp. 171–81.
bDeep invasion is defined as invasion beyond the subcutaneous fat or >6 mm (as measured from the granular layer of adjacent normal epidermis to the base of the tumor); perineural invasion for T3 classification is defined as tumor cells within the nerve sheath of a nerve lying deeper than the dermis or measuring ≥0.1 mm in caliber, or presenting with clinical or radiographic involvement of named nerves without skull base invasion or transgression.
TX
Primary tumor cannot be identified.
Tis
Carcinoma in situ.
T1
Tumor ≤2 cm in greatest dimension.
T2
Tumor >2 cm, but ≤4 cm in greatest dimension.
T3
Tumor >4 cm in maximum dimension or minor bone erosion or perineural invasion or deep invasion.b
T4
Tumor with gross cortical bone/marrow, skull base invasion and/or skull base foramen invasion.
–T4a
Tumor with gross cortical bone/marrow invasion.
–T4b
Tumor with skull base invasion and/or skull base foramen involvement.
Table 2. Definitions of Pathological Regional Lymph Nodes (pN) for Cutaneous Carcinoma of the Head and Necka,b
N Category
N Criteria
ENE = extranodal extension.
aReprinted with permission from AJCC: Cutaneous carcinoma of the head and neck. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp. 171–81.
bA designation of “U” or “L” may be used for any N category to indicate metastasis above the lower border of the cricoid (U) or below the lower border of the cricoid (L). Similarly, clinical and pathological ENE should be recorded as ENE negative or ENE positive.
NX
Regional lymph nodes cannot be assessed.
N0
No regional lymph node metastasis.
N1
Metastasis in a single ipsilateral lymph node, ≤3 cm in greatest dimension and ENE negative.
N2
Metastasis in a single ipsilateral lymph node, ≤3 cm in greatest dimension and ENE positive; or >3 cm but ≤6 cm in greatest dimension and ENE negative; or metastases in multiple ipsilateral lymph nodes, none >6 cm in greatest dimension and ENE negative; or in bilateral or contralateral lymph node(s), none >6 cm in greatest dimension, ENE negative.
–N2a
Metastasis in single ipsilateral node ≤3 cm in greatest dimension and ENE positive; or a single ipsilateral node >3 cm but ≤6 cm in greatest dimension and ENE negative.
–N2b
Metastasis in multiple ipsilateral nodes, none >6 cm in greatest dimension and ENE negative.
–N2c
Metastasis in bilateral or contralateral lymph node(s), none >6 cm in greatest dimension and ENE negative.
N3
Metastasis in a lymph node >6 cm in greatest dimension and ENE negative; or in a single ipsilateral node >3 cm in greatest dimension and ENE positive; or multiple ipsilateral, contralateral, or bilateral nodes, any with ENE-positive status; or a single contralateral node of any size and ENE positive.
–N3a
Metastasis in a lymph node >6 cm in greatest dimension and ENE negative.
–N3b
Metastasis in a single ipsilateral node >3 cm in greatest dimension and ENE positive; or multiple ipsilateral, contralateral, or bilateral nodes, any with ENE-positive status; or a single contralateral node of any size and ENE positive.
Table 3. Definitions of Clinical Regional Lymph Nodes (cN) for Cutaneous Carcinoma of the Head and Necka,b
N Category
N Criteria
ENE = extranodal extension.
aReprinted with permission from AJCC: Cutaneous carcinoma of the head and neck. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp. 171–81.
bA designation of “U” or “L” may be used for any N category to indicate metastasis above the lower border of the cricoid (U) or below the lower border of the cricoid (L). Similarly, clinical and pathological ENE should be recorded as ENE negative or ENE positive.
NX
Regional lymph nodes cannot be assessed.
N0
No regional lymph node metastasis.
N1
Metastasis in a single ipsilateral lymph node, ≤3 cm in greatest dimension and ENE negative.
N2
Metastasis in a single ipsilateral node >3 cm but ≤6 cm in greatest dimension and ENE negative; or metastases in multiple ipsilateral lymph nodes, none >6 cm in greatest dimension and ENE negative; or in bilateral and contralateral lymph nodes, none >6 cm in greatest dimension and ENE negative.
–N2a
Metastasis in a single ipsilateral node >3 cm but ≤6 cm in greatest dimension and ENE negative.
–N2b
Metastasis in multiple ipsilateral lymph nodes, none >6 cm in greatest dimension and ENE negative.
–N2c
Metastasis in bilateral or contralateral lymph nodes, none >6 cm in greatest dimension and ENE negative.
N3
Metastasis in a lymph node >6 cm in greatest dimension and ENE negative; or metastasis in any node(s) and clinically overt ENE (ENE positive).
–N3a
Metastasis in a lymph node >6 cm in greatest dimension and ENE negative.
–N3b
Metastasis in any node(s) and ENE positive.
Table 4. Distant Metastasis (M) for Cutaneous Carcinoma of the Head and Necka
M Category
M Criteria
aReprinted with permission from AJCC: Cutaneous carcinoma of the head and neck. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp. 171–81.
M0
No distant metastasis.
M1
Distant metastasis.
Table 5. AJCC Prognostic Stage Groups for Cutaneous Carcinoma of the Head and Necka
Stage
T
N
M
Illustration
M = distant metastasis; N = regional lymph nodes; T = primary tumor.
aReprinted with permission from AJCC: Cutaneous carcinoma of the head and neck. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp. 171–81.
The AJCC has designated staging by TNM classification.[1] The TNM classification is used to stage all cell types of eyelid carcinomas, except melanoma.
Table 6. Definitions of Primary Tumor (T) for Eyelid Carcinomaa
T Category
T Criteria
aReprinted with permission from AJCC: Eyelid carcinoma. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp. 779–85.
TX
Primary tumor cannot be assessed.
T0
No evidence of primary tumor.
Tis
Carcinoma in situ.
T1
Tumor ≤10 mm in greatest dimension.
–T1a
Tumor does not invade the tarsal plate or eyelid margin.
–T1b
Tumor invades the tarsal plate or eyelid margin.
–T1c
Tumor involves full thickness of the eyelid.
T2
Tumor >10 mm but ≤20 mm in greatest dimension.
–T2a
Tumor does not invade the tarsal plate or eyelid margin.
–T2b
Tumor invades the tarsal plate or eyelid margin.
–T2c
Tumor involves full thickness of the eyelid.
T3
Tumor >20 mm but ≤30 mm in greatest dimension.
–T3a
Tumor does not invade the tarsal plate or eyelid margin.
–T3b
Tumor invades the tarsal plate or eyelid margin.
–T3c
Tumor involves full thickness of the eyelid.
T4
Any eyelid tumor that invades adjacent ocular, orbital, or facial structures.
–T4a
Tumor invades ocular or intraorbital structures.
–T4b
Tumor invades (or erodes through) the bony walls of the orbit or extends to the paranasal sinuses or invades the lacrimal sac/nasolacrimal duct or brain.
Table 7. Definitions of Regional Lymph Node (N) for Eyelid Carcinomaa
N Category
N Criteria
aReprinted with permission from AJCC: Eyelid carcinoma. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp. 779–85.
NX
Regional lymph nodes cannot be assessed.
N0
No evidence of lymph node involvement.
N1
Metastasis in a single ipsilateral regional lymph node, ≤3 cm in greatest dimension.
–N1a
Metastasis in a single ipsilateral lymph node based on clinical evaluation or imaging findings.
–N1b
Metastasis in a single ipsilateral lymph node based on lymph node biopsy.
N2
Metastasis in a single ipsilateral lymph node, >3 cm in greatest dimension; or in bilateral or contralateral lymph nodes.
–N2a
Metastasis documented based on clinical evaluation or imaging findings.
–N2b
Metastasis documented based on microscopic findings on lymph node biopsy.
Table 8. Definitions of Distant Metastasis (M) for Eyelid Carcinomaa
M Category
M Criteria
aReprinted with permission from AJCC: Eyelid carcinoma. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp. 779–85.
M0
No distant metastasis.
M1
Distant metastasis.
Table 9. AJCC Prognostic Stage Groups for Eyelid Carcinomaa
Stage
T
N
M
M = distant metastasis; N = regional lymph nodes; T = primary tumor.
aReprinted with permission from AJCC: Eyelid carcinoma. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp. 779–85.
0
Tis
N0
M0
IA
T1
N0
M0
IB
T2a
N0
M0
IIA
T2b–c
N0
M0
T3
N0
M0
IIB
T4
N0
M0
IIIA
Any T
N1
M0
IIIB
Any T
N2
M0
IV
Any T
Any N
M1
References
Cutaneous carcinoma of the head and neck. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. Springer; 2017, pp 171–81.
Esmaeli B, Dutton JJ, Graue GF, et al.: Eyelid carcinoma. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. Springer; 2017, pp 779-85.
Treatment Option Overview
Treatments for squamous cell carcinoma and basal cell carcinoma of the skin are described in Table 10.
Table 10. Treatment Option Overview for Nonmelanoma Skin Cancer
There is a wide range of approaches for treating basal cell carcinoma (BCC) of the skin, including excision, radiation therapy, cryosurgery, electrodesiccation and curettage, photodynamic or laser-beam light exposure, and topical therapies. Each of these approaches is useful in specific clinical situations. Depending on case selection, these approaches produce recurrence-free rates ranging from 85% to 95%.[1–9]
A systematic review of 27 randomized controlled trials comparing various treatments for BCC has been published.[10] Eighteen of the studies were published in full, and nine were published in abstract form only. Only 19 of the 27 trials were analyzed by intention-to-treat criteria. Because the case fatality rate of BCC is so low, the primary end point of most trials is complete response and/or recurrence rate after treatment. Most of the identified studies were not of high quality and had short follow-up periods, which will lead to overestimations of tumor control; only one study had a follow-up period of as long as 4 years. A literature review of recurrence rates in case series with long-term follow-up after treatment of BCCs indicated that only 50% of recurrences occurred within the first 2 years, 66% after 3 years, and 18% after 5 years.[11] A common finding was that the 10-year recurrence rates were about double the 2-year recurrence rates.
Treatment of Basal Cell Carcinoma of the Skin (Localized Disease)
Treatment options for BCC of the skin (localized disease) include:
A traditional surgical treatment, surgical excision with margin evaluation usually relies on surgical margins ranging from 3 mm to 10 mm, depending on the diameter of the tumor. Re-excision may be required if the surgical margin is found to be inadequate on permanent sectioning. In one trial, 35 of 199 primary BCCs (18%) were incompletely excised by the initial surgery and underwent a re-excision.[12] In addition, many laboratories examine only a small fraction of the total tumor margin pathologically. Therefore, the declaration of tumor-free margins can be subject to sampling error.[13]
In randomized trials, excision has been compared with radiation therapy, Mohs micrographic surgery, photodynamic therapy (PDT), and cryosurgery.
Evidence (surgical excision with margin evaluation):
In a single-center trial, 360 patients with facial BCCs smaller than 4 cm in diameter were randomly assigned to undergo either surgical excision or radiation therapy (55% interstitial brachytherapy, 33% contact radiation therapy, and 12% conventional external-beam radiation therapy [EBRT]).[14][Level of evidence B1] Excisional margins, assessed by frozen section during the procedure in 91% of cases, had to be at least 2 mm, with re-excision if necessary. Thirteen patients were not treated and were dropped from the analysis.
At 4 years (mean follow-up of 41 months), the actuarial failure rates (confirmed persistent or recurrent tumor) were 0.7% in the surgery arm and 7.5% in the radiation therapy arm (P = .003).[15][Level of evidence B1]
The cosmetic results were also rated as better after surgery by both patients and dermatologists, and also by three independent professionals. At 4 years, 87% of surgery patients rated cosmesis as good, versus 69% of radiation therapy patients.[15]
In a two-center, intent-to-treat analysis, 374 patients with 408 primary facial BCCs were randomly assigned to undergo either surgical excision or Mohs micrographic surgery with at least a 3-mm margin around the visible tumor until there were no positive margins in either case.[12][Level of evidence B1]
After 30 months of follow-up, the recurrence rate was 5 out of 171 tumors (3%) in the excision group and 3 out of 160 (2%) in the Mohs micrographic surgery group (absolute difference, 1%; 95% confidence interval [CI], -2.5% to +3.7%; P = .724). There was no difference in complication rates, and overall cosmetic outcomes were similar.[12][Level of evidence B1]
Total operative costs were nearly twice as high in the Mohs group (405.79 Euros vs. 216.86 Euros; P < .001).
A multicenter randomized trial included 101 adults with previously untreated nodular skin BCCs, excluding lesions of the midface, orbital areas, and ears. Patients were treated with either excision (at least 5-mm margins) or PDT using topical methyl aminolevulinate cream (160 mg/g) followed by red-light exposure (wavelength 570–670 nm, 75 J/cm2) twice, 7 days apart.[16][Level of evidence B3] A per-protocol/per-lesion analysis was performed on the 97 patients who had an excision or at least one cycle of PDT.
At 3 months, the complete response (CR) rate was 98% of lesions (51 of 52) in the surgery group versus 91% of lesions (48 of 53) in the PDT group (P = .25). CR rates assessed at 12 months were 96% for the surgery group versus 83% for the PDT group (P = .15).[16][Level of evidence B3] The investigators interpreted the results as noninferiority of PDT, but the study may have been underpowered.
Both the investigators and the patients rated the cosmetic results as either excellent or good in a higher proportion of PDT treatments at each time point of follow-up. At 12 months, patient ratings of excellent or good were 98% in the PDT group versus 84% in the surgery group (P = .03), and investigator ratings were 79% versus 38% (P = .001).
In a randomized single-center trial, 96 primary BCCs (patient number unclear) smaller than 2 cm in diameter involving the head and neck area were randomly assigned to either excision with a 3-mm safe margin or cryosurgery (i.e., curettage plus two freeze-thaw cycles by liquid nitrogen spray gun).[17][Level of evidence B3]
At 1 year, there were no recurrences in the excision group versus three recurrences in the cryosurgery group (P = NS), but this is a very short follow-up time.[17][Level of evidence B3]
Patients and five independent professionals who were blinded to the treatment arm rated the cosmetic outcomes. Their overall assessments favored excision.
Mohs micrographic surgery
Mohs micrographic surgery is a form of tumor excision that involves progressive radial sectioning and real-time examination of the resection margins until adequate uninvolved margins have been achieved, avoiding wider margins than needed. It is a specialized technique used to achieve the narrowest margins necessary to avoid tumor recurrence while maximally preserving cosmesis. The tumor is microscopically delineated, with serial radial resection, until it is completely removed as assessed with real-time frozen sections. Noncontrolled case series suggested that the disease control rates were superior to other treatment methods for BCC.[18–20] However, as noted in the Surgical excision with margin evaluation section, the disease control rate was not clearly better when it was directly compared with the disease control rate for surgical excision of facial BCCs in a randomized trial of primary BCCs.[12]
EnlargeMohs surgery. A surgical procedure to remove skin cancer in several steps. First, a thin layer of cancerous tissue is removed. Then, a second thin layer of tissue is removed and viewed under a microscope to check for cancer cells. More layers are removed one at a time until the tissue viewed under a microscope shows no remaining cancer. This type of surgery is used to remove as little normal tissue as possible and is often used to remove skin cancer on the face.
This surgery is best suited to the management of tumors that have recurred after initial incision or of tumors in cosmetically sensitive areas (e.g., eyelid periorbital area, nasolabial fold, nose-cheek angle, posterior cheek sulcus, pinna, ear canal, forehead, scalp, fingers, and genitalia).[19,21] It is also used to treat tumors with poorly defined clinical borders.
Radiation therapy
Radiation therapy is particularly useful in the management of patients with primary lesions that would otherwise require difficult or extensive surgery (e.g., lesions on the nose or ears).[22] Radiation therapy eliminates the need for skin grafting when surgery would result in an extensive defect. Cosmetic results are generally good, with a small amount of hypopigmentation or telangiectasia in the treatment port. Radiation therapy can also be used for lesions that recur after a primary surgical approach.[23]
Radiation therapy is avoided in patients with conditions that predispose them to radiation-induced cancers, such as xeroderma pigmentosum or basal cell nevus syndrome.
Evidence (radiation therapy):
As noted above, radiation therapy has been compared with excision in a randomized trial that showed better response and cosmesis associated with surgery.[14,15][Level of evidence B1]
In a single-center trial, 93 patients with BCC were randomly assigned to receive either EBRT (130 kV x-rays, dosimetry depending on lesion size) or cryotherapy (two freeze-thaw cycles with liquid nitrogen by spray gun). Patients with lesions on the nose or ear were excluded because the investigators felt that EBRT is the treatment of choice for tumors in these locations.[24][Level of evidence B3]
Radiation was superior to cryotherapy in local control at 2 years.
By 1 year, the recurrence rate was 4% in the radiation arm and 39% in the cryotherapy arm in a per-protocol analysis. The investigators did not perform a statistical analysis, but the authors of a systematic literature review calculated a relative risk of 0.11 in favor of radiation (95% CI, 0.03–0.43).[10][Level of evidence B3]
Curettage and electrodesiccation
Curettage and electrodesiccation is a widely employed method for removing primary BCCs, especially superficial lesions of the neck, trunk, and extremities that are considered to be at low risk of recurrence. A sharp curette is used to scrape the tumor down to its base, followed by electrodesiccation of the lesion base. Although curettage and electrodesiccation is a quick method for destroying the tumor, the adequacy of treatment cannot be assessed immediately because the surgeon cannot visually detect the depth of microscopic tumor invasion. This procedure is also sometimes called electrosurgery.
Evidence (curettage and electrodesiccation):
A Cochrane Collaboration systematic review found no randomized trials comparing this treatment method with other approaches.[10]
In a large, single-center case series of 2,314 previously untreated BCCs managed at a major skin cancer unit, the 5-year recurrence rate of BCCs of the neck, trunk, and extremities after curettage and electrodesiccation was 3.3%. However, rates increased substantially for tumors larger than 6 mm in diameter at other anatomical sites.[25][Level of evidence C2]
Cryosurgery
Cryosurgery may be considered for patients with small, clinically well-defined primary tumors.[26–28] It is infrequently used for the management of BCC, but cryosurgery may be useful for patients with medical conditions that preclude other types of surgery.[8,29–35] Contraindications for cryosurgery include:
Abnormal cold tolerance.
Cryoglobulinemia or cryofibrinogenemia.
Raynaud disease (in the case of lesions on the hands and feet).
Platelet deficiency disorders.
Tumors of the scalp, ala nasi, nasolabial fold, tragus, postauricular sulcus, free eyelid margin, upper lip vermillion border, and lower legs.
Tumors near nerves.
Caution should also be used before treating nodular ulcerative neoplasia more than 3 cm in diameter, carcinomas fixed to the underlying bone or cartilage, tumors situated on the lateral margins of the fingers and at the ulnar fossa of the elbow, or recurrent carcinomas following surgical excision. Permanent pigment loss at the treatment site is unavoidable, so the treatment is not well suited to patients with dark skin.
Edema is common after treatment, especially around the periorbital region, temple, and forehead. Treated tumors usually exude necrotic material, after which an eschar forms and persists for about 4 weeks. Atrophy and hypertrophic scarring have been reported, as have instances of motor and sensory neuropathy.
Evidence (cryosurgery):
As noted in the Radiation therapy section, a small 93-patient trial compared cryosurgery with radiation therapy, with only 1 year of follow-up.[24][Level of evidence B3]
There was a statistically significant higher recurrence rate with cryosurgery than with radiation therapy (39% vs. 4%).
In a small, single-center, randomized study, 88 patients were assigned to undergo either cryosurgery in two freeze-thaw cycles; or PDT using delta-aminolevulinic acid as the photosensitizing agent and 635 nm wavelength light with 60 J/cm2 energy delivered by neodymium-doped yttrium aluminum garnet (Nd:YAG) laser.[36][Level of evidence B1]
Overall clinical efficacy was similar in evaluable lesions at 1 year (5 of 39 recurrences for cryosurgery vs. 2 of 44 recurrences for PDT), but more re-treatments were needed with PDT to achieve complete responses.[36][Level of evidence B1]
Cosmetic outcomes favored PDT (93% good or excellent after PDT vs. 54% after cryosurgery, P < .001).
In another randomized study of 118 patients, reported in abstract form, cryosurgery was compared with PDT using methyl aminolevulinic acid.[37,38][Level of evidence B3]
Tumor control rates at 3 years were similar (74%), but cosmetic outcomes were better in the PDT group. These cryosurgery-PDT comparisons were reported on a per-protocol basis rather than an intent-to-treat basis.[37,38][Level of evidence B3]
Photodynamic therapy
PDT with photosensitizers is used in the management of a wide spectrum of superficial epithelial tumors.[39] A topical photosensitizing agent such as 5-aminolevulinic acid or methyl aminolevulinate is applied to the tumor, followed by exposure to a specific wavelength of light (laser or broad band), depending on the absorption characteristics of the photosensitizer. In the case of multiple BCCs, the use of short-acting systemic (intravenous) photosensitizers such as verteporfin has been investigated.[40] Upon light activation, the photosensitizer reacts with oxygen in the tissue to form singlet oxygen species, resulting in local cell destruction.
Evidence (PDT):
In case series, PDT has been associated with high initial CR rates. However, substantial regrowth rates of up to 50% have been reported with long-term follow-up.[39]
Two small trials, one reported in abstract form, comparing PDT with cryosurgery are summarized in the Cryosurgery section, showing similar antitumor efficacy but better cosmesis with PDT.[36–38]
Topical fluorouracil (5-FU)
Topical 5-FU, as a 5% cream, may be useful in specific limited circumstances. The U.S. Food and Drug Administration (FDA) approved this treatment for superficial BCCs in patients for whom conventional methods are impractical, such as individuals with multiple lesions or difficult treatment sites. Safety and efficacy in other indications have not been established.[41,42][Level of evidence C3] Given the superficial nature of the effects of topical 5-FU, nonvisible dermal involvement may persist, giving a false impression of treatment success. In addition, the brisk accompanying inflammatory reaction may cause substantial skin toxicity and discomfort in a large proportion of patients.
Imiquimod topical therapy
Imiquimod is an agonist for the toll-like receptor 7 and/or 8, inducing a helper T-cell cytokine cascade and interferon production. It purportedly acts as an immunomodulator.
Although the FDA approved imiquimod for treatment of superficial BCCs, some investigators in the field do not recommend it for initial monotherapy for BCC. Some reserve its use for patients with small lesions in low-risk sites who cannot undergo treatment with more established therapies.[42] Imiquimod is available as a 5% cream and is used in schedules ranging from twice weekly to twice daily over 5 to 15 weeks. Most of the experience is limited to case series of BCCs that are smaller than 2 cm2 in area and that are not in high-risk locations (e.g., within 1 cm of the hairline, eyes, nose, mouth, or ear; or in the anogenital, hand, or foot regions).[42] Follow-up times have also been generally short. Reported CR rates vary widely, from about 40% to 100%.[42][Level of evidence C3]
There have been a number of randomized trials of imiquimod.[43–48] However, the designs of all of them make interpretation of long-term efficacy impossible. Most were industry-sponsored dose-finding studies, with small numbers of patients on any given regimen. In addition, patients were only monitored for 6 to 12 weeks, with excision at that time to determine histological response.[42][Level of evidence B3]
Carbon dioxide laser
The carbon dioxide laser is used very infrequently in the management of BCC because of the difficulty in controlling tumor margins.[49] Few clinicians have extensive experience with the technique for BCC treatment. There are no randomized trials comparing it with other modalities.
Treatment of Metastatic Basal Cell Carcinoma (or Locally Advanced Disease Untreatable by Local Modalities)
Treatment options for metastatic BCC of the skin (or locally advanced disease untreatable by local modalities) include:
BCCs frequently exhibit constitutive activation of the Hedgehog/PTCH1 signaling pathway. Vismodegib and sonidegib, two inhibitors of Smoothened, a transmembrane protein involved in the Hedgehog pathway, are approved for the treatment of adults with metastatic BCC, patients with locally advanced BCC that has recurred after surgery, and patients who are not candidates for surgery or radiation therapy.
Evidence (vismodegib):
FDA approval was supported by an international, multicenter, open-label, two-cohort trial enrolling 104 patients: 33 with metastatic BCC and 71 with locally advanced BCC with inoperable disease or for whom surgery was inappropriate. Patients received vismodegib 150 mg daily.[50][Level of evidence C3] Objective response rate (RR) assessed by an independent review committee was the primary end point. The study was sized to test whether the RR was higher than 10% in patients with metastatic BCC and higher than 20% in patients with locally advanced BCC by exact binomial 1-sided tests. Of the 104 patients, 96 were evaluable for RR, with 8 patients who had locally advanced BCC excluded from analysis after the independent pathologist did not identify BCC in the biopsy specimens. In both cohorts, the median duration of treatment was 10.2 months (range, 0.7–18.7 months).
In 33 patients with metastatic BCC, the RR was 30% (95% CI, 16%–48%; P = .001). In 63 patients with locally advanced BCC, the RR was 43% (95% CI, 31%–56%; P < .001), with complete responses in 13 patients (21%). In both cohorts, the median duration of response was 7.6 months.[50][Level of evidence C3]
The most common adverse events were muscle spasms, alopecia, dysgeusia, weight loss, and fatigue. Adverse events led to the discontinuation of vismodegib in 12% of patients.
There were fatal adverse events in seven patients: three deaths from unknown causes; and one death each from hypovolemic shock, myocardial infarction, meningeal disease, and ischemic stroke. The relationship between the study drug and the deaths is unknown.
Evidence (sonidegib):
Sonidegib was evaluated at two doses in a multinational, double-blind, multiple-cohort trial conducted in patients with metastatic BCC (n = 36) or locally advanced BCC (n = 194).[51]Level of evidence B3] Patients were randomly assigned (in a 2:1 fashion) to receive either 200 mg or 800 mg orally, once a day. The primary end point was RR, with data collected up to 6 months after randomization of the last patient and determined by blinded central review. A sample size of 210 patients was targeted to ensure 150 patients for the primary efficacy analysis, which required locally advanced disease to be assessable by modified Response Evaluation Criteria In Solid Tumors (RECIST) criteria. Success was prespecified as a 30% RR.
In the 200-mg cohort, a central review identified 18 of 42 patients with locally advanced BCC (43%; 95% CI, 28%–59%) and 2 of 13 patients with metastatic BCC (15%; 95% CI, 2%–45%) who had an objective response and qualified for the primary efficacy analysis. The median duration of response was not reached. RR was similar in the two-dose cohorts, with fewer adverse events at the lower dose, leading to FDA approval of the 200-mg once-daily dose.[51][Level of evidence B3]
Frequent adverse events included muscle spasms, alopecia, dysgeusia, fatigue, nausea, vomiting, decreased appetite, decreased weight, myalgia, and pain.
Four patients in the 800-mg cohort died during the study: two from cardiac death and two from metastatic disease progression.
Chemotherapy
No standard chemotherapy regimens exist, and there are only anecdotal reports in the literature.[52]
Because there is no curative therapy for metastatic BCC of the skin, clinical trials are appropriate. Information about ongoing clinical trials is available from the NCI website.
Treatment of Recurrent Nonmetastatic Basal Cell Carcinoma of the Skin
After treatment of BCC, patients are monitored clinically and examined regularly. Most recurrences occur within 5 years, but about 18% of recurrences are diagnosed beyond that point.[11]
Patients who develop a primary BCCs are also at increased risk of subsequent primary skin cancers because their sun-damaged skin is susceptible to additional cancers.[53–55] This effect is sometimes termed field carcinogenesis. Age at diagnosis of the first BCC (<65 years), red hair, and initial BCC on the upper extremities appear to be associated with a higher risk of subsequent new BCCs.[56]
Treatment options for recurrent nonmetastatic BCC of the skin include:
Surgical excision.
Mohs micrographic surgery.
Mohs micrographic surgery is commonly used for local recurrences of BCC.
Evidence (surgical excision vs. Mohs micrographic surgery):
In a separate group within a randomized trial that compared excision with Mohs micrographic surgery for primary BCCs, 204 patients with recurrent BCCs were randomly assigned to undergo either excision or Mohs micrographic surgery.[12][Level of evidence B1]
The recurrence rates were 8 of 102 patients assigned to excision and 2 of 102 patients assigned to Mohs micrographic surgery, after a mean follow-up of 2.08 years (P = NS).[12][Level of evidence B1]
There were more postoperative complications—including wound infections, graft necrosis, or bleeding—in the excision group than in the Mohs surgery group (19% vs. 8%, P = .021).
As with primary tumors, the operative costs associated with Mohs surgery were higher than those associated with excision (489.06 Euros vs. 323.49 Euros; P = .001).
Current Clinical Trials
Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.
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Gaitanis G, Alexopoulos EC, Bassukas ID: Cryosurgery is more effective in the treatment of primary, non-superficial basal cell carcinomas when applied during and not prior to a five week imiquimod course: a randomized, prospective, open-label study. Eur J Dermatol 21 (6): 952-8, 2011 Nov-Dec. [PUBMED Abstract]
Wang I, Bendsoe N, Klinteberg CA, et al.: Photodynamic therapy vs. cryosurgery of basal cell carcinomas: results of a phase III clinical trial. Br J Dermatol 144 (4): 832-40, 2001. [PUBMED Abstract]
Basset-Séguin N, Ibbotson S, Emtestam L, et al.: Photodynamic therapy using methyl aminolaevulinate is as efficacious as cryotherapy in basal cell carcinoma, with better cosmetic results. [Abstract] Br J Dermatol 149 (Suppl 64): A-P-66, 46, 2003.
Basset-Séguin N, Ibbotson S, Emtestam L, et al.: Methyl aminolaevulinate photodynamic therapy vs. cryotherapy in primary superficial basal cell carcinoma: results of a 36-month follow-up. [Abstract] Br J Dermatol 153 (Suppl 1): A-P-30, 29. 2005.
Hsi RA, Rosenthal DI, Glatstein E: Photodynamic therapy in the treatment of cancer: current state of the art. Drugs 57 (5): 725-34, 1999. [PUBMED Abstract]
Lui H, Hobbs L, Tope WD, et al.: Photodynamic therapy of multiple nonmelanoma skin cancers with verteporfin and red light-emitting diodes: two-year results evaluating tumor response and cosmetic outcomes. Arch Dermatol 140 (1): 26-32, 2004. [PUBMED Abstract]
Efudex® (fluorouracil) cream, 5% [package insert]. Aliso Viejo, Ca: Valeant Pharmaceuticals International, 2005. Available online. Last accessed March 7, 2025.
Love WE, Bernhard JD, Bordeaux JS: Topical imiquimod or fluorouracil therapy for basal and squamous cell carcinoma: a systematic review. Arch Dermatol 145 (12): 1431-8, 2009. [PUBMED Abstract]
Beutner KR, Geisse JK, Helman D, et al.: Therapeutic response of basal cell carcinoma to the immune response modifier imiquimod 5% cream. J Am Acad Dermatol 41 (6): 1002-7, 1999. [PUBMED Abstract]
Geisse JK, Rich P, Pandya A, et al.: Imiquimod 5% cream for the treatment of superficial basal cell carcinoma: a double-blind, randomized, vehicle-controlled study. J Am Acad Dermatol 47 (3): 390-8, 2002. [PUBMED Abstract]
Geisse J, Caro I, Lindholm J, et al.: Imiquimod 5% cream for the treatment of superficial basal cell carcinoma: results from two phase III, randomized, vehicle-controlled studies. J Am Acad Dermatol 50 (5): 722-33, 2004. [PUBMED Abstract]
Shumack S, Robinson J, Kossard S, et al.: Efficacy of topical 5% imiquimod cream for the treatment of nodular basal cell carcinoma: comparison of dosing regimens. Arch Dermatol 138 (9): 1165-71, 2002. [PUBMED Abstract]
Marks R, Gebauer K, Shumack S, et al.: Imiquimod 5% cream in the treatment of superficial basal cell carcinoma: results of a multicenter 6-week dose-response trial. J Am Acad Dermatol 44 (5): 807-13, 2001. [PUBMED Abstract]
Schulze HJ, Cribier B, Requena L, et al.: Imiquimod 5% cream for the treatment of superficial basal cell carcinoma: results from a randomized vehicle-controlled phase III study in Europe. Br J Dermatol 152 (5): 939-47, 2005. [PUBMED Abstract]
Reszko A, Aasi SZ, Wilson LD, et al.: Cancer of the skin. In: DeVita VT Jr, Lawrence TS, Rosenberg SA: Cancer: Principles and Practice of Oncology. 9th ed. Lippincott Williams & Wilkins, 2011, pp 1610-33.
Sekulic A, Migden MR, Oro AE, et al.: Efficacy and safety of vismodegib in advanced basal-cell carcinoma. N Engl J Med 366 (23): 2171-9, 2012. [PUBMED Abstract]
Migden MR, Guminski A, Gutzmer R, et al.: Treatment with two different doses of sonidegib in patients with locally advanced or metastatic basal cell carcinoma (BOLT): a multicentre, randomised, double-blind phase 2 trial. Lancet Oncol 16 (6): 716-28, 2015. [PUBMED Abstract]
Khandekar JD: Complete response of metastatic basal cell carcinoma to cisplatin chemotherapy: a report on two patients. Arch Dermatol 126 (12): 1660, 1990. [PUBMED Abstract]
Robinson JK: Risk of developing another basal cell carcinoma. A 5-year prospective study. Cancer 60 (1): 118-20, 1987. [PUBMED Abstract]
Karagas MR, Stukel TA, Greenberg ER, et al.: Risk of subsequent basal cell carcinoma and squamous cell carcinoma of the skin among patients with prior skin cancer. Skin Cancer Prevention Study Group. JAMA 267 (24): 3305-10, 1992. [PUBMED Abstract]
Schinstine M, Goldman GD: Risk of synchronous and metachronous second nonmelanoma skin cancer when referred for Mohs micrographic surgery. J Am Acad Dermatol 44 (3): 497-9, 2001. [PUBMED Abstract]
Kiiski V, de Vries E, Flohil SC, et al.: Risk factors for single and multiple basal cell carcinomas. Arch Dermatol 146 (8): 848-55, 2010. [PUBMED Abstract]
Treatment of Squamous Cell Carcinoma of the Skin
Localized squamous cell carcinoma (SCC) of the skin is a highly curable disease.[1] There are a variety of treatment approaches to localized SCC, including excision, radiation therapy, cryosurgery, and electrodesiccation and curettage.
There is little to no good-quality evidence that allows direct comparison of outcomes for patients with sporadic, clinically localized SCCs treated with local therapies. A systematic literature review found only one randomized controlled trial in the management of such patients, and that trial compared adjuvant therapy with observation after initial local therapy rather than different local therapies.[2] In that small single-center trial, 66 patients with high-risk, clinically localized SCC were randomly assigned, after surgical excision of the primary tumor (with or without radiation, depending on clinical judgment), to either receive combined isotretinoin (1 mg/kg orally per day) plus interferon alfa (3 × 106 U subcutaneously 3 times/week) for 6 months or undergo observation.[3] In the 65 evaluable patients after a median follow-up of 21.5 months, there was no difference in the combined (primary) end point of SCC recurrence or second primary tumor (45% vs. 38%; hazard ratio, 1.13; 95% confidence interval [CI], 0.53–2.41), or in either of the individual components of the primary end point.[3][Level of evidence B1]
Cemiplimab and pembrolizumab, programmed death receptor-1 (PD-1) inhibitors, are the only systemic therapies for the treatment of locally advanced and metastatic cutaneous SCC. The U.S. Food and Drug Administration (FDA) approved cemiplimab and pembrolizumab based on objective response rates (RRs) from early-phase trials.[4–6][Level of evidence C3] Toxicities associated with checkpoint inhibitors were seen, including death. Clinical trials are recommended to further identify optimal treatment. Ongoing trials include PD-1 inhibitors in the neoadjuvant, adjuvant, and advanced/metastatic settings, as monotherapy and in combinations.
Treatment of Squamous Cell Carcinoma of the Skin (Localized Disease)
Treatment options for SCC of the skin (localized disease) include:
Excision is probably the most common therapy for SCC.[7] This traditional surgical treatment usually relies on surgical margins ranging from 4 mm to 10 mm, depending on the diameter of the tumor and degree of differentiation. In a prospective case series of 141 SCCs, a 4-mm margin was adequate to encompass all subclinical microscopic tumor extension in more than 95% of well-differentiated tumors up to 19 mm in diameter. Wider margins of 6 mm to 10 mm were needed for larger or less-differentiated tumors and tumors in high-risk locations (e.g., scalp, ears, eyelids, nose, and lips).[8] Re-excision may be required if the surgical margin is inadequate on permanent sectioning.
Mohs micrographic surgery
Mohs micrographic surgery is a form of tumor excision that involves progressive radial sectioning and real-time examination of the resection margins until adequate uninvolved margins have been achieved, avoiding wider margins than needed. It is a specialized technique used to achieve the narrowest margins necessary to avoid tumor recurrence while maximally preserving cosmesis. The tumor is microscopically delineated, with serial radial resection, until it is completely removed as assessed with real-time frozen sections. However, because the technique removes tumor growing in contiguity and may miss noncontiguous in-transit cutaneous micrometastases, some practitioners remove an additional margin of skin in high-risk lesions, even after the Mohs surgical procedure confirms uninvolved margins.[7][Level of evidence C3] In case series, Mohs surgery has been associated with a lower local recurrence rate than the other local modalities,[9] but there are no randomized trials allowing direct comparison.[2]
EnlargeMohs surgery. A surgical procedure to remove skin cancer in several steps. First, a thin layer of cancerous tissue is removed. Then, a second thin layer of tissue is removed and viewed under a microscope to check for cancer cells. More layers are removed one at a time until the tissue viewed under a microscope shows no remaining cancer. This type of surgery is used to remove as little normal tissue as possible and is often used to remove skin cancer on the face.
This surgery is best suited to the management of tumors in cosmetically sensitive areas (e.g., eyelid periorbital area, nasolabial fold, nose-cheek angle, posterior cheek sulcus, pinna, ear canal, forehead, scalp, fingers, and genitalia) or for tumors that have recurred after initial excision.[10,11] Mohs micrographic surgery is also used to treat high-risk tumors with poorly defined clinical borders or with perineural invasion.
Radiation therapy
Radiation therapy is a logical treatment choice, particularly for patients with primary lesions requiring difficult or extensive surgery (e.g., lesions on the nose, lips, or ears).[7,12] Radiation therapy eliminates the need for skin grafting in cases where surgery would result in an extensive defect. Cosmetic results are generally good, with a small amount of hypopigmentation or telangiectasia in the treatment port. Radiation therapy can also be used for lesions that recur after a primary surgical approach.[13]
Radiation therapy is avoided in patients with conditions that predispose them to radiation-induced cancers, such as xeroderma pigmentosum or basal cell nevus syndrome.
Although radiation therapy, with or without excision of the primary tumor, is used for histologically proven clinical lymph node metastases and has been associated with favorable disease-free survival rates, the retrospective nature of these case series makes it difficult to know the impact of nodal radiation on survival.[14,15][Level of evidence C2]
Curettage and electrodesiccation
Curettage and electrodesiccation is used to treat SCC of the skin. A sharp curette is used to scrape the tumor down to its base, followed by electrodesiccation of the lesion base. Although curettage and electrodesiccation is a quick method for destroying the tumor, the adequacy of treatment cannot be assessed immediately because the surgeon cannot visually detect the depth of microscopic tumor invasion. Its use is limited to small (<1 cm), well-defined, and well-differentiated tumors.[7][Level of evidence C2] This procedure is also sometimes called electrosurgery.
Cryosurgery
Cryosurgery may be considered for patients with small, clinically well-defined primary tumors. It may be useful for patients with medical conditions that preclude other types of surgery.[16,17] Contraindications for cryosurgery include:
Abnormal cold tolerance.
Cryoglobulinemia or cryofibrinogenemia.
Raynaud disease (in the case of lesions on the hands and feet).
Platelet deficiency disorders.
Tumors of the scalp, ala nasi, nasolabial fold, tragus, postauricular sulcus, free eyelid margin, upper lip vermillion border, and lower legs.
Tumors near nerves.
Caution should also be used before treating nodular ulcerative neoplasia larger than 3 cm in diameter, carcinomas fixed to the underlying bone or cartilage, tumors situated on the lateral margins of the fingers and at the ulnar fossa of the elbow, or recurrent carcinomas following surgical excision. Permanent pigment loss at the treatment site is unavoidable, so the treatment is not well suited to patients with dark skin.
Edema is common after treatment, especially around the periorbital region, temple, and forehead. Treated tumors usually exude necrotic material, after which an eschar forms and persists for about 4 weeks. Atrophy and hypertrophic scarring have been reported, as have instances of motor and sensory neuropathy.
Treatment of SCC in situ (Bowen disease)
The management of SCC in situ (Bowen disease) is similar to that for good-risk SCC. However, because Bowen disease is noninvasive, surgical excision, including Mohs micrographic surgery, is usually not necessary. In addition, high complete response (CR) rates are achievable with photodynamic therapy (PDT).
Evidence (PDT):
In a multicenter trial, 229 patients (209 evaluated in a per-protocol/per-lesion analysis) were randomly assigned to receive PDT (methyl aminolevulinate + 570–670 nm red light; n = 91); placebo cream with red light (n = 15); or treatment by physician choice (cryotherapy, n = 77; topical fluorouracil [5-FU], n = 26).[18][Level of evidence B1]
The sustained complete clinical RRs at 12 months were 80% for PDT, 67% for placebo cream with red light, and 69% for treatment of physician choice (P = .04 for the comparison between PDT and the two combined physician-choice groups).[18][Level of evidence B1]
The cosmetic results were best in the PDT group. (For comparison, the CR rates at 3 months were 93% for PDT and 21% for placebo/PDT.)
Treatment of Metastatic Squamous Cell Carcinoma (or Advanced Disease Untreatable by Local Modalities)
As is the case with basal cell carcinoma (BCC), metastatic and far-advanced SCC is unusual, and reports of systemic therapy are limited to case reports, small case series, or early-phase trials with tumor response as the end point.[Level of evidence C3] The metastatic rates are 5% for primary tumors of sun-exposed skin, 9% for tumors of the external ear, and 14% for tumors of the lip. Metastases occur at an even higher rate (about 38%) for primary SCCs in scar carcinomas or in nonexposed areas of skin.[9] About 69% of metastases are diagnosed within 1 year, 91% within 3 years, and 96% within 5 years.
Immunotherapy (PD-1 inhibitors)
Two PD-1 inhibitors, cemiplimab and pembrolizumab, have been approved by the FDA as systemic therapy for recurrent or metastatic SCC not amenable to curative surgery or radiation therapy (cemiplimab, pembrolizumab) and locally advanced SCC not amenable to curative surgery (cemiplimab).
Cemiplimab
The FDA approved cemiplimab for systemic therapy for metastatic or locally advanced SCC not amenable to curative surgery or radiation therapy. Approval was based on RR as assessed by an independent review committee in two open-label, multicenter, early-phase trials.[4,5][Level of evidence C3] The FDA-approved dose is a fixed-dose equivalent (350 mg as a 30-minute intravenous [IV] infusion administered every 3 weeks) of the trial dose given as 3 mg/kg IV over 30 minutes every 2 weeks. Toxicities associated with checkpoint inhibitors were seen, including death.
Evidence (cemiplimab):
A phase I expansion cohort trial (NCT02383212) that required patients to have at least one measurable lesion enrolled patients with metastatic (n = 16) or locally advanced (n = 10) SCC. Cemiplimab was administered as 3 mg/kg IV over 30 minutes every 2 weeks.[4]
Formal hypothesis testing was not included in phase I. However, responses, as assessed by an independent review committee, were seen in 13 of 26 patients using Response Evaluation Criteria In Solid Tumors (RECIST) criteria for radiological scans.[4]
A phase II trial (NCT02760498) entered patients into one of two cohorts: patients with metastatic SCC (nodal or distant; 59 patients) [4] or patients with locally advanced SCC who were not eligible for local surgery or radiation therapy (78 patients).[5]
Patients were required to have at least one measurable lesion and were excluded for an autoimmune disease that required systemic therapy within 5 years, previous checkpoint inhibitor therapy, solid organ transplant, Eastern Cooperative Oncology Group performance status below 1, and hepatitis or infection with HIV. Patients received treatment with 3 mg/kg IV every 2 weeks until progressive disease. RRs were assessed by an independent review committee using RECIST criteria for radiological scans and World Health Organization criteria for medical photography for a composite response. RRs were assessed after all patients had at least 6 months of follow-up.
Metastatic disease: Twenty-eight of 59 patients had a response (47%; 95% CI, 34%−61%); 4 patients (7%) had a CR. The median duration of follow-up was 7.9 months with median duration of response not reached. When results from the 16 patients with metastatic disease in the phase I study were pooled with the results from the 59 patients with metastatic disease in the phase II cohort, the RR in 75 patients remained 47% (95% CI, 35%−59%).
Locally advanced disease: A total of 78 patients with locally advanced disease (i.e., no nodal metastases) were enrolled in the phase II cohort. The RR was 44% (34 patients; 95% CI, 32−55), with CRs reported in 10 patients (13%). The median duration of follow-up was 9.3 months at the time of data cut-off, with a median duration of response not reached.
Exploratory immunohistochemistry analysis did not show predictive value of baseline PD-L1.
Adverse events were consistent with PD-1 inhibitors. In the phase II trial, approximately 7% to 8% of patients discontinued treatment because of adverse events, and there were five treatment-emergent adverse events leading to death.
Pembrolizumab
Pembrolizumab is approved for systemic therapy for recurrent or metastatic SCC not amenable to surgery or radiation therapy. Approval was based on RR as assessed by an independent review committee of a multicenter, multicohort, open-label phase II trial in patients with recurrent or metastatic SCC not amenable to surgery or radiation therapy.[6][Level of evidence C3] The cohort of patients with locally advanced disease is not yet reported. Patients received pembrolizumab 200 mg every 3 weeks. An alternate dosing regimen of pembrolizumab, 400 mg every 6 weeks, is approved across all adult indications based on pharmacokinetic modeling and exposure-response analyses.
Evidence (pembrolizumab):
A single-arm phase II trial (KEYNOTE-629 [NCT03284424]) enrolled 105 patients into the cohort of recurrent or metastatic SCC.[6] Patients were required to have measurable disease and were excluded for an autoimmune disease or a medical condition requiring immunosuppression or an Eastern Cooperative Oncology Group Performance Status above grade 1. Treatment continued for up to 2 years in the absence of disease progression, unacceptable toxicity, or investigator or patient decision to withdraw. If stable, patients with radiological-only evidence of progressive disease at first assessment were permitted to continue treatment until progressive disease was confirmed. The primary end point was RR per RECIST v1.1.
An interim analysis at 11 months of follow-up (range, 0.4−16.3 months) demonstrated an RR of 34% (95% CI, 25%−44%) with four CRs. Median duration of response has not been reached (range, 3−13± months).
Exploratory analysis of programmed death ligand 1 combined positive score by immunohistochemistry did not predict response to treatment.
Adverse events were consistent with PD-1 inhibitors. Treatment-emergent adverse events led to discontinuation in 13 patients (12%); five (5%) were considered treatment-emergent adverse events, including pneumonitis, cranial nerve neuropathy, and renal failure. Grade 5 treatment-emergent adverse events occurred in 12 patients (11%) and included infection, cardiac failure, and respiratory failure. One death from cranial nerve neuropathy was considered treatment related.
As treatment options and long-term outcomes are limited, clinical trials are recommended. Trial options include PD-1 inhibitors and cemiplimab in the advanced setting, as well as in the neoadjuvant and adjuvant settings; other checkpoint inhibitors; checkpoint inhibitor combinations; and combinations with epidermal growth factor receptor inhibitors.
Treatment of Recurrent Nonmetastatic Squamous Cell Carcinoma of the Skin
SCCs have definite metastatic potential, and patients are monitored regularly after initial treatment. Overall, local recurrence rates after treatment of primary SCCs have ranged from about 3% to 23%, depending on anatomical site.[9] About 58% of local recurrences manifest within 1 year, 83% within 3 years, and 95% within 5 years. Tumors that are 2 cm or larger in diameter, 4 mm or greater in depth, or poorly differentiated have a relatively poor prognosis [19] and even higher local recurrence and metastasis rates than those listed.[9] Reported local recurrence rates also vary by treatment modality, with the lowest rates associated with Mohs micrographic surgery. However, at least some of the variation may be the result of patient selection factors. No randomized trials directly compare the various local treatment modalities.
Treatment options for recurrent nonmetastatic SCCs include:
Surgical excision.
Mohs micrographic surgery.
Radiation therapy.
Recurrent nonmetastatic SCCs are considered high risk and are generally treated with excision, often using Mohs micrographic surgery. Radiation therapy is used for lesions that cannot be completely resected.
As is the case with BCC, patients who develop a primary SCC are also at increased risk of subsequent primary skin cancers.[20,21]
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
Preston DS, Stern RS: Nonmelanoma cancers of the skin. N Engl J Med 327 (23): 1649-62, 1992. [PUBMED Abstract]
Lansbury L, Leonardi-Bee J, Perkins W, et al.: Interventions for non-metastatic squamous cell carcinoma of the skin. Cochrane Database Syst Rev (4): CD007869, 2010. [PUBMED Abstract]
Brewster AM, Lee JJ, Clayman GL, et al.: Randomized trial of adjuvant 13-cis-retinoic acid and interferon alfa for patients with aggressive skin squamous cell carcinoma. J Clin Oncol 25 (15): 1974-8, 2007. [PUBMED Abstract]
Migden MR, Rischin D, Schmults CD, et al.: PD-1 Blockade with Cemiplimab in Advanced Cutaneous Squamous-Cell Carcinoma. N Engl J Med 379 (4): 341-351, 2018. [PUBMED Abstract]
Migden MR, Khushalani NI, Chang ALS, et al.: Cemiplimab in locally advanced cutaneous squamous cell carcinoma: results from an open-label, phase 2, single-arm trial. Lancet Oncol 21 (2): 294-305, 2020. [PUBMED Abstract]
Grob JJ, Gonzalez R, Basset-Seguin N, et al.: Pembrolizumab Monotherapy for Recurrent or Metastatic Cutaneous Squamous Cell Carcinoma: A Single-Arm Phase II Trial (KEYNOTE-629). J Clin Oncol 38 (25): 2916-2925, 2020. [PUBMED Abstract]
Motley R, Kersey P, Lawrence C, et al.: Multiprofessional guidelines for the management of the patient with primary cutaneous squamous cell carcinoma. Br J Dermatol 146 (1): 18-25, 2002. [PUBMED Abstract]
Brodland DG, Zitelli JA: Surgical margins for excision of primary cutaneous squamous cell carcinoma. J Am Acad Dermatol 27 (2 Pt 1): 241-8, 1992. [PUBMED Abstract]
Rowe DE, Carroll RJ, Day CL: Prognostic factors for local recurrence, metastasis, and survival rates in squamous cell carcinoma of the skin, ear, and lip. Implications for treatment modality selection. J Am Acad Dermatol 26 (6): 976-90, 1992. [PUBMED Abstract]
Thomas RM, Amonette RA: Mohs micrographic surgery. Am Fam Physician 37 (3): 135-42, 1988. [PUBMED Abstract]
Rowe DE, Carroll RJ, Day CL: Mohs surgery is the treatment of choice for recurrent (previously treated) basal cell carcinoma. J Dermatol Surg Oncol 15 (4): 424-31, 1989. [PUBMED Abstract]
Caccialanza M, Piccinno R, Moretti D, et al.: Radiotherapy of carcinomas of the skin overlying the cartilage of the nose: results in 405 lesions. Eur J Dermatol 13 (5): 462-5, 2003 Sep-Oct. [PUBMED Abstract]
Lovett RD, Perez CA, Shapiro SJ, et al.: External irradiation of epithelial skin cancer. Int J Radiat Oncol Biol Phys 19 (2): 235-42, 1990. [PUBMED Abstract]
Shimm DS, Wilder RB: Radiation therapy for squamous cell carcinoma of the skin. Am J Clin Oncol 14 (5): 383-6, 1991. [PUBMED Abstract]
Veness MJ, Palme CE, Smith M, et al.: Cutaneous head and neck squamous cell carcinoma metastatic to cervical lymph nodes (nonparotid): a better outcome with surgery and adjuvant radiotherapy. Laryngoscope 113 (10): 1827-33, 2003. [PUBMED Abstract]
Almeida Gonçalves JC: Advanced cancer of the extremities treated by cryosurgery. G Ital Dermatol Venereol 146 (4): 249-55, 2011. [PUBMED Abstract]
Morton C, Horn M, Leman J, et al.: Comparison of topical methyl aminolevulinate photodynamic therapy with cryotherapy or Fluorouracil for treatment of squamous cell carcinoma in situ: Results of a multicenter randomized trial. Arch Dermatol 142 (6): 729-35, 2006. [PUBMED Abstract]
Cherpelis BS, Marcusen C, Lang PG: Prognostic factors for metastasis in squamous cell carcinoma of the skin. Dermatol Surg 28 (3): 268-73, 2002. [PUBMED Abstract]
Karagas MR, Stukel TA, Greenberg ER, et al.: Risk of subsequent basal cell carcinoma and squamous cell carcinoma of the skin among patients with prior skin cancer. Skin Cancer Prevention Study Group. JAMA 267 (24): 3305-10, 1992. [PUBMED Abstract]
Schinstine M, Goldman GD: Risk of synchronous and metachronous second nonmelanoma skin cancer when referred for Mohs micrographic surgery. J Am Acad Dermatol 44 (3): 497-9, 2001. [PUBMED Abstract]
Treatment of Actinic Keratosis
Actinic keratoses commonly appear in areas of chronic sun exposure, such as the face and dorsa of the hands. Actinic cheilitis is a related condition that usually appears on the lower lips.[1] These conditions represent early epithelial transformation that may eventually evolve into invasive squamous cell carcinoma (SCC).
Actinic keratoses are noninvasive lesions. The progression rate is extremely low. In a prospective study, the progression rate to SCC was less than 1 in 1,000 per year, calling into question the cost-effectiveness of treating all actinic keratoses to prevent SCC.[2] Moreover, in a population-based longitudinal study, there was a spontaneous regression rate of approximately 26% for solar keratoses within 1 year of a screening examination.[3] Therefore, studies designed to test the efficacy of any treatment for progression of actinic keratoses to SCC are impractical (or impossible). Nevertheless, a variety of treatment approaches have been reviewed.[4]
Treatment options for actinic keratosis depend on whether the lesions are isolated or whether there are multiple lesions in the same field.
Treatment options for actinic keratosis (not listed hierarchically) include:
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
Picascia DD, Robinson JK: Actinic cheilitis: a review of the etiology, differential diagnosis, and treatment. J Am Acad Dermatol 17 (2 Pt 1): 255-64, 1987. [PUBMED Abstract]
Marks R, Rennie G, Selwood TS: Malignant transformation of solar keratoses to squamous cell carcinoma. Lancet 1 (8589): 795-7, 1988. [PUBMED Abstract]
Marks R, Foley P, Goodman G, et al.: Spontaneous remission of solar keratoses: the case for conservative management. Br J Dermatol 115 (6): 649-55, 1986. [PUBMED Abstract]
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 skin cancer. 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 Skin Cancer Treatment is:
Shaheer A. Khan, DO (Columbia University Irving 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.
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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 Skin Cancer Treatment. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: /types/skin/hp/skin-treatment-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389366]
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.
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More information about contacting us or receiving help with the Cancer.gov website can be found on our Contact Us for Help page. Questions can also be submitted to Cancer.gov through the website’s Email Us.
SCLC accounts for approximately 15% of bronchogenic carcinomas.
At the time of diagnosis, approximately 30% of patients with SCLC have tumors confined to the hemithorax of origin, mediastinum, or supraclavicular lymph nodes. These patients have limited-stage disease (LD).[1] Patients with tumors that have spread beyond the supraclavicular areas have extensive-stage disease (ED).
SCLC is more responsive to chemotherapy and radiation therapy than other cell types of lung cancer. However, a cure is difficult to achieve because SCLC has a greater tendency to be widely disseminated by the time of diagnosis.
Incidence and Mortality
The overall incidence and mortality rates of SCLC in the United States have decreased during the past few decades.[2]
Estimated new cases and deaths from lung cancer (SCLC and non-small cell lung cancer [NSCLC] combined) in the United States in 2025:[3]
New cases: 226,650.
Deaths: 124,730.
Risk Factors
Increasing age is the most important risk factor for most cancers. Other risk factors for lung cancer include:
History of or current tobacco use: cigarettes, pipes, and cigars.[4]
Exposure to cancer-causing substances in secondhand smoke.[5,6]
Occupational exposure to asbestos, arsenic, chromium, beryllium, nickel, and other agents.[7]
Radiation exposure from any of the following sources:
Beta carotene supplements in heavy smokers.[17,18]
Clinical Features
Lung cancer may present with symptoms or be found incidentally on chest imaging. Symptoms and signs may result from the location of the primary local invasion or compression of adjacent thoracic structures, distant metastases, or paraneoplastic phenomena. The most common symptoms at presentation are worsening cough and dyspnea. Other presenting symptoms include:
Chest pain.
Hoarseness.
Malaise.
Anorexia.
Weight loss.
Hemoptysis.
Symptoms may result from local invasion or compression of adjacent thoracic structures, such as compression involving the esophagus causing dysphagia, compression involving the laryngeal nerves causing hoarseness, or compression involving the superior vena cava causing facial edema and distension of the superficial veins of the head and neck. Symptoms from distant metastases may also be present and include neurological defects or personality changes from brain metastases and pain from bone metastases.
Infrequently, patients with SCLC may present with symptoms and signs of one of the following paraneoplastic syndromes:
Inappropriate antidiuretic hormone secretion.
Cushing syndrome from secretion of adrenocorticotropic hormone.
Physical examination may identify enlarged supraclavicular lymphadenopathy, pleural effusion or lobar collapse, unresolved pneumonia, or signs of associated disease such as chronic obstructive pulmonary disease.
Diagnosis
Treatment options for patients are determined by histology, stage, and general health and comorbidities of the patient. Investigations of patients with suspected SCLC focus on confirming the diagnosis and determining the extent of the disease.
The procedures used to determine the presence of cancer include:
History.
Physical examination.
Routine laboratory evaluations.
Chest x-ray.
Chest CT scan with infusion of contrast material.
Biopsy.
Before a patient begins lung cancer treatment, an experienced lung cancer pathologist must review the pathological material. This is critical because SCLC, which responds well to chemotherapy and is generally not treated surgically, can be confused on microscopic examination with NSCLC.[19] Immunohistochemistry and electron microscopy are invaluable techniques for diagnosis and subclassification, but most lung tumors can be classified by light microscopic criteria.
Regardless of stage, the prognosis for patients with SCLC is unsatisfactory despite improvements in diagnosis and therapy during the past 25 years. Without treatment, SCLC has the most aggressive clinical course of any type of pulmonary tumor, with a median survival from diagnosis of only 2 to 4 months. About 10% of people with SCLC remain free of disease during the 2 years from the start of therapy, which is the time period during which most relapses occur. However, even these patients are at risk of dying of lung cancer (both small and non-small cell types).[20] The overall survival rate at 5 years is 5% to 10%.[1,20–22]
An important prognostic factor for SCLC is the extent of disease. Patients with LD have a better prognosis than patients with ED. For patients with LD, the median survival is 16 to 24 months and the 5-year survival rates is 14% with current forms of treatment.[1,21,23,24] Patients diagnosed with LD who smoke should be encouraged to stop smoking before undergoing combined-modality therapy because continued smoking may compromise survival.[25]
Patients with LD have improved long-term survival with combined-modality therapy.[24,26][Level of evidence A1] Although long-term survivors have been reported among patients who received either surgery or chemotherapy alone, chemotherapy combined with thoracic radiation therapy (TRT) is considered the standard of care.[27] Adding TRT increases absolute survival by approximately 5% over chemotherapy alone.[26,28] Multiple trials and meta-analyses have evaluated the optimal timing of TRT relative to chemotherapy, with the weight of evidence suggesting a small benefit to early TRT.[1,29,30][Level of evidence A1]
In patients with ED, the median survival 6 to 12 months with currently available therapy, but long-term disease-free survival is rare.
Prophylactic cranial radiation prevents central nervous system recurrence and can improve survival in patients with good performance status who have had a complete response or a very good partial response to chemoradiation in LD or chemotherapy in ED.[31,32][Level of evidence A1]
Thoracic radiation may also improve long-term outcomes for these patients.[33]
All patients with this type of cancer may appropriately be considered for inclusion in clinical trials at the time of diagnosis. Information about ongoing clinical trials is available from the NCI website.
References
Murray N, Coy P, Pater JL, et al.: Importance of timing for thoracic irradiation in the combined modality treatment of limited-stage small-cell lung cancer. The National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol 11 (2): 336-44, 1993. [PUBMED Abstract]
Govindan R, Page N, Morgensztern D, et al.: Changing epidemiology of small-cell lung cancer in the United States over the last 30 years: analysis of the surveillance, epidemiologic, and end results database. J Clin Oncol 24 (28): 4539-44, 2006. [PUBMED Abstract]
American Cancer Society: Cancer Facts and Figures 2025. American Cancer Society, 2025. Available online. Last accessed January 16, 2025.
Alberg AJ, Ford JG, Samet JM, et al.: Epidemiology of lung cancer: ACCP evidence-based clinical practice guidelines (2nd edition). Chest 132 (3 Suppl): 29S-55S, 2007. [PUBMED Abstract]
Tulunay OE, Hecht SS, Carmella SG, et al.: Urinary metabolites of a tobacco-specific lung carcinogen in nonsmoking hospitality workers. Cancer Epidemiol Biomarkers Prev 14 (5): 1283-6, 2005. [PUBMED Abstract]
Anderson KE, Kliris J, Murphy L, et al.: Metabolites of a tobacco-specific lung carcinogen in nonsmoking casino patrons. Cancer Epidemiol Biomarkers Prev 12 (12): 1544-6, 2003. [PUBMED Abstract]
Straif K, Benbrahim-Tallaa L, Baan R, et al.: A review of human carcinogens–part C: metals, arsenic, dusts, and fibres. Lancet Oncol 10 (5): 453-4, 2009. [PUBMED Abstract]
Friedman DL, Whitton J, Leisenring W, et al.: Subsequent neoplasms in 5-year survivors of childhood cancer: the Childhood Cancer Survivor Study. J Natl Cancer Inst 102 (14): 1083-95, 2010. [PUBMED Abstract]
Gray A, Read S, McGale P, et al.: Lung cancer deaths from indoor radon and the cost effectiveness and potential of policies to reduce them. BMJ 338: a3110, 2009. [PUBMED Abstract]
Berrington de González A, Kim KP, Berg CD: Low-dose lung computed tomography screening before age 55: estimates of the mortality reduction required to outweigh the radiation-induced cancer risk. J Med Screen 15 (3): 153-8, 2008. [PUBMED Abstract]
Shimizu Y, Kato H, Schull WJ: Studies of the mortality of A-bomb survivors. 9. Mortality, 1950-1985: Part 2. Cancer mortality based on the recently revised doses (DS86). Radiat Res 121 (2): 120-41, 1990. [PUBMED Abstract]
Katanoda K, Sobue T, Satoh H, et al.: An association between long-term exposure to ambient air pollution and mortality from lung cancer and respiratory diseases in Japan. J Epidemiol 21 (2): 132-43, 2011. [PUBMED Abstract]
Cao J, Yang C, Li J, et al.: Association between long-term exposure to outdoor air pollution and mortality in China: a cohort study. J Hazard Mater 186 (2-3): 1594-600, 2011. [PUBMED Abstract]
Hales S, Blakely T, Woodward A: Air pollution and mortality in New Zealand: cohort study. J Epidemiol Community Health 66 (5): 468-73, 2012. [PUBMED Abstract]
Lissowska J, Foretova L, Dabek J, et al.: Family history and lung cancer risk: international multicentre case-control study in Eastern and Central Europe and meta-analyses. Cancer Causes Control 21 (7): 1091-104, 2010. [PUBMED Abstract]
Shiels MS, Cole SR, Kirk GD, et al.: A meta-analysis of the incidence of non-AIDS cancers in HIV-infected individuals. J Acquir Immune Defic Syndr 52 (5): 611-22, 2009. [PUBMED Abstract]
The effect of vitamin E and beta carotene on the incidence of lung cancer and other cancers in male smokers. The Alpha-Tocopherol, Beta Carotene Cancer Prevention Study Group. N Engl J Med 330 (15): 1029-35, 1994. [PUBMED Abstract]
Omenn GS, Goodman GE, Thornquist MD, et al.: Effects of a combination of beta carotene and vitamin A on lung cancer and cardiovascular disease. N Engl J Med 334 (18): 1150-5, 1996. [PUBMED Abstract]
Travis WD, Colby TV, Corrin B, et al.: Histological typing of lung and pleural tumours. 3rd ed. Springer-Verlag, 1999.
Johnson BE, Grayson J, Makuch RW, et al.: Ten-year survival of patients with small-cell lung cancer treated with combination chemotherapy with or without irradiation. J Clin Oncol 8 (3): 396-401, 1990. [PUBMED Abstract]
Fry WA, Menck HR, Winchester DP: The National Cancer Data Base report on lung cancer. Cancer 77 (9): 1947-55, 1996. [PUBMED Abstract]
Lassen U, Osterlind K, Hansen M, et al.: Long-term survival in small-cell lung cancer: posttreatment characteristics in patients surviving 5 to 18+ years–an analysis of 1,714 consecutive patients. J Clin Oncol 13 (5): 1215-20, 1995. [PUBMED Abstract]
Turrisi AT, Kim K, Blum R, et al.: Twice-daily compared with once-daily thoracic radiotherapy in limited small-cell lung cancer treated concurrently with cisplatin and etoposide. N Engl J Med 340 (4): 265-71, 1999. [PUBMED Abstract]
Jänne PA, Freidlin B, Saxman S, et al.: Twenty-five years of clinical research for patients with limited-stage small cell lung carcinoma in North America. Cancer 95 (7): 1528-38, 2002. [PUBMED Abstract]
Videtic GM, Stitt LW, Dar AR, et al.: Continued cigarette smoking by patients receiving concurrent chemoradiotherapy for limited-stage small-cell lung cancer is associated with decreased survival. J Clin Oncol 21 (8): 1544-9, 2003. [PUBMED Abstract]
Pignon JP, Arriagada R, Ihde DC, et al.: A meta-analysis of thoracic radiotherapy for small-cell lung cancer. N Engl J Med 327 (23): 1618-24, 1992. [PUBMED Abstract]
Chandra V, Allen MS, Nichols FC, et al.: The role of pulmonary resection in small cell lung cancer. Mayo Clin Proc 81 (5): 619-24, 2006. [PUBMED Abstract]
Warde P, Payne D: Does thoracic irradiation improve survival and local control in limited-stage small-cell carcinoma of the lung? A meta-analysis. J Clin Oncol 10 (6): 890-5, 1992. [PUBMED Abstract]
Perry MC, Eaton WL, Propert KJ, et al.: Chemotherapy with or without radiation therapy in limited small-cell carcinoma of the lung. N Engl J Med 316 (15): 912-8, 1987. [PUBMED Abstract]
Takada M, Fukuoka M, Kawahara M, et al.: Phase III study of concurrent versus sequential thoracic radiotherapy in combination with cisplatin and etoposide for limited-stage small-cell lung cancer: results of the Japan Clinical Oncology Group Study 9104. J Clin Oncol 20 (14): 3054-60, 2002. [PUBMED Abstract]
Aupérin A, Arriagada R, Pignon JP, et al.: Prophylactic cranial irradiation for patients with small-cell lung cancer in complete remission. Prophylactic Cranial Irradiation Overview Collaborative Group. N Engl J Med 341 (7): 476-84, 1999. [PUBMED Abstract]
Slotman B, Faivre-Finn C, Kramer G, et al.: Prophylactic cranial irradiation in extensive small-cell lung cancer. N Engl J Med 357 (7): 664-72, 2007. [PUBMED Abstract]
Slotman BJ, van Tinteren H, Praag JO, et al.: Use of thoracic radiotherapy for extensive stage small-cell lung cancer: a phase 3 randomised controlled trial. Lancet 385 (9962): 36-42, 2015. [PUBMED Abstract]
Cellular Classification of SCLC
Before initiating treatment for a patient with small cell lung cancer (SCLC), an experienced lung cancer pathologist should review the pathological material.
Pathological Classification
The current classification of subtypes of SCLC includes:[1]
Small cell carcinoma.
Combined small cell carcinoma (i.e., SCLC combined with additional components from any of the non-small cell lung carcinoma histological types).
SCLC arising from neuroendocrine cells forms one extreme of the spectrum of neuroendocrine carcinomas of the lung.
Neuroendocrine tumors include:
Low-grade typical carcinoid.
Intermediate-grade atypical carcinoid.
High-grade neuroendocrine tumors, including large-cell neuroendocrine carcinoma (LCNEC) and SCLC.
Because of differences in clinical behavior, therapy, and epidemiology, these tumors are classified separately in the World Health Organization (WHO) revised classification. The variant form of SCLC called mixed small cell/large cell carcinoma was not retained in the revised WHO classification. Instead, SCLC is now divided into SCLC and combined SCLC.[2] No minimum percentage of the additional component is required for a combined SCLC diagnosis with the exception of mixed LCNEC and SCLC, in which a 10% minimum LCNEC component is required.[3]
SCLC presents as a proliferation of small cells with the following morphological features:[4]
Scant cytoplasm.
Ill-defined borders.
Finely granular salt and pepper chromatin.
Absent or inconspicuous nucleoli.
Frequent nuclear molding.
A high mitotic count.
Nearly all SCLC are immunoreactive for keratin, thyroid transcription factor 1, and epithelial membrane antigen. Neuroendocrine and neural differentiation result in the expression of dopa decarboxylase, calcitonin, neuron-specific enolase, chromogranin A, CD56 (also known as nucleosomal histone kinase 1 or neural-cell adhesion molecule), gastrin-releasing peptide, and insulin-like growth factor 1. One or more markers of neuroendocrine differentiation can be found in approximately 75% of SCLC.[5]
Although preinvasive and in situ malignant changes are frequently found in patients with non-small cell lung cancer, these findings are rare in patients with SCLC.[6]
References
Travis WD, Colby TV, Corrin B, et al.: Histological typing of lung and pleural tumours. 3rd ed. Springer-Verlag, 1999.
Lei Y, Feng H, Qiang H, et al.: Clinical characteristics and prognostic factors of surgically resected combined small cell lung cancer: a retrospective study. Lung Cancer 146: 244-251, 2020. [PUBMED Abstract]
Simbolo M, Centonze G, Ali G, et al.: Integrative molecular analysis of combined small-cell lung carcinomas identifies major subtypes with different therapeutic opportunities. ESMO Open 7 (1): 100308, 2022. [PUBMED Abstract]
Brambilla E, Travis WD, Colby TV, et al.: The new World Health Organization classification of lung tumours. Eur Respir J 18 (6): 1059-68, 2001. [PUBMED Abstract]
Guinee DG, Fishback NF, Koss MN, et al.: The spectrum of immunohistochemical staining of small-cell lung carcinoma in specimens from transbronchial and open-lung biopsies. Am J Clin Pathol 102 (4): 406-14, 1994. [PUBMED Abstract]
Kumar V, Abbas A, Fausto N, eds.: Robins and Cotran Pathologic Basis of Disease. 7th ed. Elsevier Inc, 2005.
Stage Information for SCLC
Staging Systems
Several staging systems have been proposed for small cell lung cancer (SCLC).
American Joint Committee on Cancer (AJCC) Tumor, Node, and Metastasis (TNM).[1] The 8th edition of the AJCC Cancer Staging Manual recommends the use of the TNM to classify SCLC. For more information, see the AJCC Stage Groupings and TNM Definitions section in Non-Small Cell Lung Cancer Treatment.
Veterans Administration Lung Study Group (VALG).[2]
International Association for the Study of Lung Cancer (IASLC).[3]
Limited-Stage Disease
No universally accepted definition of this term is available. Limited-stage disease (LD) SCLC is confined to the hemithorax of origin, mediastinum, or supraclavicular nodes, which can be encompassed within a tolerable radiation therapy port.
Patients with pleural effusion, massive pulmonary tumor, and contralateral supraclavicular nodes have been both included in and excluded from LD by various groups.
Extensive-Stage Disease
Extensive-stage disease (ED) SCLC has spread beyond the supraclavicular areas and is too widespread to be included within the definition of LD. Patients with distant metastases (M1) are always considered to have ED.[3,4]
IASLC-AJCC TNM Staging System
The AJCC TNM defines LD as any T, except for T3–4, due to multiple lung nodules that do not fit in a tolerable radiation field, any N, and M0.[1] This corresponds to TNM stages I to IIIB. Extensive disease is TNM stage IV with distant metastases (M1), including malignant pleural effusions.[3,4] For more information, see the AJCC Stage Groupings and TNM Definitions section in Non-Small Cell Lung Cancer Treatment.
The IASLC conducted an analysis of clinical TNM staging for SCLC using the sixth edition of the AJCC TNM staging system for lung cancer. Survival rates for patients with clinical stages I and II disease are significantly different from those for patients with stage III disease with N2 or N3 involvement.[3] Patients with pleural effusion have an intermediate prognosis between LD and ED with hematogenous metastases and will be classified as having M1 disease (or ED). Application of the TNM system will not change how patients are managed; however, the analysis suggests that, in the context of clinical trials in LD, accurate TNM staging and stratification may be important.[3]
Staging Evaluation
Staging procedures for SCLC are important to distinguish patients with disease limited to their thorax from those with distant metastases. At the time of initial diagnosis, approximately two-thirds of patients with SCLC have clinical evidence of metastases; most of the remaining patients have clinical evidence of extensive nodal involvement in the hilar, mediastinal, and sometimes supraclavicular regions.
Determining the stage of cancer allows an assessment of prognosis and a determination of treatment, particularly when chest radiation therapy or surgical excision is added to chemotherapy for patients with LD. If ED is confirmed, further evaluation should be individualized according to the signs and symptoms unique to the individual patient. Standard staging procedures include:
A thorough physical examination.
Routine blood counts and serum chemistries.
Chest and upper abdominal computed tomography (CT) scanning.
A radionuclide bone scan.
A brain magnetic resonance imaging scan or CT scan.
Bone marrow aspirate or biopsy in selected patients in which treatment would change based on the results.
The role of positron emission tomography (PET) is still under study. SCLC is fluorine F 18-fludeoxyglucose (18F-FDG) avid at the primary site and at metastatic sites. PET may be used in staging patients with SCLC who are potential candidates for the addition of thoracic radiation therapy to chemotherapy, as PET may lead to upstaging or downstaging of patients and to alteration of radiation fields resulting from the identification of additional sites of nodal metastases.
Evidence (18F-FDG PET):
In a study of 120 patients with LD SCLC or ED SCLC, FDG-PET led to restaging of ten patients to a higher stage and three patients to a lower stage.[5] FDG-PET was more sensitive and specific than CT scans for nonbrain distant metastases.
In a small series of 24 patients with LD by conventional staging, two patients were restaged to ED.[2] Unsuspected nodal metastases were documented in 25% of patients, which altered the radiation plan in these patients. At this time, sensitivity, specificity, and positive- or negative-predictive value of PET scanning and its enhancement of staging accuracy are uncertain.
References
Lung. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. Springer; 2017, pp. 431–56.
Bradley JD, Dehdashti F, Mintun MA, et al.: Positron emission tomography in limited-stage small-cell lung cancer: a prospective study. J Clin Oncol 22 (16): 3248-54, 2004. [PUBMED Abstract]
Shepherd FA, Crowley J, Van Houtte P, et al.: The International Association for the Study of Lung Cancer lung cancer staging project: proposals regarding the clinical staging of small cell lung cancer in the forthcoming (seventh) edition of the tumor, node, metastasis classification for lung cancer. J Thorac Oncol 2 (12): 1067-77, 2007. [PUBMED Abstract]
Ihde D, Souhami B, Comis R, et al.: Small cell lung cancer. Lung Cancer 17 (Suppl 1): S19-21, 1997. [PUBMED Abstract]
Brink I, Schumacher T, Mix M, et al.: Impact of [18F]FDG-PET on the primary staging of small-cell lung cancer. Eur J Nucl Med Mol Imaging 31 (12): 1614-20, 2004. [PUBMED Abstract]
Treatment Option Overview for SCLC
Chemotherapy and radiation therapy have been shown to improve survival for patients with small cell lung cancer (SCLC).
Chemotherapy
Chemotherapy improves the survival of patients with limited-stage disease (LD) or extensive-stage disease (ED), but it is curative in only a few patients.[1,2] Because patients with SCLC tend to develop distant metastases, localized forms of treatment, such as surgical resection or radiation therapy, rarely produce long-term survival.[3] Incorporating current chemotherapy regimens into the treatment program prolongs survival, with at least a fourfold to fivefold improvement in median survival compared with patients who are given no therapy.
The combination of platinum and etoposide is the most widely used standard chemotherapeutic regimen.[4–6][Level of evidence A1] No consistent survival benefit has resulted from platinum versus nonplatinum combinations, increased dose intensity or dose density, altered mode of administration (e.g., alternating or sequential administration) of various chemotherapeutic agents, or maintenance chemotherapy.[7–12][Level of evidence A1]
Radiation Therapy
SCLC is highly radiosensitive and thoracic radiation therapy improves survival of patients with LD and ED tumors.[13–16][Level of evidence A1] Prophylactic cranial irradiation prevents central nervous system recurrence and may improve the long-term survival of patients with good performance status who have responded to chemoradiation therapy.[17–19][Level of evidence A1] This type of irradiation also offers palliation of symptomatic metastatic disease.
Treatment options for patients with LD, ED, or recurrent SCLC are summarized in Table 1.
Table 1. Treatment Options for Patients With SCLC
Stage
Treatment Options
ED = extensive-stage disease; LD = limited-stage disease.
Clinical trials evaluating new drug regimens, surgical resection of the primary tumor, or new radiation therapy schedules and techniques (e.g., timing, three-dimensional treatment planning, and dose fractionation)
Phase I and II clinical trials evaluating new drugs
Despite treatment advances, most patients with SCLC die of their tumor even with the best available therapy. Most of the improvements in survival of patients with SCLC are attributable to clinical trials that have attempted to improve on the best available and most accepted therapy. Patient entry into such studies is highly desirable.
Information about ongoing clinical trials is available from the NCI website.
References
Comis RL, Friedland DM, Good BC: Small-cell lung cancer: a perspective on the past and a preview of the future. Oncology (Huntingt) 12 (1 Suppl 2): 44-50, 1998. [PUBMED Abstract]
Agra Y, Pelayo M, Sacristan M, et al.: Chemotherapy versus best supportive care for extensive small cell lung cancer. Cochrane Database Syst Rev (4): CD001990, 2003. [PUBMED Abstract]
Prasad US, Naylor AR, Walker WS, et al.: Long term survival after pulmonary resection for small cell carcinoma of the lung. Thorax 44 (10): 784-7, 1989. [PUBMED Abstract]
Johnson BE, Grayson J, Makuch RW, et al.: Ten-year survival of patients with small-cell lung cancer treated with combination chemotherapy with or without irradiation. J Clin Oncol 8 (3): 396-401, 1990. [PUBMED Abstract]
Lassen U, Osterlind K, Hansen M, et al.: Long-term survival in small-cell lung cancer: posttreatment characteristics in patients surviving 5 to 18+ years–an analysis of 1,714 consecutive patients. J Clin Oncol 13 (5): 1215-20, 1995. [PUBMED Abstract]
Fry WA, Menck HR, Winchester DP: The National Cancer Data Base report on lung cancer. Cancer 77 (9): 1947-55, 1996. [PUBMED Abstract]
Ihde DC, Mulshine JL, Kramer BS, et al.: Prospective randomized comparison of high-dose and standard-dose etoposide and cisplatin chemotherapy in patients with extensive-stage small-cell lung cancer. J Clin Oncol 12 (10): 2022-34, 1994. [PUBMED Abstract]
Arriagada R, Le Chevalier T, Pignon JP, et al.: Initial chemotherapeutic doses and survival in patients with limited small-cell lung cancer. N Engl J Med 329 (25): 1848-52, 1993. [PUBMED Abstract]
Klasa RJ, Murray N, Coldman AJ: Dose-intensity meta-analysis of chemotherapy regimens in small-cell carcinoma of the lung. J Clin Oncol 9 (3): 499-508, 1991. [PUBMED Abstract]
Elias AD, Ayash L, Frei E, et al.: Intensive combined modality therapy for limited-stage small-cell lung cancer. J Natl Cancer Inst 85 (7): 559-66, 1993. [PUBMED Abstract]
Murray N, Livingston RB, Shepherd FA, et al.: Randomized study of CODE versus alternating CAV/EP for extensive-stage small-cell lung cancer: an Intergroup Study of the National Cancer Institute of Canada Clinical Trials Group and the Southwest Oncology Group. J Clin Oncol 17 (8): 2300-8, 1999. [PUBMED Abstract]
Amarasena IU, Walters JA, Wood-Baker R, et al.: Platinum versus non-platinum chemotherapy regimens for small cell lung cancer. Cochrane Database Syst Rev (4): CD006849, 2008. [PUBMED Abstract]
Pignon JP, Arriagada R, Ihde DC, et al.: A meta-analysis of thoracic radiotherapy for small-cell lung cancer. N Engl J Med 327 (23): 1618-24, 1992. [PUBMED Abstract]
Warde P, Payne D: Does thoracic irradiation improve survival and local control in limited-stage small-cell carcinoma of the lung? A meta-analysis. J Clin Oncol 10 (6): 890-5, 1992. [PUBMED Abstract]
Murray N, Coy P, Pater JL, et al.: Importance of timing for thoracic irradiation in the combined modality treatment of limited-stage small-cell lung cancer. The National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol 11 (2): 336-44, 1993. [PUBMED Abstract]
Slotman BJ, van Tinteren H, Praag JO, et al.: Use of thoracic radiotherapy for extensive stage small-cell lung cancer: a phase 3 randomised controlled trial. Lancet 385 (9962): 36-42, 2015. [PUBMED Abstract]
Turrisi AT, Glover DJ: Thoracic radiotherapy variables: influence on local control in small cell lung cancer limited disease. Int J Radiat Oncol Biol Phys 19 (6): 1473-9, 1990. [PUBMED Abstract]
Aupérin A, Arriagada R, Pignon JP, et al.: Prophylactic cranial irradiation for patients with small-cell lung cancer in complete remission. Prophylactic Cranial Irradiation Overview Collaborative Group. N Engl J Med 341 (7): 476-84, 1999. [PUBMED Abstract]
Slotman B, Faivre-Finn C, Kramer G, et al.: Prophylactic cranial irradiation in extensive small-cell lung cancer. N Engl J Med 357 (7): 664-72, 2007. [PUBMED Abstract]
Treatment of Limited-Stage SCLC
Treatment Options for Patients With Limited-Stage SCLC
Clinical trials evaluating new drug regimens, surgical resection of the primary tumor, or new radiation therapy schedules and techniques (e.g., timing, three-dimensional treatment planning, and dose fractionation).
Chemotherapy and radiation therapy
Combined-modality treatment with etoposide and cisplatin with thoracic radiation therapy (TRT) is the most widely used treatment for patients with limited-stage disease (LD) SCLC.
Evidence (combined-modality treatment):
Survival. The following results have been reported in clinical trials:
Mature results of prospective randomized trials suggest that combined-modality therapy produces a modest but significant improvement in survival of 5% at 3 years compared with chemotherapy alone.[1–3][Level of evidence A1]
Clinical trials have consistently achieved median survivals of 18 to 24 months and 2-year survival rates of 40% to 50%, with a treatment-related mortality rate of less than 3%.[3–7][Level of evidence A1]
No consistent survival benefit has resulted from the following treatment approaches:[8–16]
Increased dose intensity.
Increased dose density.
Administration of additional drugs or other (non–etoposide-containing) platinum-based combination regimens.
Altered modes of administration of various chemotherapeutic agents.
Maintenance chemotherapy.
Length of treatment. The optimal duration of chemotherapy for patients with LD SCLC is not clearly defined, but no improvement exists in survival after the duration of drug administration exceeds 3 to 6 months. The preponderance of evidence available from randomized trials indicates that maintenance chemotherapy does not prolong survival for patients with LD SCLC.[8–15][Level of evidence A1]
Dose and timing. The optimal dose and timing of TRT remain controversial.
Multiple clinical trials and meta-analyses addressing the timing of TRT have been published, with the weight of evidence suggesting a small benefit to early TRT (i.e., TRT administered during the first or second cycle of chemotherapy administration).[3–6,8,9,15,17–20][Level of evidence A1]
The amount of time from start to completion of TRT in LD SCLC may also affect overall survival (OS). In an analysis of four trials, the completion of therapy in less than 30 days was associated with an improved 5-year survival rate (relative risk, 0.62; 95% confidence interval [CI], 0.49–0.80; P = .0003).[20][Level of evidence A1]
Both once-daily and twice-daily chest radiation schedules have been used in regimens with etoposide and cisplatin.
One randomized study showed a modest survival advantage in favor of twice-daily radiation therapy given for 3 weeks, compared with once-daily radiation therapy to 45 Gy given for 5 weeks (26% vs. 16% at 5 years; P = .04).[17][Level of evidence A1] Esophagitis was increased with twice-daily treatment.
The phase III CONVERT study (NCT00433563) randomly assigned patients to receive either 45 Gy radiation therapy in 30 twice-daily fractions of 1.5 Gy over 19 days or 66 Gy in 33 once-daily fractions of 2 Gy over 45 days, starting on day 22 after commencing cisplatin-etoposide chemotherapy (given as four to six cycles every 3 weeks in both groups).[21] The primary end point was OS, defined as time from randomization until death from any cause, analyzed by modified intention-to-treat. A 12% higher OS at 2 years in the once-daily group versus the twice-daily group was considered clinically significant to show superiority of the once-daily regimen.
At a median follow-up of 45 months (interquartile range [IQR], 35–58), median OS was 30 months (95% CI, 24–34) in the twice-daily group versus 25 months (95% CI, 21–31) in the once-daily group (hazard ratio for death in the once-daily group, 1.18 [95% CI, 0.95–1.45]; P = .14).
The two-year OS rate was 56% (95% CI, 50%–62%) in the twice-daily group and 51% (45%–57%) in the once-daily group (absolute difference between the treatment groups, 5.3% [95% CI, -3.2% to 13.7%]).
Most toxicities were similar between the groups, except there was significantly more grade 4 neutropenia with twice-daily radiation therapy (129 [49%] vs. 101 [38%]; P = .05). In contrast to the earlier study, there was no difference between the groups in terms of rates of grade 3 to 4 esophagitis or pneumonitis.
Twice-daily radiation therapy has not been broadly adopted. Once-daily fractions to doses higher than 60 Gy are feasible and commonly used; their clinical benefits are yet to be defined in phase III trials.[21][Level of evidence A1]
Adjuvant treatment after chemoradiation therapy
Evidence (adjuvant treatment after chemoradiation therapy):
ADRIATIC (NCT03703297) was a phase III, randomized, double-blind, placebo-controlled, multicenter, global study, published in abstract form, that assessed durvalumab with or without tremelimumab as consolidation treatment for patients with LD SCLC. Patients had stage I to III disease (inoperable if stage I or II) that had not progressed after chemoradiation therapy. PCI was permitted before randomization. Patients were randomly assigned 1 to 42 days after concurrent chemoradiation therapy to receive durvalumab (1,500 mg) plus placebo, durvalumab (1,500 mg) plus tremelimumab (75 mg), or placebo plus placebo every 4 weeks for four cycles, followed by durvalumab or placebo every 4 weeks until investigator-determined progression or intolerable toxicity, or for a maximum of 24 months. The dual primary end points were OS and progression-free survival (PFS) per blinded independent central review for durvalumab versus placebo. The trial randomly assigned 730 patients, including 264 to receive durvalumab and 266 to receive placebo. The abstract was published after the first planned interim analysis of durvalumab versus placebo.[22]
The median duration of follow-up was 37.2 months for OS and 27.6 months for PFS.[22][Level of evidence A1]
The median OS was 55.9 months in the durvalumab arm (95% CI, 37.3–not estimable) and 33.4 months in the placebo arm (95% CI, 25.5–39.9). The 24-month OS rate was 68.0% in the durvalumab arm and 58.5% in the placebo arm. The 36-month OS rate was 56.5% in the durvalumab arm and 47.6% in the placebo arm.
The median PFS was 16.6 months in the durvalumab arm (95% CI, 10.2–28.2) and 9.2 months (95% CI, 7.4–12.9) in the placebo arm. The 18-month PFS rate was 48.8% in the durvalumab arm and 36.1% in the placebo arm. The 24-month PFS rate was 46.2% in the durvalumab arm and 34.2% in the placebo arm.
Grade 3 or 4 all-cause adverse events occurred in 24.3% of patients in the durvalumab arm and 24.2% of patients in the placebo arm. Adverse events led to treatment discontinuation in 16.3% of patients in the durvalumab arm and 10.6% of patients in the placebo arm, and to death in 2.7% of patients in the durvalumab arm and 1.9% of patients in the placebo arm. Any-grade pneumonitis/radiation pneumonitis was reported in 38.0% of patients who received durvalumab and 30.2% of patients who received the placebo.
This is the first new treatment option for patients with LD SCLC in over 35 years.
Combination chemotherapy alone
Patients with a contraindication to radiation therapy may receive chemotherapy alone. Patients presenting with superior vena cava syndrome are treated immediately with combination chemotherapy, radiation therapy, or both, depending on the severity of presentation.[23,24] For more information, see Cardiopulmonary Syndromes.
Surgery followed by chemotherapy or chemoradiation therapy
The role of surgery in the management of patients with SCLC is unproven. Small case series and population studies have reported favorable outcomes for the minority of LD patients with very limited disease, with small tumors pathologically confined to the lung of origin or the lung and ipsilateral hilar lymph nodes from surgical resection with adjuvant chemotherapy.[25–29][Level of evidence C2] Patients who have undergone surgery and then been diagnosed with SCLC generally receive adjuvant chemotherapy with or without radiation therapy. In patients who receive chemotherapy with radiation therapy, there is no improvement in survival with the addition of surgery.[29][Level of evidence C2] Given the absence of data from randomized trials, the potential benefits and risks of surgery in the management of individual patients with SCLC must be considered.
Evidence (role of surgery):
A randomized study evaluated the role of surgery in addition to chemoradiation therapy for 328 patients with LD SCLC. The study found no OS benefit with the addition of pulmonary resection.[30][Level of evidence A1]
PCI
Patients who have achieved a complete remission may receive PCI. Patients whose cancer can be controlled outside the brain have a 60% actuarial risk of developing central nervous system (CNS) metastases within 2 to 3 years after starting treatment.[29,31,32] Most of these patients have disease that relapses only in the brain, and nearly all of those with CNS relapse die of their cranial metastases. The risk of developing CNS metastases can be reduced by more than 50% with the administration of PCI.[31]
Evidence (role of PCI):
A meta-analysis of seven randomized trials evaluated the value of PCI for patients in complete remission. The addition of PCI improved the rates of brain recurrence, disease-free survival, and OS. The 3-year OS rate increased from 15% to 21% with PCI.[31][Level of evidence A1]
The randomized RTOG-0212 study (NCT00005062) included 720 patients with LD SCLC in complete remission after chemoradiation therapy. The trial demonstrated that standard-dose PCI (25 Gy in 10 fractions) was as effective as, and less toxic than, higher doses of brain radiation.[33]
Randomized trials such as RTOG-0212 (NCT00005062) showed that doses higher than 25 Gy in 10 daily fractions do not improve long-term survival.[33–35]
Neurological sequelae
Retrospective studies have shown that long-term survivors of SCLC (>2 years from the start of treatment) have a high incidence of CNS impairment.[29,32,36–38] Prospective studies have shown that patients treated with PCI do not have significantly worse neuropsychological function than patients not treated with PCI.[38] Most patients with SCLC have neuropsychological abnormalities before the start of PCI and have no detectable neurological decline for as long as 2 years after the start of PCI.[38] Patients treated for SCLC continue to have declining neuropsychological function after 2 years from the start of treatment.[36–38] Additional neuropsychological testing of patients beyond 2 years from the start of treatment is needed before concluding that PCI does not contribute to the decline in intellectual function.
Treatment options for older patients
The optimal therapeutic approach in older patients remains unclear. A population analysis showed that increasing age was associated with decreased performance status and increased comorbidity.[39] Older patients were less likely to be treated with combined chemoradiation therapy, more intensive chemotherapy, and PCI. Older patients were also less likely to respond to therapy and had poorer survival outcomes. Whether these findings were a result of age and its associated comorbidities or suboptimal treatment delivery remains uncertain.
No specific phase III trial in older patients with LD SCLC has been reported. However, three secondary analyses of two cooperative group trials evaluating outcomes in patients aged 70 years or older have been published.[40–42] The survival outcomes for the older patients were identical to those of their younger counterparts in both trials. The older patients experienced more toxic effects, particularly hematological, compared with younger patients. There was a significant increase in treatment-related mortality in the EST-3588 trial that compared etoposide and cisplatin with either once-daily or twice-daily radiation therapy (1% for patients aged <70 years vs. 10% for patients aged ≥70 years; P = .01).[41] Because the older patients enrolled in these phase III trials may not be representative of LD SCLC patients in the general population, caution must be exercised in extrapolating these results to the general population of older patients.
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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Warde P, Payne D: Does thoracic irradiation improve survival and local control in limited-stage small-cell carcinoma of the lung? A meta-analysis. J Clin Oncol 10 (6): 890-5, 1992. [PUBMED Abstract]
Murray N, Coy P, Pater JL, et al.: Importance of timing for thoracic irradiation in the combined modality treatment of limited-stage small-cell lung cancer. The National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol 11 (2): 336-44, 1993. [PUBMED Abstract]
Turrisi AT, Glover DJ: Thoracic radiotherapy variables: influence on local control in small cell lung cancer limited disease. Int J Radiat Oncol Biol Phys 19 (6): 1473-9, 1990. [PUBMED Abstract]
McCracken JD, Janaki LM, Crowley JJ, et al.: Concurrent chemotherapy/radiotherapy for limited small-cell lung carcinoma: a Southwest Oncology Group Study. J Clin Oncol 8 (5): 892-8, 1990. [PUBMED Abstract]
Takada M, Fukuoka M, Kawahara M, et al.: Phase III study of concurrent versus sequential thoracic radiotherapy in combination with cisplatin and etoposide for limited-stage small-cell lung cancer: results of the Japan Clinical Oncology Group Study 9104. J Clin Oncol 20 (14): 3054-60, 2002. [PUBMED Abstract]
Johnson BE, Bridges JD, Sobczeck M, et al.: Patients with limited-stage small-cell lung cancer treated with concurrent twice-daily chest radiotherapy and etoposide/cisplatin followed by cyclophosphamide, doxorubicin, and vincristine. J Clin Oncol 14 (3): 806-13, 1996. [PUBMED Abstract]
Spiro SG, James LE, Rudd RM, et al.: Early compared with late radiotherapy in combined modality treatment for limited disease small-cell lung cancer: a London Lung Cancer Group multicenter randomized clinical trial and meta-analysis. J Clin Oncol 24 (24): 3823-30, 2006. [PUBMED Abstract]
De Ruysscher D, Pijls-Johannesma M, Vansteenkiste J, et al.: Systematic review and meta-analysis of randomised, controlled trials of the timing of chest radiotherapy in patients with limited-stage, small-cell lung cancer. Ann Oncol 17 (4): 543-52, 2006. [PUBMED Abstract]
Giaccone G, Dalesio O, McVie GJ, et al.: Maintenance chemotherapy in small-cell lung cancer: long-term results of a randomized trial. European Organization for Research and Treatment of Cancer Lung Cancer Cooperative Group. J Clin Oncol 11 (7): 1230-40, 1993. [PUBMED Abstract]
Goodman GE, Crowley JJ, Blasko JC, et al.: Treatment of limited small-cell lung cancer with etoposide and cisplatin alternating with vincristine, doxorubicin, and cyclophosphamide versus concurrent etoposide, vincristine, doxorubicin, and cyclophosphamide and chest radiotherapy: a Southwest Oncology Group Study. J Clin Oncol 8 (1): 39-47, 1990. [PUBMED Abstract]
Fukuoka M, Furuse K, Saijo N, et al.: Randomized trial of cyclophosphamide, doxorubicin, and vincristine versus cisplatin and etoposide versus alternation of these regimens in small-cell lung cancer. J Natl Cancer Inst 83 (12): 855-61, 1991. [PUBMED Abstract]
Bleehen NM, Girling DJ, Machin D, et al.: A randomised trial of three or six courses of etoposide cyclophosphamide methotrexate and vincristine or six courses of etoposide and ifosfamide in small cell lung cancer (SCLC). I: Survival and prognostic factors. Medical Research Council Lung Cancer Working Party. Br J Cancer 68 (6): 1150-6, 1993. [PUBMED Abstract]
Sculier JP, Paesmans M, Bureau G, et al.: Randomized trial comparing induction chemotherapy versus induction chemotherapy followed by maintenance chemotherapy in small-cell lung cancer. European Lung Cancer Working Party. J Clin Oncol 14 (8): 2337-44, 1996. [PUBMED Abstract]
Fried DB, Morris DE, Poole C, et al.: Systematic review evaluating the timing of thoracic radiation therapy in combined modality therapy for limited-stage small-cell lung cancer. J Clin Oncol 22 (23): 4837-45, 2004. [PUBMED Abstract]
Kubota K, Hida T, Ishikura S, et al.: Etoposide and cisplatin versus irinotecan and cisplatin in patients with limited-stage small-cell lung cancer treated with etoposide and cisplatin plus concurrent accelerated hyperfractionated thoracic radiotherapy (JCOG0202): a randomised phase 3 study. Lancet Oncol 15 (1): 106-13, 2014. [PUBMED Abstract]
Turrisi AT, Kim K, Blum R, et al.: Twice-daily compared with once-daily thoracic radiotherapy in limited small-cell lung cancer treated concurrently with cisplatin and etoposide. N Engl J Med 340 (4): 265-71, 1999. [PUBMED Abstract]
Huncharek M, McGarry R: A meta-analysis of the timing of chest irradiation in the combined modality treatment of limited-stage small cell lung cancer. Oncologist 9 (6): 665-72, 2004. [PUBMED Abstract]
Pijls-Johannesma MC, De Ruysscher D, Lambin P, et al.: Early versus late chest radiotherapy for limited stage small cell lung cancer. Cochrane Database Syst Rev (1): CD004700, 2005. [PUBMED Abstract]
De Ruysscher D, Pijls-Johannesma M, Bentzen SM, et al.: Time between the first day of chemotherapy and the last day of chest radiation is the most important predictor of survival in limited-disease small-cell lung cancer. J Clin Oncol 24 (7): 1057-63, 2006. [PUBMED Abstract]
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Spigel DR, Cheng Y, Cho BC, et al.: ADRIATIC: Durvalumab (D) as consolidation treatment (tx) for patients (pts) with limited-stage small-cell lung cancer (LS-SCLC). [Abstract] J Clin Oncol 42 (Suppl 17): A-LBA5, 2024.
Urban T, Lebeau B, Chastang C, et al.: Superior vena cava syndrome in small-cell lung cancer. Arch Intern Med 153 (3): 384-7, 1993. [PUBMED Abstract]
Würschmidt F, Bünemann H, Heilmann HP: Small cell lung cancer with and without superior vena cava syndrome: a multivariate analysis of prognostic factors in 408 cases. Int J Radiat Oncol Biol Phys 33 (1): 77-82, 1995. [PUBMED Abstract]
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Shepherd FA, Ginsberg RJ, Patterson GA, et al.: A prospective study of adjuvant surgical resection after chemotherapy for limited small cell lung cancer. A University of Toronto Lung Oncology Group study. J Thorac Cardiovasc Surg 97 (2): 177-86, 1989. [PUBMED Abstract]
Prasad US, Naylor AR, Walker WS, et al.: Long term survival after pulmonary resection for small cell carcinoma of the lung. Thorax 44 (10): 784-7, 1989. [PUBMED Abstract]
Smit EF, Groen HJ, Timens W, et al.: Surgical resection for small cell carcinoma of the lung: a retrospective study. Thorax 49 (1): 20-2, 1994. [PUBMED Abstract]
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Lad T, Piantadosi S, Thomas P, et al.: A prospective randomized trial to determine the benefit of surgical resection of residual disease following response of small cell lung cancer to combination chemotherapy. Chest 106 (6 Suppl): 320S-323S, 1994. [PUBMED Abstract]
Nugent JL, Bunn PA, Matthews MJ, et al.: CNS metastases in small cell bronchogenic carcinoma: increasing frequency and changing pattern with lengthening survival. Cancer 44 (5): 1885-93, 1979. [PUBMED Abstract]
Aupérin A, Arriagada R, Pignon JP, et al.: Prophylactic cranial irradiation for patients with small-cell lung cancer in complete remission. Prophylactic Cranial Irradiation Overview Collaborative Group. N Engl J Med 341 (7): 476-84, 1999. [PUBMED Abstract]
Le Péchoux C, Dunant A, Senan S, et al.: Standard-dose versus higher-dose prophylactic cranial irradiation (PCI) in patients with limited-stage small-cell lung cancer in complete remission after chemotherapy and thoracic radiotherapy (PCI 99-01, EORTC 22003-08004, RTOG 0212, and IFCT 99-01): a randomised clinical trial. Lancet Oncol 10 (5): 467-74, 2009. [PUBMED Abstract]
Le Péchoux C, Laplanche A, Faivre-Finn C, et al.: Clinical neurological outcome and quality of life among patients with limited small-cell cancer treated with two different doses of prophylactic cranial irradiation in the intergroup phase III trial (PCI99-01, EORTC 22003-08004, RTOG 0212 and IFCT 99-01). Ann Oncol 22 (5): 1154-63, 2011. [PUBMED Abstract]
Wolfson AH, Bae K, Komaki R, et al.: Primary analysis of a phase II randomized trial Radiation Therapy Oncology Group (RTOG) 0212: impact of different total doses and schedules of prophylactic cranial irradiation on chronic neurotoxicity and quality of life for patients with limited-disease small-cell lung cancer. Int J Radiat Oncol Biol Phys 81 (1): 77-84, 2011. [PUBMED Abstract]
Johnson BE, Patronas N, Hayes W, et al.: Neurologic, computed cranial tomographic, and magnetic resonance imaging abnormalities in patients with small-cell lung cancer: further follow-up of 6- to 13-year survivors. J Clin Oncol 8 (1): 48-56, 1990. [PUBMED Abstract]
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Ludbrook JJ, Truong PT, MacNeil MV, et al.: Do age and comorbidity impact treatment allocation and outcomes in limited stage small-cell lung cancer? a community-based population analysis. Int J Radiat Oncol Biol Phys 55 (5): 1321-30, 2003. [PUBMED Abstract]
Schild SE, Stella PJ, Geyer SM, et al.: The outcome of combined-modality therapy for stage III non-small-cell lung cancer in the elderly. J Clin Oncol 21 (17): 3201-6, 2003. [PUBMED Abstract]
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Treatment of Extensive-Stage SCLC
Treatment Options for Patients With Extensive-Stage SCLC
Clinical trials evaluating new drug regimens or alternative drug doses and schedules.
Immune checkpoint modulation and combination chemotherapy
Studies have evaluated the role of immune checkpoint inhibitors (programmed cell death-1 [PD-1] or programmed death-ligand 1 [PD-L1] inhibitors) in frontline treatment of patients with ED SCLC. Two PD-L1 inhibitors, atezolizumab and durvalumab, prolonged overall survival (OS) when combined with platinum and etoposide, compared with the same combination chemotherapy regimen alone. For more information, see the Combination chemotherapy section. Treatment with a PD-1 inhibitor, pembrolizumab, in combination with chemotherapy, did not meet statistical significance for the prespecified end point of OS in the KEYNOTE-604 (NCT03066778) phase III trial.[1][Level of evidence B1]
Evidence (immune checkpoint modulation and combination chemotherapy):
Atezolizumab. IMpower133 (NCT02763579), a double-blind, placebo-controlled, randomized, phase III trial, compared four cycles of carboplatin and etoposide with either atezolizumab (n = 201) or placebo (n = 202), followed by maintenance with either atezolizumab or placebo (as per the original randomization) until unacceptable toxic effects, disease progression, or no additional benefit.[2]
At the planned interim analysis for OS, with a median follow-up of 22.9 months, the median OS was 12.3 months in the atezolizumab group and 10.3 months in the placebo group (hazard ratio [HR] for death, 0.76; 95% confidence interval [CI], 0.60−0.95; descriptive P = .0154).[2][Level of evidence A1]
The median progression-free survival (PFS) was 5.2 months for the atezolizumab group and 4.3 months for the placebo group (HR for disease progression or death, 0.77; 95% CI, 0.63−0.95; P = .02).
The toxicity event rate was similar for both arms, consistent with known adverse events of the individual agents. Grade 3 or 4 adverse events occurred in 56.6% of patients in the atezolizumab group and 56.1% of patients in the placebo group.
Durvalumab. CASPIAN (NCT03043872) was a randomized, open-label, phase III trial that assigned patients to durvalumab plus platinum-etoposide (n = 268), durvalumab plus tremelimumab (a cytotoxic T lymphocyte antigen-4 [CTLA-4] inhibitor) plus platinum-etoposide (n = 268), or platinum-etoposide alone (n = 269). In the immunotherapy arms, patients received four cycles of platinum-etoposide plus durvalumab with or without tremelimumab, followed by durvalumab maintenance until intolerance or disease progression or until other discontinuation criteria were met. In the chemotherapy-alone arm, up to six cycles of chemotherapy could be given, as well as PCI, at the investigator’s discretion. At the time of planned interim OS analysis, the durvalumab plus platinum-etoposide group met the predefined threshold for statistical significance.[3]
The median OS was 12.9 months in the durvalumab plus platinum-etoposide group versus 10.5 months in the platinum-etoposide group (HR for OS, 0.75; 95% CI, 0.62−0.91; nominal P = .0032).[3][Level of evidence A1]
The toxicity event rate was similar in both arms, consistent with known adverse events of the individual agents. Grade 3 or 4 events occurred in 62% of patients in both study arms.
Combination chemotherapy
Chemotherapy for patients with ED SCLC is commonly given as a two-drug combination of platinum and etoposide in doses associated with at least moderate toxic effects (as in limited-stage [LD] SCLC).[4] Cisplatin is associated with significant toxic effects and requires fluid hydration, which can be problematic in patients with cardiovascular disease. Carboplatin is active in SCLC, is dosed according to renal function, and is associated with less nonhematological toxic effects.
Other regimens appear to produce similar survival outcomes but have been studied less extensively or are in less common use.
Table 2. Combination Chemotherapy for Extensive-Stage SCLC
Doses and schedules used in current programs yield overall response rates of 50% to 80% and complete response rates of 0% to 30% in patients with ED SCLC.[5,6][Level of evidence A1]
Intracranial metastases from small cell carcinoma may respond to chemotherapy as readily as metastases in other organs.[7,8]
Evidence (standard regimens):
Two meta-analyses evaluated the role of platinum combinations versus nonplatinum combinations.
A Cochrane analysis did not identify a difference in 6-, 12-, or 24-month survival.[9]
A meta-analysis of 19 trials published between 1981 and 1999 showed a significant survival advantage for patients receiving platinum-based chemotherapy compared with those receiving a nonplatinum agent.[6][Level of evidence A1]
The Hellenic Oncology Group conducted a phase III trial comparing cisplatin and etoposide with carboplatin plus etoposide.[10] The median survival was 11.8 months in the cisplatin arm and 12.5 months in the carboplatin arm.[10][Level of evidence A1] Although this difference was not statistically significant, the trial was underpowered to prove equivalence of the two treatment regimens in patients with either LD or ED.
Irinotecan. Five trials and two meta-analyses have evaluated the combination of etoposide and cisplatin versus irinotecan and cisplatin. Only one of the trials showed the superiority of the irinotecan-and-cisplatin combination.[11][Level of evidence A1] Subsequent trials and the meta-analyses support that the regimens provide equivalent clinical benefit with differing toxicity profiles.[12–17][Level of evidence A1] Irinotecan-and-cisplatin regimens led to less grade 3 to 4 anemia, neutropenia, and thrombocytopenia but more grade 3 to 4 vomiting and diarrhea than etoposide-and-cisplatin regimens. Treatment-related deaths were comparable between the two groups.
Topotecan. In a randomized trial of 784 patients, the combination of oral topotecan given with cisplatin for 5 days was not superior to etoposide and cisplatin.[18] The 1-year survival rate was 31% (95% CI, 27%–36%) and was deemed to be noninferior, as the difference of -0.03 met the predefined criteria of no more than 10% absolute difference in 1-year survival.[18][Level of evidence A1]
Paclitaxel. No consistent survival benefit has resulted from the addition of paclitaxel to etoposide and cisplatin.[19,20]
Evidence (duration of treatment):
The optimal duration of chemotherapy is not clearly defined, but no obvious improvement in survival occurs when the duration of drug administration exceeds 6 months.[10,21,22]
Reported data from randomized trials show no clear evidence that maintenance chemotherapy improves survival duration.[23–25][Level of evidence A1] However, a meta-analysis of 14 published randomized trials assessing the benefit of duration/maintenance therapy reported an odds ratio of 0.67 for both 1- and 2-year OS (95% CI, 0.56–0.79; P < .001 for 1-year OS and 0.53–0.86; P < .001 for 2-year OS). This corresponded to an increase of 9% in 1-year OS and 4% in 2-year OS.[26][Level of evidence A1]
Evidence (dose intensification):
The role of dose intensification in patients with SCLC remains unclear.[27–31] Early studies showed that under-treatment compromised outcome and suggested that early dose intensification may improve survival.[27,28] A number of clinical trials have examined the use of colony-stimulating factors to support dose-intensified chemotherapy in SCLC.[29–37] These studies have yielded conflicting results.
Four studies have shown that a modest increase in dose intensity (25%–34%) was associated with a significant improvement in survival, with no compromise in quality of life (QOL).[29–32][Level of evidence A1]
Two of three studies that examined combinations of the variables of interval, dose per cycle, and number of cycles showed no advantage.[32–35][Level of evidence A1]
The European Organisation for Research and Treatment of Cancer trial (EORTC-08923) reported a randomized comparison of standard-dose cyclophosphamide, doxorubicin, and etoposide given every 3 weeks for five cycles versus intensified treatment given at 125% of the dose every 2 weeks for four cycles with granulocyte colony-stimulating factor (G-CSF) support.[35] The median dose intensity delivered was 70% higher in the experimental arm; the median cumulative dose was similar in both arms. There was no difference between treatment groups in median or 2-year survival.
A randomized phase III trial compared ifosfamide, cisplatin, and etoposide (ICE), which was given every 4 weeks, with twice weekly ICE with G-CSF and autologous blood support.[36] Despite achieving a relative dose intensity of 1.84 in the dose-accelerated arm, there was no difference in response rate (88% vs. 80%, respectively), median survival (14.4 vs. 13.9 months, respectively), or 2-year survival (19% vs. 22%, respectively) for dose-dense treatment compared with standard treatment.[36][Level of evidence A1] Patients who received dose-dense treatment spent less time on treatment and had fewer episodes of infection.
A randomized phase II study of identical design reported a significantly better median survival for the dose-dense arm (29.8 vs. 17.4 months, respectively; P = .02) and 2-year survival (62% vs. 36%, respectively; P = .05).[37] However, given the small study size (only 70 patients), these results should be viewed with caution.
Factors influencing treatment with chemotherapy
Performance status.
More patients with ED SCLC have greatly impaired performance status at the time of diagnosis than patients with LD. Such patients have a poor prognosis and tolerate aggressive chemotherapy or combined-modality therapy poorly. Single-agent intravenous, oral, and low-dose biweekly regimens have been developed for these patients.[33,38–44]
Prospective randomized studies have shown that patients with a poor prognosis who are treated with conventional regimens live longer than those treated with single-agent, low-dose regimens or abbreviated courses of therapy. A study comparing chemotherapy every 3 weeks with treatment given as required for symptom control showed an improvement in QOL in patients receiving regular treatment.[41][Level of evidence B1]
Other studies have tested intensive one-drug or two-drug regimens. A study conducted by the Medical Research Council demonstrated similar efficacy for an etoposide-plus-vincristine regimen and a four-drug regimen.[42] The latter regimen was associated with a greater risk of toxic effects and early death but was superior with respect to palliation of symptoms and psychological distress.[42][Level of evidence A3] Studies comparing a convenient oral treatment with single-agent oral etoposide versus combination therapy showed that the overall response rate and OS were significantly worse in the oral etoposide arm.[38,43][Level of evidence A1]
Age.
Subgroup analyses of phase II and III trials of patients with SCLC by age showed that myelosuppression and doxorubicin-induced cardiac toxic effects were more severe in older patients than in younger patients, and that the incidence of treatment-related death tended to be higher in older patients.[44] About 80% of older patients, however, received optimal treatment, and their survival was comparable with that of younger patients. The standard chemotherapy regimens for the general population could be applied to older patients in good general condition (i.e., performance status of 0–1, normal organ function, and no comorbidity). There is no evidence of a difference in response rate, disease-free survival (DFS), or OS in older patients compared with younger patients.
Radiation therapy
Radiation therapy to sites of metastatic disease unlikely to be immediately palliated by chemotherapy, especially brain, epidural, and bone metastases, is a standard treatment option for patients with ED SCLC. Brain metastases are treated with whole-brain radiation therapy.
Chest radiation therapy is sometimes given for superior vena cava syndrome, but chemotherapy alone, with radiation reserved for nonresponding patients, is appropriate initial treatment. For more information, see Cardiopulmonary Syndromes.
Thoracic radiation therapy for patients who respond to chemotherapy
Patients with ED SCLC treated with chemotherapy who have achieved a response may receive thoracic radiation therapy.
Evidence (thoracic radiation therapy):
A randomized trial of 498 patients who responded after receiving four to six cycles of chemotherapy compared thoracic radiation therapy with 30 Gy in 10 fractions versus no radiation therapy. All patients received PCI.[45][Level of evidence A1]
OS was the primary study end point and not statistically different between the two groups at 1 year (33% for the thoracic radiation therapy group vs. 28% for the control group, P = .066).
However, in a secondary analysis, the 2-year OS rate was 13% in the thoracic radiation group (95% CI, 9%–19%) versus 3% in the control group (95% CI, 2%–8%; P = .004). The OS during the entire course of follow-up was not reported.
Thoracic radiation therapy resulted in a 6-month PFS rate of 24% in the thoracic radiation group (95% CI, 19%–30%) versus 7% in the control group (95% CI, 4%–11%; P = .001).
Intrathoracic recurrences, both isolated (19.8% vs. 46.0%) and in combination with recurrences at other sites (43.7% vs. 79.8%), were reduced by approximately 50%.
Thoracic radiation therapy was well tolerated.
PCI
Patients with ED treated with chemotherapy who have achieved a response can be considered for administration of PCI.
Evidence (PCI):
A randomized trial of 286 patients who responded after four to six cycles of chemotherapy compared PCI with no further therapy.[46][Level of evidence B1
The cumulative risk of brain metastases within 1 year was 14.6% in the radiation group (95% CI, 8.3%–20.9%) and 40.4% in the control group (95% CI, 32.1%– 48.6%).
Radiation was associated with an increase in median DFS from 12.0 weeks to 14.7 weeks and in median OS from 5.4 months to 6.7 months after randomization.
The 1-year survival rate was 27.1% (95% CI, 19.4%–35.5%) in the radiation group and 13.3% (95% CI, 8.1%–19.9%) in the control group.[46]
Radiation had side effects but did not have a clinically significant effect on global health status.[46]
Only 29% of the randomly assigned patients had brain imaging at diagnosis.[47]
Combination chemotherapy and radiation therapy
Combination chemotherapy plus chest radiation therapy does not appear to improve survival compared with chemotherapy alone in patients with ED SCLC.
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
Rudin CM, Awad MM, Navarro A, et al.: Pembrolizumab or Placebo Plus Etoposide and Platinum as First-Line Therapy for Extensive-Stage Small-Cell Lung Cancer: Randomized, Double-Blind, Phase III KEYNOTE-604 Study. J Clin Oncol 38 (21): 2369-2379, 2020. [PUBMED Abstract]
Liu SV, Reck M, Mansfield AS, et al.: Updated Overall Survival and PD-L1 Subgroup Analysis of Patients With Extensive-Stage Small-Cell Lung Cancer Treated With Atezolizumab, Carboplatin, and Etoposide (IMpower133). J Clin Oncol 39 (6): 619-630, 2021. [PUBMED Abstract]
Goldman JW, Dvorkin M, Chen Y, et al.: Durvalumab, with or without tremelimumab, plus platinum-etoposide versus platinum-etoposide alone in first-line treatment of extensive-stage small-cell lung cancer (CASPIAN): updated results from a randomised, controlled, open-label, phase 3 trial. Lancet Oncol 22 (1): 51-65, 2021. [PUBMED Abstract]
Okamoto H, Watanabe K, Kunikane H, et al.: Randomised phase III trial of carboplatin plus etoposide vs split doses of cisplatin plus etoposide in elderly or poor-risk patients with extensive disease small-cell lung cancer: JCOG 9702. Br J Cancer 97 (2): 162-9, 2007. [PUBMED Abstract]
Roth BJ, Johnson DH, Einhorn LH, et al.: Randomized study of cyclophosphamide, doxorubicin, and vincristine versus etoposide and cisplatin versus alternation of these two regimens in extensive small-cell lung cancer: a phase III trial of the Southeastern Cancer Study Group. J Clin Oncol 10 (2): 282-91, 1992. [PUBMED Abstract]
Pujol JL, Carestia L, Daurès JP: Is there a case for cisplatin in the treatment of small-cell lung cancer? A meta-analysis of randomized trials of a cisplatin-containing regimen versus a regimen without this alkylating agent. Br J Cancer 83 (1): 8-15, 2000. [PUBMED Abstract]
Twelves CJ, Souhami RL, Harper PG, et al.: The response of cerebral metastases in small cell lung cancer to systemic chemotherapy. Br J Cancer 61 (1): 147-50, 1990. [PUBMED Abstract]
Nugent JL, Bunn PA, Matthews MJ, et al.: CNS metastases in small cell bronchogenic carcinoma: increasing frequency and changing pattern with lengthening survival. Cancer 44 (5): 1885-93, 1979. [PUBMED Abstract]
Amarasena IU, Walters JA, Wood-Baker R, et al.: Platinum versus non-platinum chemotherapy regimens for small cell lung cancer. Cochrane Database Syst Rev (4): CD006849, 2008. [PUBMED Abstract]
Controlled trial of twelve versus six courses of chemotherapy in the treatment of small-cell lung cancer. Report to the Medical Research Council by its Lung Cancer Working Party. Br J Cancer 59 (4): 584-90, 1989. [PUBMED Abstract]
Noda K, Nishiwaki Y, Kawahara M, et al.: Irinotecan plus cisplatin compared with etoposide plus cisplatin for extensive small-cell lung cancer. N Engl J Med 346 (2): 85-91, 2002. [PUBMED Abstract]
Hanna N, Bunn PA, Langer C, et al.: Randomized phase III trial comparing irinotecan/cisplatin with etoposide/cisplatin in patients with previously untreated extensive-stage disease small-cell lung cancer. J Clin Oncol 24 (13): 2038-43, 2006. [PUBMED Abstract]
Lara PN, Natale R, Crowley J, et al.: Phase III trial of irinotecan/cisplatin compared with etoposide/cisplatin in extensive-stage small-cell lung cancer: clinical and pharmacogenomic results from SWOG S0124. J Clin Oncol 27 (15): 2530-5, 2009. [PUBMED Abstract]
Schmittel A, Sebastian M, Fischer von Weikersthal L, et al.: A German multicenter, randomized phase III trial comparing irinotecan-carboplatin with etoposide-carboplatin as first-line therapy for extensive-disease small-cell lung cancer. Ann Oncol 22 (8): 1798-804, 2011. [PUBMED Abstract]
Zatloukal P, Cardenal F, Szczesna A, et al.: A multicenter international randomized phase III study comparing cisplatin in combination with irinotecan or etoposide in previously untreated small-cell lung cancer patients with extensive disease. Ann Oncol 21 (9): 1810-6, 2010. [PUBMED Abstract]
Jiang J, Liang X, Zhou X, et al.: A meta-analysis of randomized controlled trials comparing irinotecan/platinum with etoposide/platinum in patients with previously untreated extensive-stage small cell lung cancer. J Thorac Oncol 5 (6): 867-73, 2010. [PUBMED Abstract]
Guo S, Liang Y, Zhou Q: Complement and correction for meta-analysis of patients with extensive-stage small cell lung cancer managed with irinotecan/cisplatin versus etoposide/cisplatin as first-line chemotherapy. J Thorac Oncol 6 (2): 406-8; author reply 408, 2011. [PUBMED Abstract]
Eckardt JR, von Pawel J, Papai Z, et al.: Open-label, multicenter, randomized, phase III study comparing oral topotecan/cisplatin versus etoposide/cisplatin as treatment for chemotherapy-naive patients with extensive-disease small-cell lung cancer. J Clin Oncol 24 (13): 2044-51, 2006. [PUBMED Abstract]
Mavroudis D, Papadakis E, Veslemes M, et al.: A multicenter randomized clinical trial comparing paclitaxel-cisplatin-etoposide versus cisplatin-etoposide as first-line treatment in patients with small-cell lung cancer. Ann Oncol 12 (4): 463-70, 2001. [PUBMED Abstract]
Niell HB, Herndon JE, Miller AA, et al.: Randomized phase III intergroup trial of etoposide and cisplatin with or without paclitaxel and granulocyte colony-stimulating factor in patients with extensive-stage small-cell lung cancer: Cancer and Leukemia Group B Trial 9732. J Clin Oncol 23 (16): 3752-9, 2005. [PUBMED Abstract]
Spiro SG, Souhami RL, Geddes DM, et al.: Duration of chemotherapy in small cell lung cancer: a Cancer Research Campaign trial. Br J Cancer 59 (4): 578-83, 1989. [PUBMED Abstract]
Bleehen NM, Girling DJ, Machin D, et al.: A randomised trial of three or six courses of etoposide cyclophosphamide methotrexate and vincristine or six courses of etoposide and ifosfamide in small cell lung cancer (SCLC). I: Survival and prognostic factors. Medical Research Council Lung Cancer Working Party. Br J Cancer 68 (6): 1150-6, 1993. [PUBMED Abstract]
Giaccone G, Dalesio O, McVie GJ, et al.: Maintenance chemotherapy in small-cell lung cancer: long-term results of a randomized trial. European Organization for Research and Treatment of Cancer Lung Cancer Cooperative Group. J Clin Oncol 11 (7): 1230-40, 1993. [PUBMED Abstract]
Sculier JP, Paesmans M, Bureau G, et al.: Randomized trial comparing induction chemotherapy versus induction chemotherapy followed by maintenance chemotherapy in small-cell lung cancer. European Lung Cancer Working Party. J Clin Oncol 14 (8): 2337-44, 1996. [PUBMED Abstract]
Schiller JH, Adak S, Cella D, et al.: Topotecan versus observation after cisplatin plus etoposide in extensive-stage small-cell lung cancer: E7593–a phase III trial of the Eastern Cooperative Oncology Group. J Clin Oncol 19 (8): 2114-22, 2001. [PUBMED Abstract]
Bozcuk H, Artac M, Ozdogan M, et al.: Does maintenance/consolidation chemotherapy have a role in the management of small cell lung cancer (SCLC)? A metaanalysis of the published controlled trials. Cancer 104 (12): 2650-7, 2005. [PUBMED Abstract]
Cohen MH, Creaven PJ, Fossieck BE, et al.: Intensive chemotherapy of small cell bronchogenic carcinoma. Cancer Treat Rep 61 (3): 349-54, 1977 May-Jun. [PUBMED Abstract]
Arriagada R, Le Chevalier T, Pignon JP, et al.: Initial chemotherapeutic doses and survival in patients with limited small-cell lung cancer. N Engl J Med 329 (25): 1848-52, 1993. [PUBMED Abstract]
Fukuoka M, Masuda N, Negoro S, et al.: CODE chemotherapy with and without granulocyte colony-stimulating factor in small-cell lung cancer. Br J Cancer 75 (2): 306-9, 1997. [PUBMED Abstract]
Woll PJ, Hodgetts J, Lomax L, et al.: Can cytotoxic dose-intensity be increased by using granulocyte colony-stimulating factor? A randomized controlled trial of lenograstim in small-cell lung cancer. J Clin Oncol 13 (3): 652-9, 1995. [PUBMED Abstract]
Steward WP, von Pawel J, Gatzemeier U, et al.: Effects of granulocyte-macrophage colony-stimulating factor and dose intensification of V-ICE chemotherapy in small-cell lung cancer: a prospective randomized study of 300 patients. J Clin Oncol 16 (2): 642-50, 1998. [PUBMED Abstract]
Thatcher N, Girling DJ, Hopwood P, et al.: Improving survival without reducing quality of life in small-cell lung cancer patients by increasing the dose-intensity of chemotherapy with granulocyte colony-stimulating factor support: results of a British Medical Research Council Multicenter Randomized Trial. Medical Research Council Lung Cancer Working Party. J Clin Oncol 18 (2): 395-404, 2000. [PUBMED Abstract]
James LE, Gower NH, Rudd RM, et al.: A randomised trial of low-dose/high-frequency chemotherapy as palliative treatment of poor-prognosis small-cell lung cancer: a Cancer research Campaign trial. Br J Cancer 73 (12): 1563-8, 1996. [PUBMED Abstract]
Pujol JL, Douillard JY, Rivière A, et al.: Dose-intensity of a four-drug chemotherapy regimen with or without recombinant human granulocyte-macrophage colony-stimulating factor in extensive-stage small-cell lung cancer: a multicenter randomized phase III study. J Clin Oncol 15 (5): 2082-9, 1997. [PUBMED Abstract]
Ardizzoni A, Tjan-Heijnen VC, Postmus PE, et al.: Standard versus intensified chemotherapy with granulocyte colony-stimulating factor support in small-cell lung cancer: a prospective European Organization for Research and Treatment of Cancer-Lung Cancer Group Phase III Trial-08923. J Clin Oncol 20 (19): 3947-55, 2002. [PUBMED Abstract]
Lorigan P, Woll PJ, O’Brien ME, et al.: Randomized phase III trial of dose-dense chemotherapy supported by whole-blood hematopoietic progenitors in better-prognosis small-cell lung cancer. J Natl Cancer Inst 97 (9): 666-74, 2005. [PUBMED Abstract]
Buchholz E, Manegold C, Pilz L, et al.: Standard versus dose-intensified chemotherapy with sequential reinfusion of hematopoietic progenitor cells in small cell lung cancer patients with favorable prognosis. J Thorac Oncol 2 (1): 51-8, 2007. [PUBMED Abstract]
Girling DJ: Comparison of oral etoposide and standard intravenous multidrug chemotherapy for small-cell lung cancer: a stopped multicentre randomised trial. Medical Research Council Lung Cancer Working Party. Lancet 348 (9027): 563-6, 1996. [PUBMED Abstract]
Murray N, Grafton C, Shah A, et al.: Abbreviated treatment for elderly, infirm, or noncompliant patients with limited-stage small-cell lung cancer. J Clin Oncol 16 (10): 3323-8, 1998. [PUBMED Abstract]
Westeel V, Murray N, Gelmon K, et al.: New combination of the old drugs for elderly patients with small-cell lung cancer: a phase II study of the PAVE regimen. J Clin Oncol 16 (5): 1940-7, 1998. [PUBMED Abstract]
Earl HM, Rudd RM, Spiro SG, et al.: A randomised trial of planned versus as required chemotherapy in small cell lung cancer: a Cancer Research Campaign trial. Br J Cancer 64 (3): 566-72, 1991. [PUBMED Abstract]
Randomised trial of four-drug vs less intensive two-drug chemotherapy in the palliative treatment of patients with small-cell lung cancer (SCLC) and poor prognosis. Medical Research Council Lung Cancer Working Party. Br J Cancer 73 (3): 406-13, 1996. [PUBMED Abstract]
Souhami RL, Spiro SG, Rudd RM, et al.: Five-day oral etoposide treatment for advanced small-cell lung cancer: randomized comparison with intravenous chemotherapy. J Natl Cancer Inst 89 (8): 577-80, 1997. [PUBMED Abstract]
Sekine I, Yamamoto N, Kunitoh H, et al.: Treatment of small cell lung cancer in the elderly based on a critical literature review of clinical trials. Cancer Treat Rev 30 (4): 359-68, 2004. [PUBMED Abstract]
Slotman BJ, van Tinteren H, Praag JO, et al.: Use of thoracic radiotherapy for extensive stage small-cell lung cancer: a phase 3 randomised controlled trial. Lancet 385 (9962): 36-42, 2015. [PUBMED Abstract]
Slotman B, Faivre-Finn C, Kramer G, et al.: Prophylactic cranial irradiation in extensive small-cell lung cancer. N Engl J Med 357 (7): 664-72, 2007. [PUBMED Abstract]
Shivnani AT: Prophylactic cranial irradiation in small-cell lung cancer. N Engl J Med 357 (19): 1977; author reply 1978, 2007. [PUBMED Abstract]
Treatment of Recurrent SCLC
Treatment Options for Patients With Recurrent SCLC
Treatment options for patients with recurrent small cell lung cancer (SCLC) include:
Phase I and II clinical trials evaluating new drugs, including bispecific T-cell engager (BiTE) immunotherapies.
At the time of recurrence, many patients with SCLC are potential candidates for further therapy.
For patients with recurrent SCLC, immune checkpoint modulation with anti–programmed death-ligand 1 (anti–PD-L1) antibodies may lead to durable responses either as single agents or in combination with cytotoxic T lymphocyte antigen-4 (anti–CTLA-4). Impacts on long-term survival from these approaches are being assessed in randomized trials.
Chemotherapy
Although second-line chemotherapy has produced tumor regression, responses are usually short lived. The median survival is rarely more than 12 months and usually less than 6 months after second-line therapy.[1] Response to first-line chemotherapy predicts subsequent response to second-line therapy.
As in other chemosensitive tumors (e.g., Hodgkin lymphoma and ovarian epithelial cancer), two main categories of patients receiving second-line chemotherapy have been described: sensitive and resistant. Sensitive patients have a first-line response that lasted more than 90 days after treatment was completed. These patients have the greatest benefit from second-line chemotherapy. Patients with sensitive disease respond to the same initial regimen in approximately 50% of cases; however, cumulative toxic effects may ensue.[2] Resistant patients either did not respond to first-line chemotherapy or responded initially but relapsed within 90 days of completion of their primary therapy.[3] Results from phase II studies of drugs such as topotecan, irinotecan, and gemcitabine indicate that response rates to agents vary depending on whether patients have sensitive, resistant, or refractory disease.[4–8][Level of evidence C2]
Topotecan is a standard chemotherapy for recurrent SCLC.[9,10] Lurbinectedin, a selective inhibitor of oncogenic transcription, is another option.[11] Patients with sensitive disease may achieve response to a number of agents including topotecan, irinotecan, taxanes, vinorelbine, paclitaxel, or gemcitabine.[4–8,12–14][Level of evidence C2] Response rates for combination agents are generally higher than those reported for single agents,[15,16] and one phase III study reported improved survival for patients with sensitive disease treated with combination cisplatin, etoposide, and irinotecan. However, higher rates of toxicity have been seen.[17]
Topotecan
Evidence (topotecan and other chemotherapy agents):
A randomized comparison of second-line treatment with either cyclophosphamide, doxorubicin, and vincristine or topotecan in patients with sensitive disease reported no significant difference in response rates or survival. However, palliation of common lung cancer symptoms was better with topotecan.[9][Level of evidence A3]
A phase III trial comparing chemotherapy with best supportive care (BSC) in patients with relapsed SCLC demonstrated that the addition of oral topotecan to BSC significantly increased overall survival (OS) and resulted in better symptom control compared with BSC alone.[10][Level of evidence A1] The study enrolled 141 patients with chemosensitive or chemoresistant relapsed SCLC who were unsuitable for further standard intravenous chemotherapy. The median survivals for patients receiving topotecan plus BSC were 25.9 weeks versus 13.9 weeks for BSC alone (P = .01).[10]
A randomized phase III trial (CWRU-SKF-1598 [NCT00003917]) of 304 patients assessed the use of oral topotecan (2.3 mg/m2/day for 5 days every 21 days) or intravenous topotecan (1.5 mg/m2/day for 5 days every 21 days). Confirmed response rates were 18.3% and 21.9%, respectively.[12][Level of evidence B1] Secondary end points of median survival and 1-year survival rates were also similar (33 weeks vs. 35 weeks and 33% vs. 29%, respectively). Patients receiving oral topotecan experienced less grade 4 neutropenia (47% vs. 64.2%) but more diarrhea of all grades (35.9% vs. 19.9%) than with intravenous topotecan. Quality-of-life (QOL) analysis (using a nonvalidated QOL questionnaire) demonstrated no significant difference between the two arms.
Lurbinectedin
Evidence (lurbinectedin):
A single-arm, open-label, phase II basket trial (NCT02454972) enrolled 105 patients with SCLC who had been previously treated with one line of a chemotherapy-containing regimen.[11]
The overall response rate after treatment with lurbinectedin was 35% (95% confidence interval [CI], 26%−45%), with a median response duration of 5.3 months (95% CI, 4.1−6.4).
The overall response rate was 45% (95% CI, 32%−58%) for patients with chemosensitive disease and 22% (95% CI, 11%−37%) for patients with chemoresistant disease.
The median duration of response was 6.2 months (95% CI, 3.5−7.3) for patients with chemosensitive disease and 4.7 months (95% CI, 2.6−5.6) for patients with chemoresistant disease.[11][Level of evidence C3]
Other chemotherapy agents
Evidence (other chemotherapy agents):
A phase III trial (University Hospital Medical Information Network Clinical Trials Registry [UMIN000000828]) in Japan included 180 patients with extensive-stage SCLC, who had responded to first-line platinum-doublet chemotherapy but had their disease progress more than 90 days after completion of chemotherapy. Patients were randomly assigned 1:1 to receive intravenous topotecan for four cycles, which is the standard of care, or five 2-week cycles of cisplatin, etoposide, and irinotecan.[17]
The primary end point of OS was significantly prolonged with the combination of cisplatin, etoposide, and irinotecan (18.2 months; 95% CI, 15.7–20.6) compared with topotecan alone (12.5 months; 95% CI, 10.8–14.9; hazard ratio, 0.67; 90% CI, 0.51–0.88; P = .0079).
Rates of grade 3 to 4 toxicities were higher in patients treated with the combination regimen. Toxicities included febrile neutropenia (31% for the combination arm vs. 7% for topotecan alone) and thrombocytopenia (41% for the combination arm vs. 28% for topotecan alone).[17][Level of evidence A1]
Immunotherapy
Tarlatamab
Tarlatamab is a BiTE immunotherapy drug that targets delta-like ligand 3 (DLL3) and CD3. BiTE technology is a targeted immuno-oncology platform designed to engage a patient’s own T cells to any tumor-specific antigen, activating the cytotoxic potential of T cells to eliminate detectable cancer.
Evidence (tarlatamab):
The phase II DeLLphi-301 trial (NCT05060016) evaluated the efficacy and safety of two doses of tarlatamab (10 mg or 100 mg every 2 weeks) in 220 patients with previously treated SCLC. Patients had previously received a median of two lines of treatment. The primary end point was objective response rate by blinded independent central review.[18]
The objective response rates were 40% (97.5% CI, 29%–52%) for patients who received 10 mg of tarlatamab and 32% (97.5% CI, 21%–44%) for patients who received 100 mg of tarlatamab. The median duration of response was not reached.
The median progression-free survival was 4.9 months (95% CI, 2.9–6.7) with 10 mg of tarlatamab and 3.9 months (95% CI, 2.6–4.4) with 100 mg of tarlatamab.
The most common adverse events were cytokine release syndrome (51% with 10 mg, 61% with 100 mg), decreased appetite, pyrexia, constipation, and anemia.
Cytokine release syndrome occurred after the first one to two doses and was managed with supportive care.
Neurological adverse events suggestive of immune effector cell–associated neurotoxicity syndrome were higher for patients who received 100 mg (28%) compared with patients who received 10 mg (8%).
The 10-mg dose showed improved tolerability over the 100-mg dose, with similar efficacy.
Immune checkpoint modulation
Early phase Ib and II trials showed objective response rates of 10% to 33% with nivolumab or pembrolizumab treatment in patients with disease progression after one or more lines of chemotherapy, resulting in accelerated approval from the U.S. Food and Drug Administration. However, both agents were voluntarily withdrawn after subsequent trials failed to confirm benefit.[19,20]
Palliative therapy
Patients with central nervous system (CNS) recurrences can often obtain palliation of symptoms with additional chemotherapy and/or radiation therapy. A retrospective review showed that 43% of patients had disease response when treated with additional chemotherapy at the time of CNS relapse.[21] Most patients treated with radiation therapy obtain objective responses and improvement after radiation therapy.[22]
Some patients with intrinsic endobronchial obstructing lesions or extrinsic compression caused by the tumor have achieved successful palliation with endobronchial laser therapy (for endobronchial lesions only) and/or brachytherapy.[23] Expandable metal stents can be safely inserted under local anesthesia via the bronchoscope, which results in improved symptoms and pulmonary function in patients with malignant airways obstruction.[24]
Patients with progressive intrathoracic tumor after failing initial chemotherapy can achieve significant tumor responses, palliation of symptoms, and short-term local control with external-beam radiation therapy. Only the rare patient, however, will experience long-term survival after receiving salvage radiation therapy.[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
Davies AM, Evans WK, Mackay JA, et al.: Treatment of recurrent small cell lung cancer. Hematol Oncol Clin North Am 18 (2): 387-416, 2004. [PUBMED Abstract]
Postmus PE, Berendsen HH, van Zandwijk N, et al.: Retreatment with the induction regimen in small cell lung cancer relapsing after an initial response to short term chemotherapy. Eur J Cancer Clin Oncol 23 (9): 1409-11, 1987. [PUBMED Abstract]
Giaccone G, Donadio M, Bonardi G, et al.: Teniposide in the treatment of small-cell lung cancer: the influence of prior chemotherapy. J Clin Oncol 6 (8): 1264-70, 1988. [PUBMED Abstract]
Sandler AB: Irinotecan in small-cell lung cancer: the US experience. Oncology (Williston Park) 15 (1 Suppl 1): 11-2, 2001. [PUBMED Abstract]
van der Lee I, Smit EF, van Putten JW, et al.: Single-agent gemcitabine in patients with resistant small-cell lung cancer. Ann Oncol 12 (4): 557-61, 2001. [PUBMED Abstract]
Masuda N, Fukuoka M, Kusunoki Y, et al.: CPT-11: a new derivative of camptothecin for the treatment of refractory or relapsed small-cell lung cancer. J Clin Oncol 10 (8): 1225-9, 1992. [PUBMED Abstract]
Perez-Soler R, Glisson BS, Lee JS, et al.: Treatment of patients with small-cell lung cancer refractory to etoposide and cisplatin with the topoisomerase I poison topotecan. J Clin Oncol 14 (10): 2785-90, 1996. [PUBMED Abstract]
Masters GA, Declerck L, Blanke C, et al.: Phase II trial of gemcitabine in refractory or relapsed small-cell lung cancer: Eastern Cooperative Oncology Group Trial 1597. J Clin Oncol 21 (8): 1550-5, 2003. [PUBMED Abstract]
von Pawel J, Schiller JH, Shepherd FA, et al.: Topotecan versus cyclophosphamide, doxorubicin, and vincristine for the treatment of recurrent small-cell lung cancer. J Clin Oncol 17 (2): 658-67, 1999. [PUBMED Abstract]
O’Brien ME, Ciuleanu TE, Tsekov H, et al.: Phase III trial comparing supportive care alone with supportive care with oral topotecan in patients with relapsed small-cell lung cancer. J Clin Oncol 24 (34): 5441-7, 2006. [PUBMED Abstract]
Trigo J, Subbiah V, Besse B, et al.: Lurbinectedin as second-line treatment for patients with small-cell lung cancer: a single-arm, open-label, phase 2 basket trial. Lancet Oncol 21 (5): 645-654, 2020. [PUBMED Abstract]
Eckardt JR, von Pawel J, Pujol JL, et al.: Phase III study of oral compared with intravenous topotecan as second-line therapy in small-cell lung cancer. J Clin Oncol 25 (15): 2086-92, 2007. [PUBMED Abstract]
Ardizzoni A, Hansen H, Dombernowsky P, et al.: Topotecan, a new active drug in the second-line treatment of small-cell lung cancer: a phase II study in patients with refractory and sensitive disease. The European Organization for Research and Treatment of Cancer Early Clinical Studies Group and New Drug Development Office, and the Lung Cancer Cooperative Group. J Clin Oncol 15 (5): 2090-6, 1997. [PUBMED Abstract]
Furuse K, Kubota K, Kawahara M, et al.: Phase II study of vinorelbine in heavily previously treated small cell lung cancer. Japan Lung Cancer Vinorelbine Study Group. Oncology 53 (2): 169-72, 1996 Mar-Apr. [PUBMED Abstract]
Smit EF, Fokkema E, Biesma B, et al.: A phase II study of paclitaxel in heavily pretreated patients with small-cell lung cancer. Br J Cancer 77 (2): 347-51, 1998. [PUBMED Abstract]
Rocha-Lima CM, Herndon JE, Lee ME, et al.: Phase II trial of irinotecan/gemcitabine as second-line therapy for relapsed and refractory small-cell lung cancer: Cancer and Leukemia Group B Study 39902. Ann Oncol 18 (2): 331-7, 2007. [PUBMED Abstract]
Goto K, Ohe Y, Shibata T, et al.: Combined chemotherapy with cisplatin, etoposide, and irinotecan versus topotecan alone as second-line treatment for patients with sensitive relapsed small-cell lung cancer (JCOG0605): a multicentre, open-label, randomised phase 3 trial. Lancet Oncol 17 (8): 1147-1157, 2016. [PUBMED Abstract]
Ahn MJ, Cho BC, Felip E, et al.: Tarlatamab for Patients with Previously Treated Small-Cell Lung Cancer. N Engl J Med 389 (22): 2063-2075, 2023. [PUBMED Abstract]
Antonia SJ, López-Martin JA, Bendell J, et al.: Nivolumab alone and nivolumab plus ipilimumab in recurrent small-cell lung cancer (CheckMate 032): a multicentre, open-label, phase 1/2 trial. Lancet Oncol 17 (7): 883-895, 2016. [PUBMED Abstract]
Ott PA, Elez E, Hiret S, et al.: Pembrolizumab in Patients With Extensive-Stage Small-Cell Lung Cancer: Results From the Phase Ib KEYNOTE-028 Study. J Clin Oncol 35 (34): 3823-3829, 2017. [PUBMED Abstract]
Kristensen CA, Kristjansen PE, Hansen HH: Systemic chemotherapy of brain metastases from small-cell lung cancer: a review. J Clin Oncol 10 (9): 1498-502, 1992. [PUBMED Abstract]
Carmichael J, Crane JM, Bunn PA, et al.: Results of therapeutic cranial irradiation in small cell lung cancer. Int J Radiat Oncol Biol Phys 14 (3): 455-9, 1988. [PUBMED Abstract]
Miller JI, Phillips TW: Neodymium:YAG laser and brachytherapy in the management of inoperable bronchogenic carcinoma. Ann Thorac Surg 50 (2): 190-5; discussion 195-6, 1990. [PUBMED Abstract]
Wilson GE, Walshaw MJ, Hind CR: Treatment of large airway obstruction in lung cancer using expandable metal stents inserted under direct vision via the fibreoptic bronchoscope. Thorax 51 (3): 248-52, 1996. [PUBMED Abstract]
Ochs JJ, Tester WJ, Cohen MH, et al.: “Salvage” radiation therapy for intrathoracic small cell carcinoma of the lung progressing on combination chemotherapy. Cancer Treat Rep 67 (12): 1123-6, 1983. [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.
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 small cell lung cancer. 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 Small Cell Lung Cancer Treatment are:
Janet Dancey, MD, FRCPC (Ontario Institute for Cancer Research & NCIC Clinical Trials Group)
Monaliben Patel, MD (University of Rochester Medical Center)
Arun Rajan, MD (National Cancer Institute)
Eva Szabo, MD (National Cancer Institute)
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 Small Cell Lung Cancer Treatment. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: /types/lung/hp/small-cell-lung-treatment-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389347]
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