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Home > Health Library > Myelodysplastic Syndromes Treatment (PDQ®): Treatment - Health Professional Information [NCI]
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Incidence and Mortality
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. 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 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. (Refer to the Pathologic and Prognostic Systems for Myelodysplastic Syndromes section of this summary for more information.) The acute leukemic phase is less responsive to chemotherapy than is de novo AML.
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.
MDS occur predominantly in older patients (usually those older than 60 years), with a median age at diagnosis of approximately 70 years, although patients as young as 2 years have been reported. Anemia, bleeding, easy bruising, and fatigue are common initial findings. (Refer to the PDQ summary on Fatigue for more information.) 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. Hypoplastic myelodysplastic patients tend to have profound cytopenias and may respond more frequently to immunosuppressive therapy.
Approximately 90% of MDS cases occur de novo with no identifiable cause. Potential environmental risk factors for developing MDS include exposure to the following:[7,8]
A PDQ summary containing information about myelodysplastic syndromes in children is:
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. The clinical classification of the MDS depends upon whether there is an identifiable etiology and whether the MDS has been treated previously.
The World Health Organization (WHO) classification  has supplanted the historic French-American-British (FAB) classification, as shown in Table 1.
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 pathologic 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 analogs.
Chronic myelomonocytic leukemia (CMML)
Although previously classified with the myelodysplastic syndromes, CMML is now assigned to a group of overlap myelodysplastic/myeloproliferative neoplasms. (Refer to the PDQ summary on Myelodysplastic/ Myeloproliferative Neoplasms Treatment for more information.)
Prognostic Scoring Systems
A variety of pathologic 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; 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.
The IPSS incorporates bone marrow blast percentage, number of peripheral blood cytopenias, and cytogenetic risk group.
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.
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.
The MD Anderson Cancer Center has published two prognostic scoring systems, one of which is focused on lower-risk patients.[4,5]
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.
Standard treatment options:
The mainstay of treatment for MDS has traditionally been supportive care, particularly for those 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. (Refer to the PDQ summary on Fatigue for more information on anemia.)
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 is dependent on the pretreatment serum erythropoietin level and on baseline transfusion needs.
In a meta-analysis summarizing 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 u/L. 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. 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 µ/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.
One decision model found that the likelihood of responding to growth factors was higher in patients with a low serum erythropoietin level (defined as a level <500/µL) and low transfusion needs (defined as <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. 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).[9,10,11] 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. Patients with RARS are unlikely to respond to erythropoietin alone.
The availability of the oral iron-chelating agent deferasirox has led to its widespread use in MDS patients. 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.
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. (Refer to the DNA methyltransferase inhibitors section of this summary for more information.)
Lenalidomide is FDA-approved for the treatment of lower-risk, transfusion-dependent MDS patients 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. 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.[Level of evidence: 3iiiDiv] 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.
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. 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 MDS patients 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. 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.
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). Multivariate analysis identified HLA-DR-15 (phenotype) expression, briefer period of red cell transfusion dependence, and younger age as predictors of response to ATG. One study used alemtuzumab to treat a heavily preselected population of lower-risk MDS patients, in whom the response rate was 80%.
DNA methyltransferase inhibitors
The nucleoside analogs 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. Azacitidine received FDA approval based on the results of a randomized trial that was not designed to study survival.
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). 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.[Level of evidence: 1iiA] 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.
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 and a combined OS and delay in AML transformation endpoint were similar for patients in both the decitabine and best supportive care arms, at 10.1 months versus 8.5 months, respectively, for OS (P = .38) and 8.8 months versus 6.1 months, respectively, for the combined endpoint (P = .24).[Level of evidence: 1iiA]
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, though 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) have been treated. 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  and vorinostat  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. 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 Hematopoietic Stem Cell Transplantation (HSCT)
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.[Level of evidence: 3iiiDiv] 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 of 8% to 30%).
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.
Allogeneic stem cell transplantation with reduced-intensity conditioning (RIC) has extended transplantation as a possible modality for treatment of older patients. 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 transplantation were associated with increased relapse (hazard ratio [HR] of 1.44 and 1.51, respectively).[Level of evidence: 3iiiDiv] 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 was similar in both groups (30% after myeloablative conditioning vs. 32% in RIC.
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.
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 current 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] Relapsed patients should be considered for enrollment in clinical trials.
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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® - NCI's Comprehensive Cancer Database pages.
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 who care for cancer 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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PDQ® Adult Treatment Editorial Board. PDQ Myelodysplastic Syndromes Treatment. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: https://www.cancer.gov/types/myeloproliferative/hp/myelodysplastic-treatment-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389450]
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Last Revised: 2021-06-17
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