Note: Some citations in the text of this section are followed by a level of evidence. The PDQ editorial boards use a formal ranking system to help the reader judge the strength of evidence linked to the reported results of a therapeutic strategy. (Refer to the PDQ summary on Levels of Evidence for more information.)

The mainstay of treatment of the myelodysplastic syndromes (MDS) has traditionally been supportive care.[1,2] Prophylactic platelet transfusion should be avoided to forestall alloimmunization, which will make platelet transfusion for bleeding difficult. Anemia should be treated with red cell transfusions regularly, and patients receiving chronic red cell transfusions should be considered for iron chelation therapy with subcutaneously administered desferrioxamine and vitamin C or oral deferasirox.[1,3] (For information on anemia, refer to the Fatigue summary.) Desferrioxamine may improve granulocyte and platelet counts in some patients, and it may reduce red cell transfusion requirements.[4] The use of erythropoietin may improve anemia. The likelihood of response to exogenous erythropoietin administration is clearly 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 those patients who were anemic but who did not yet require a transfusion, patients who did not have ringed sideroblasts, and patients who had a serum erythropoietin level of less than 200 u/L.[5] Effective treatment requires substantially higher doses of erythropoietin than are used for other indications (150–300 µg/kg/day).

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 ineffective in patients with a high erythropoietin level and high transfusion needs.[6] Some patients with poor response to erythropoietin alone may have improved response with the addition of low doses of granulocyte colony-stimulating factor (GCSF) (0.5–1.0 µg/kg/day).[7-9] Rates of response to the combination treatment vary with the French-American-British (FAB) classification, with responses more likely in those with refractory anemia and ringed sideroblasts RARS, and less likely for those with excess blasts.[10] Patients with RARS are unlikely to respond to erythropoietin alone.[5]

A pooled analysis of published MDS trials from 1985 to 2005 examined 1,587 patients from 83 studies of growth factors. The growth factors included recombinant human erythropoietin and GCSF. With the exclusion from analysis of patients with more advanced MDS subtypes and with standardized response criteria, an approximate 40% overall response rate to growth factors was found.[11] The use of high-dose darbepoietin (300 µg/dose weekly) has been reported to produce a major erythroid response rate of almost 50% in patients whose endogenous erythropoietin level was less than 500 u/mL.[12]

Hormones, such as glucocorticoids and androgens, are generally of little benefit to patients with MDS.

Recombinant myeloid growth factors such as granulocyte-macrophage colony-stimulating factor (GM-CSF) have been studied in myelodysplasia.[13] Circulating granulocytes usually increase in a dose-dependent manner during therapy with GM-CSF but usually return to pretreatment levels when the agent is discontinued. Platelet and reticulocyte counts usually do not respond. The effect of GM-CSF treatment on infection rate, morbidity, mortality, and disease progression is not yet known.[14-17] Some patients respond to GM-CSF with increased circulating blasts.[15] A randomized trial in which granulocytopenic MDS patients were assigned to GM-CSF or observation showed no advantage to the prophylactic use of that cytokine.[18]

The nucleoside 5-azacitidine is an inhibitor of DNA methyltransferase. Following a series of phase II studies suggesting significant activity of 5-azacitidine in patients with MDS, a randomized trial was conducted by the Cancer and Leukemia Group B. In the trial, 191 patients were randomized to receive 5-azacitidine (75 mg/m²/day subcutaneously daily for 7 days every 28 days) or observation. The antineoplastic nucleoside 5-azacitidine was continued for a minimum of four cycles. Patients who did not improve on the observation arm crossed over to receive 5-azacitidine. Hematologic responses occurred in 60% of patients on the 5-azacitidine arm (7% complete response, 16% partial response, and 37% improved response) compared with 5% in the observation arm (responses in the latter group consisted of hematologic improvement associated with an increased white cell count caused by the progression to acute leukemia). The response data of the original Cancer and Leukemia Group B trial have been reanalyzed in the CALGB-8421, CALGB-8921, and CALGB-9221 studies, respectively, using the International Working Group MDS Response Criteria; total hematologic response rate was 47% and included 10% complete responses.[19] Median time to leukemic transformation or death was 21 months for azacitidine versus 13 months for supportive care (P = .007). Median duration of response was 15 months, and fewer than 1% of treated patients died on study. Quality-of-life assessment found significant major advantages in physical function, symptoms, and psychological state for patients initially randomized to azacitidine.[20-22][Level of evidence: 1iiDii]

Preliminary results were reported from a phase III randomized control trial of 5-azacitidine versus other regimens.[23] The other regimens included low-dose cytarabine, acute myeloid leukemia-type remission induction chemotherapy, or best supportive care, and the trial was limited to patients with higher-risk MDS subtypes. The median and 2-year overall survival (OS) favored the 5-azacitidine arm, at 24 months versus 16 months (P = .0001) and 51% versus 26% (P < .0001), respectively.[23][Level of evidence: 1iiA]

The azacitidine congener decitabine demonstrated similar activity in phase II trials with an overall response rate of 49% and a median response duration of 39 weeks.[24] A randomized trial of decitabine versus supportive care in patients with International Prognostic Scoring System (IPSS) Int-1 or greater led to an overall response rate of 30% in the decitabine arm versus 7% in the observation arm (P < .001).[25] Median time to AML or death was 12.1 months in the treated arm versus 7.8 months in the supportive care arm (P = not significant). Fourteen percent of patients treated with decitabine died on the study. Quality-of-life assessment found advantages to decitabine similar to those of 5-azacitidine. Although considerably fewer than originally planned, the median number of cycles administered was three, the decrease possibly attributable to the toxicity of the dose schedule studied[25][Level of evidence: 1iiDii]

Median number of cycles required to see first hematologic response to 5-azacitidine was 3; 90% of responders showed response by 6 cycles;[19] the median number of cycles of decitabine required to see first response was 2.2.[25]

Phase I and II studies have suggested that decitabine can be given as daily intravenous or subcutaneous infusions at doses that differ from the labeled schedule, which requires a minimum 3-day hospitalization; hematologic response rates are at least as good as in the phase III study.[26,27]

Administration of both nucleosides has been associated with reversal of methylation of cytosines in the promoter regions of silenced genes; however, it is not clear whether the clinical activity of these drugs requires methylation reversal.[28-30] While the mechanism of the clinical activity of 5-azacitidine and decitabine are not fully known, these two nucleosides demonstrated the highest single-agent response rates in this group of disorders. Both of these drugs have been approved for refractory anemia, RARS (if accompanied by neutropenia, or thrombocytopenia, or requiring transfusions), RAEB, and refractory anemia with excess blasts in transformation.[31] Trials studying the combinations of both azacytosine nucleosides with histone deacetylase inhibitors have been completed, including the Eastern Cooperative Oncology Group's ECOG-E1905 trial, and are ongoing, including the NCT00336170 study.[30,32,33]

Lenalidomide (CC-5013), a congener of thalidomide, induced erythroid responses in approximately 50% of MDS patients in a phase I and II study, including transfusion independence in 20 out of 32 patients.[34] Patients with MDS that was characterized by interstitial deletions of chromosome 5q31.1 (5q-) appeared particularly sensitive, with responses in 10 out of 12 patients compared with 13 out of 23 patients with a normal karyotype. In a phase II study of 148 low-risk and intermediate-risk I patients with 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.[35] Lenalidomide administration is limited by dose-limiting neutropenia and thrombocytopenia.[34][Level of evidence: 3iiiDiv]

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).[36] Multivariate analysis identified HLA-DR-15 (phenotype) expression, briefer period of red cell transfusion dependence, and younger age as predictors of response to ATG.[37]

Although therapy with cytotoxic agents has occasionally been beneficial, results are usually disappointing, and responses are often brief when achieved.[1,2,38] Low-dose cytarabine has benefitted some patients; however, this treatment was associated with a higher infection rate when compared to 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. In those patients who responded to low-dose cytarabine, response appeared to be caused by a cytotoxic effect of the drug.[39] Low doses of oral melphalan have a similar response rate to low-dose cytarabine in small trials; however, the long-term consequences of ongoing alkylator therapy in this patient population are unknown and potentially harmful.[40] Topotecan, at doses that induce bone marrow aplasia (2.0 mg/m²/day continuous infusion for 5 days), induced complete hematologic remissions in 28% of patients. Toxic effects were significant, and the median duration of remission was 8 months. The extent to which the hematologic improvement induced by this therapy may be offset by adverse changes in quality of life is not clear.[41][Level of evidence: 3iiiDiv] The combination of topotecan and cytarabine has induced complete remission in 56% of patients with MDS; however, median duration of complete response was only 50 weeks, and patients required monthly maintenance therapy.[42][Level of evidence: 3iiDiv] The combination of fludarabine, cytarabine, and granulocyte-colony stimulating factor also appears to have a high response rate (74% complete response); however, this benefit was restricted to patients with good-risk or intermediate-risk cytogenetic abnormalities according to the IPSS.[43][Level of evidence: 3iiDiv]

Autologous bone marrow or peripheral blood progenitor cell transplantation is under clinical evaluation for subsets of patients who achieve remission following cytotoxic remission induction therapy. A retrospective review of 114 patients from the European Group for Blood and Marrow Transplantation reported 25% disease-free survival (dfs) following high-dose therapy and autologous rescue for patients treated in first complete remission. Cytogenetics and the IPSS score were not provided for this patient cohort. Given that the overall remission rate for this group of diseases is not better than approximately 50%, participation in clinical trials is encouraged.[44][Level of evidence: 3iiiA]

Patients with advanced MDS or acute myeloid leukemia (AML), which has progressed from MDS, may be treated with remission induction chemotherapy similar to patients with de novo AML. A retrospective review has suggested that the complete remission rate for patients with RAEB who are treated with dose-intensive cytarabine-based regimens is comparable to the complete response rate for patients with de novo AML; however, event-free survival (EFS) was inferior for RAEB patients. Only 50% of RAEB patients in this series had cytopenias documented for at least 1 month prior to treatment; thus, some of these patients may have had evolving AML with less than 30% bone marrow blasts rather than the more typical MDS.[45][Level of evidence: 3iiDiii] In multivariate analysis, diagnosis of RAEB (as opposed to AML) was not a predictor of EFS. Rather, cytogenetic subset, duration of hematologic abnormalities, and increasing age were all strong predictors of failure to achieve complete remission, and decreased EFS. This suggests that risk assessment for chemotherapy outcome in MDS and AML should not be based solely on FAB classification. Previous studies using conventional seven plus three AML induction regimens have reported inferior remission rates in patients with MDS or AML following MDS.[46]

Allogeneic bone marrow transplantation (BMT) for young patients with MDS offers the potential for long-term dfs.[38] In two large studies, 45% to 60% of patients with de novo MDS were projected to be long-term disease-free survivors.[47,48] Outcome tends to be better in younger patients with fewer bone marrow blasts, but long-term benefit has been noted in all FAB classification types, and in patients with marrow fibrosis, a variety of karyotypic findings, and different preparative regimens.[47-49] A retrospective review of outcomes of allogeneic BMT according to pretransplant IPSS score showed that the IPSS score predicted relapse rate and dfs. The 5-year dfs rates were 60% for the low-risk and intermediate-1 risk group, 36% for the intermediate-2 risk group, and 28% for the high-risk group.[50][Level of evidence: 3iiDii] A review of 118 young MDS patients (median age 24, age range 0.3–53 years) who received allogeneic BMT from matched unrelated donors reported an actuarial survival of 28% at 2 years. Transplant-related mortality was influenced by the age of the patient (18 years or younger, 40%; age 18 to 35 years, 61%; 35 years or older, 81%). Relapse rate was influenced by FAB classification. This study included patients who received transplants as early as 1986, which may have influenced the patient survival data.[51][Level of evidence: 3iiiA] Outcomes may not be as good for patients with treatment-related MDS (5-year dfs of 8% to 30%).[52]

Allogeneic stem cell transplantation with nonmyeloablative conditioning is under clinical evaluation for treatment of MDS. A retrospective analysis of 836 allogeneic transplants for MDS using HLA-matched sibling donors was performed and included 215 patients who received nonmyeloablative conditioning regimens. The 3-year probabilities of progression-free survival and OS were similar in both groups (39% after myeloablative condition vs. 33% in reduced intensity conditioning RIC and 45% vs. 41%, respectively; these differences were not significant). Relapses were more common in the reduced intensity group, but nonrelapse mortality was decreased.[53][Level of evidence: 3iiiA]

The farnesyl transferase inhibitor tipifarnib, which is under clinical evaluation, has been examined in 82 patients; 32% of patients responded, and 15% had complete responses. Median response duration was 11 months.[54][Level of evidence: 3iiiDiv]. Arsenic trioxide induced major hematologic improvement in approximately 20% of 185 MDS patients treated in two multicenter phase II trials.[55,56]

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