Treatment Option Overview
Although therapy with cytotoxic agents has occasionally been beneficial, results are usually disappointing, and responses are often brief when achieved.[1,2,39] 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. 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. 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.[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.[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.[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.[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.[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.