Randomized Open-Label Phase II Study of Decitabine in Patients With Low- or Intermediate-Risk Myelodysplastic Syndromes

SUMMARY: The MyeloDysplastic Syndromes (MDS) are disorders of hematopoietic stem cells, characterized by one or more peripheral blood cytopenias. These syndromes may arise de novo or can be secondary, following treatment with chemotherapy and/or radiation therapy for other malignancies. It can also manifest after environmental exposures. The International Prognostic Scoring System (IPSS), based on the score, divides patients with MDS into Lower Risk (IPSS low and intermediate-1 scores) and Higher Risk (IPSS intermediate-2 and high scores) groups. This classification remains arbitrary because of the heterogeneity in the Lower Risk group and poor outcomes in certain Lower Risk subset of patients. DACOGEN® (Decitabine) exerts its antineoplastic effects by inhibitng DNA methyltransferase, resulting in hypomethylation of DNA and apoptosis. The authors in this Phase II study evaluated the outcomes in patients with Low or Intermediate-1 risk MDS using lower doses of DACOGEN® given subcutaneously on two different treatment schedules. Of the 67 randomized patients, 43 patients received DACOGEN® 20mg/m2 SC QD for three consecutive days every 28 days (Schedule A) or 20mg/m2 SC given on days 1, 8 and 15, of a 28 day cycle (Schedule B). Treatment was planned for up to one year. Primary endpoint was Overall Improvement Rate (OIR) and this included Complete Remission (CR), Partial Remission (PR), marrow CR or Hematologic Improvement (HI). Secondary end points included HI, transfusion independence, cytogenetic response, overall survival (OS), and time to acute myeloid leukemia or death. Taken as a group, there was no difference in the OIR (23%), HI, transfusion independence or cytogenetic response between schedule A and schedule B. However, patients on schedule A had more CR's making this a protocol defined superior schedule. Median OS was not reached. Transfusion independency was noted in 67% of the patient's on schedule A and 59% of the patient's on schedule B. Further, approximately 70% of the patients were alive at 500 days. The most frequent adverse events in schedule A and B were anemia (23% vs 18%), neutropenia (28% vs 36%) and thrombocytopenia (16% vs 32%). Based on these promising results, the authors recommended DACOGEN® given on three consecutive days SC every 28 days as per Schedule A, for patients with Low or Intermediate-1 risk MDS. Garcia-Manero G, Jabbour E, Borthakur G, et al. J Clin Oncol 2013;31:2548-2553