Abstract
BACKGROUND: Hypomethylating agents have demonstrated activity in patients with myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Preclinical and single-arm trials have suggested that adding histone deacetylase (HDAC) inhibitors may synergize the epigenetic modulation of hypomethylating agents and improve treatment results. METHODS: The objective of this study was to evaluate the possible benefit of adding valproic acid, an HDAC inhibitor, to decitabine in the treatment of MDS and AML. RESULTS: Patients with higher risk MDS or with AML aged ≥60 years were eligible. Patients were randomized in a Bayesian response-adaptive design to receive intravenous decitabine 20 mg/m(2) daily for 5 days or decitabine plus oral valproic acid 50 mg/kg daily for 7 days. Courses were repeated every 4 to 6 weeks. A maximum of 150 patients were to be treated. In total, 149 patients were treated on study, including 87 patients with MDS and 62 patients with AML. The median patient age was 69 years (range, 20-89 years; 42% of patients were aged ≥70 years). Overall, 34% of patients achieved complete remission, and 55% had an objective response. The median survival was 11.9 months, and the estimated 2-year survival rate was 27%. Outcome was not different with the addition of valproic acid to decitabine versus decitabine alone in relation to the rates of complete remission, overall response, or survival. Subset analyses did not demonstrate a benefit within the MDS or AML categories. Toxicities-particularly neurotoxicities-were higher with the combination arm. CONCLUSIONS: Adding valproic acid to decitabine was not associated with improved outcome in the treatment of patients with MDS or elderly patients with AML. Future therapies may consider combining hypomethylating agents with better HDAC inhibitors and using different schedules.