leukemia higher risk myelodysplastic syndrome and chronic myelomonocytic Results of a randomized study of three schedules of low-dose decitabine in

ABSTRACT Epigenetic therapy with hypomethylating drugs is now standard of care in myelodysplastic syndrome (MDS). Response rates remain low, and mechanism-based dose optimization has not been reported. We investigated the clinical and pharmacodynamic results of different dose-schedules of decitabine. Adults with advanced MDS or chronic myelomonocytic leukemia (CMML) were randomized to one of 3 decitabine schedules: 1) 20 mg/m 2 IV daily x 5; 2) 20 mg/m 2 SQ daily x 5; and 3) 10 mg/m 2 IV daily x 10. Randomization followed a Bayesian adaptive design. Ninety-five patients were treated (77 with MDS, all with IPSS score >1.0, 18 with CMML). Overall 32 patients (34%) achieved CR, and 69 (72%) had an objective response by the new modified International Working Group criteria. The 5-day IV schedule, which had the highest dose-intensity, was selected as optimal; the CR rate in that arm was 39%, compared to 21% in the 5-day SQ arm and 24% in the 10 day IV arm (p<0.05). The high dose-intensity arm was also superior at inducing hypomethylation at day 5 and at activating P15 expression at days 12 or 28 after therapy. We conclude that a low-dose, high dose-intensity schedule of decitabine optimizes epigenetic modulation and clinical responses in MDS. From bloodjournal.hematologylibrary.org by guest on June 5, 2013. For personal use only.