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Blood, 1 January 2007, Vol. 109, No. 1, pp. 52-57.
Prepublished online as a Blood First Edition Paper on August 1, 2006; DOI 10.1182/blood-2006-05-021162.
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CLINICAL TRIALS AND OBSERVATIONS
Results of a randomized study of 3 schedules of low-dose decitabine in higher-risk myelodysplastic syndrome and chronic myelomonocytic leukemia
Hagop Kantarjian1,
Yasuhiro Oki1,
Guillermo Garcia-Manero1,
Xuelin Huang2,
Susan O'Brien1,
Jorge Cortes1,
Stefan Faderl1,
Carlos Bueso-Ramos3,
Farhad Ravandi1,
Zeev Estrov1,
Alessandra Ferrajoli1,
William Wierda1,
Jianqin Shan1,
Jan Davis1,
Francis Giles1,
Hussain I. Saba4, and
Jean-Pierre J. Issa1
Departments of Leukemia, 1 Biostatistics,
2 and Hematopathology,
3 The University of Texas M. D. Anderson Cancer Center, Houston; and the H. Lee Moffitt Cancer Center and Research Institute,
4 Tampa, FL
Epigenetic therapy with hypomethylating drugs is now the 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 1 of 3 decitabine schedules: (1) 20 mg/m2 intravenously daily for 5 days; (2) 20 mg/m2 subcutaneously daily for 5 days; and (3) 10 mg/m2 intravenously daily for 10 days. Randomization followed a Bayesian adaptive design. Ninety-five patients were treated (77 with MDS, and 18 with CMML). Overall, 32 patients (34%) achieved a complete response (CR), and 69 (73%) had an objective response by the new modified International Working Group criteria. The 5-day intravenous schedule, which had the highest dose-intensity, was selected as optimal; the CR rate in that arm was 39%, compared with 21% in the 5-day subcutaneous arm and 24% in the 10-day intravenous arm (P < .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, dose-intensity schedule of decitabine optimizes epigenetic modulation and clinical responses in MDS.
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