TY - JOUR
T1 - Results of a randomized study of 3 schedules of low-dose decitabine in higher-risk myelodysplastic syndrome and chronic myelomonocytic leukemia
AU - Kantarjian, Hagop
AU - Oki, Yasuhiro
AU - Garcia-Manero, Guillermo
AU - Huang, Xuelin
AU - O'Brien, Susan
AU - Cortes, Jorge
AU - Faderl, Stefan
AU - Bueso-Ramos, Carlos
AU - Ravandi, Farhad
AU - Estrov, Zeev
AU - Ferrajoli, Alessandra
AU - Wierda, William
AU - Shan, Jianqin
AU - Davis, Jan
AU - Giles, Francis
AU - Saba, Hussain I.
AU - Issa, Jean Pierre J.
PY - 2007/1/1
Y1 - 2007/1/1
N2 - 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, doseintensity schedule of decitabine optimizes epigenetic modulation and clinical responses in MDS.
AB - 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, doseintensity schedule of decitabine optimizes epigenetic modulation and clinical responses in MDS.
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U2 - 10.1182/blood-2006-05-021162
DO - 10.1182/blood-2006-05-021162
M3 - Article
C2 - 16882708
AN - SCOPUS:33846011361
SN - 0006-4971
VL - 109
SP - 52
EP - 57
JO - Blood
JF - Blood
IS - 1
ER -