Results of a randomized study of 3 schedules of low-dose decitabine in higher-risk myelodysplastic syndrome and chronic myelomonocytic leukemia.
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.
Kantarjian
Hagop
H
Department of Leukemia, MD Anderson Cancer Center, 1515 Holcombe Blvd, Box 428, Houston, TX 77030, USA. hkantarj@mdanderson.org
Oki
Yasuhiro
Y
Garcia-Manero
Guillermo
G
Huang
Xuelin
X
O'Brien
Susan
S
Cortes
Jorge
J
Faderl
Stefan
S
Bueso-Ramos
Carlos
C
Ravandi
Farhad
F
Estrov
Zeev
Z
Ferrajoli
Alessandra
A
Wierda
William
W
Shan
Jianqin
J
Davis
Jan
J
Giles
Francis
F
Saba
Hussain I
HI
Issa
Jean-Pierre J
JP
D000368:Aged; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage* / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use; D001374:Azacitidine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D001499:Bayes Theorem; D001855:Bone Marrow Diseases / Q000139:chemically induced; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology; D050762:Cyclin-Dependent Kinase Inhibitor p15 / Q000096:biosynthesis / Q000235:genetics; D019175:DNA Methylation / Q000187:drug effects; D000077209:Decitabine; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects; D006801:Humans; D007262:Infusions, Intravenous; D007279:Injections, Subcutaneous; D015477:Leukemia, Myelomonocytic, Chronic / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D009190:Myelodysplastic Syndromes / Q000188:drug therapy*; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics; D012074:Remission Induction; D012306:Risk; D016896:Treatment Outcome
D000964:Antimetabolites, Antineoplastic; D050762:Cyclin-Dependent Kinase Inhibitor p15; D009363:Neoplasm Proteins; D000077209:Decitabine; D001374:Azacitidine