title: Results of a randomized study of 3 schedules of low-dose decitabine in higher-risk myelodysplastic syndrome and chronic myelomonocytic leukemia.
abstract: 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.
authors.affiliation: Department of Leukemia, MD Anderson Cancer Center, 1515 Holcombe Blvd, Box 428, Houston, TX 77030, USA. hkantarj@mdanderson.org
authors.forename: Hagop
authors.initials: H
authors.lastname: Kantarjian
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Oki
authors.forename: Guillermo
authors.initials: G
authors.lastname: Garcia-Manero
authors.forename: Xuelin
authors.initials: X
authors.lastname: Huang
authors.forename: Susan
authors.initials: S
authors.lastname: O'Brien
authors.forename: Jorge
authors.initials: J
authors.lastname: Cortes
authors.forename: Stefan
authors.initials: S
authors.lastname: Faderl
authors.forename: Carlos
authors.initials: C
authors.lastname: Bueso-Ramos
authors.forename: Farhad
authors.initials: F
authors.lastname: Ravandi
authors.forename: Zeev
authors.initials: Z
authors.lastname: Estrov
authors.forename: Alessandra
authors.initials: A
authors.lastname: Ferrajoli
authors.forename: William
authors.initials: W
authors.lastname: Wierda
authors.forename: Jianqin
authors.initials: J
authors.lastname: Shan
authors.forename: Jan
authors.initials: J
authors.lastname: Davis
authors.forename: Francis
authors.initials: F
authors.lastname: Giles
authors.forename: Hussain I
authors.initials: HI
authors.lastname: Saba
authors.forename: Jean-Pierre J
authors.initials: JP
authors.lastname: Issa
mesh_terms: 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
chemical_list: D000964:Antimetabolites, Antineoplastic; D050762:Cyclin-Dependent Kinase Inhibitor p15; D009363:Neoplasm Proteins; D000077209:Decitabine; D001374:Azacitidine