title: Report of a phase 1/2 study of a combination of azacitidine and cytarabine in acute myelogenous leukemia and high-risk myelodysplastic syndromes.
abstract: Cytarabine resistance characterizes relapsed and refractory acute myelogenous leukemia (AML). Restoration of cytarabine sensitivity can potentially improve treatment outcome in this setting. Acquired hypermethylation of gene promoters and associated silencing of gene expression has been implicated in chemo resistance, and drug-induced hypomethylation can improve sensitivity to cytarabine in vitro. We conducted an adaptively randomized study of a combination of azacitidine, a hypomethylating agent, and cytarabine in 34 patients with AML. The combination administered in a concomitant fashion is safe at full doses of azacitidine and cytarabine, without unexpected toxicities. However, in this advanced AML population, it was difficult to deliver more than one cycle of therapy, and minimal anti-leukemia activity was seen in patients with relapsed/refractory disease. Complete remission was achieved in 2 of 6 minimally pre-treated patients. We conclude that the combination of azacitidine and cytarabine is feasible but has limited activity in relapsed/refractory AML.
authors.affiliation: Department of Leukemia, University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA. gborthak@mdanderson.org
authors.forename: Gautam
authors.initials: G
authors.lastname: Borthakur
authors.forename: Xuelin
authors.initials: X
authors.lastname: Huang
authors.forename: Hagop
authors.initials: H
authors.lastname: Kantarjian
authors.forename: Stefan
authors.initials: S
authors.lastname: Faderl
authors.forename: Farhad
authors.initials: F
authors.lastname: Ravandi
authors.forename: Alessandra
authors.initials: A
authors.lastname: Ferrajoli
authors.forename: Ritva
authors.initials: R
authors.lastname: Torma
authors.forename: Gail
authors.initials: G
authors.lastname: Morris
authors.forename: Donald
authors.initials: D
authors.lastname: Berry
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Issa
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001374:Azacitidine / Q000008:administration & dosage*; D003561:Cytarabine / Q000008:administration & dosage*; D019008:Drug Resistance, Neoplasm; D044127:Epigenesis, Genetic; D005260:Female; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D009190:Myelodysplastic Syndromes / Q000188:drug therapy*; D012074:Remission Induction; D016896:Treatment Outcome
chemical_list: D003561:Cytarabine; D001374:Azacitidine