Report of a phase 1/2 study of a combination of azacitidine and cytarabine in acute myelogenous leukemia and high-risk myelodysplastic syndromes.
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.
Borthakur
Gautam
G
Department of Leukemia, University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA. gborthak@mdanderson.org
Huang
Xuelin
X
Kantarjian
Hagop
H
Faderl
Stefan
S
Ravandi
Farhad
F
Ferrajoli
Alessandra
A
Torma
Ritva
R
Morris
Gail
G
Berry
Donald
D
Issa
Jean-Pierre
JP
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
D003561:Cytarabine; D001374:Azacitidine