Induction of hypomethylation and molecular response after decitabine therapy in patients with chronic myelomonocytic leukemia.
Decitabine's mechanism of action in chronic myelomonocytic leukemia remains incompletely understood. We studied the dynamics of neoplastic cell clearance during decitabine treatment (100 mg/m(2) per course every 4 weeks) using quantitative monitoring of mutant alleles by pyrosequencing. Patients with chronic myelomonocytic leukemia were first screened for JAK2 and NPM1 mutations, and 3 patients with mutations were identified. Mutant allele percentages in mononuclear cell DNA were followed after treatment, along with methylation of LINE1 and 10 other genes. The clearance of mutant alleles was modest after the first cycle, despite induction of hypomethylation. Delayed substantial clearance was observed after 2 to 4 cycles that correlated with clinical response. Two patients had complete disappearance of mutant alleles and sustained clinical remissions. In another patient, mutant allele was detectable at clinical remission, which lasted for 8 months. Our data suggest a predominantly noncytotoxic mechanism of action for decitabine, leading to altered biology of the neoplastic clone and/or normal cells. This trial was registered at www.ClinicalTrials.gov as #NCT00067808.
Oki
Yasuhiro
Y
Department of Leukemia, University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA.
Jelinek
Jaroslav
J
Shen
Lanlan
L
Kantarjian
Hagop M
HM
Issa
Jean-Pierre J
JP
D000964:Antimetabolites, Antineoplastic / Q000627:therapeutic use*; D001374:Azacitidine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D019175:DNA Methylation / Q000187:drug effects*; D000077209:Decitabine; D005260:Female; D006801:Humans; D053614:Janus Kinase 2 / Q000235:genetics; D007621:Karyotyping; D015477:Leukemia, Myelomonocytic, Chronic / Q000097:blood / Q000188:drug therapy* / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics; D000090243:Nucleophosmin; D012074:Remission Induction
D000964:Antimetabolites, Antineoplastic; C000716967:NPM1 protein, human; D009687:Nuclear Proteins; D000090243:Nucleophosmin; D000077209:Decitabine; D053614:Janus Kinase 2; D001374:Azacitidine