Phase II study of low-dose decitabine in patients with chronic myelogenous leukemia resistant to imatinib mesylate.
OBJECTIVE
To determine the activity of decitabine, a DNA methylation inhibitor, in imatinib-refractory or intolerant chronic myelogenous leukemia.


METHODS
Thirty-five patients were enrolled in this phase II study (12 in chronic phase, 17 in accelerated phase, and six in blastic phase). Decitabine was administered at 15 mg/m2 intravenously over 1 hour daily, 5 days a week for 2 weeks. DNA methylation was measured using a LINE1 bisulfite/pyrosequencing assay.


RESULTS
Complete hematologic responses were seen in 12 patients (34%) and partial hematologic responses in seven patients (20%), for an overall hematologic response rate of 54% (83% in chronic phase, 41% in accelerated phase, and 34% in blastic phase). Major cytogenetic responses were observed in six patients (17%), and minor cytogenetic responses were seen in 10 patients (29%) for an overall cytogenetic response rate of 46%. Median response duration was 3.5 months (range, 2 to 13+ months). Myelosuppression was the major adverse effect, with neutropenic fever in 28 (23%) of 124 courses of therapy. LINE1 methylation decreased from 71.3% +/- 1.4% (mean +/- standard error of the mean) to 60.7% +/- 1.4% after 1 week, 50.9% +/- 2.4% after 2 weeks, and returned to 66.5% +/- 2.7% at recovery of counts (median, 46 days). LINE1 methylation at the end of week 1 did not correlate with subsequent responses. However, at day 12, the absolute decrease in methylation was 14.5% +/- 3.0% versus 26.8% +/- 2.7% in responders versus nonresponders (P = .007).


CONCLUSIONS
Decitabine induces hypomethylation and has clinical activity in imatinib refractory chronic myelogenous leukemia. We hypothesize that the inverse correlation between hypomethylation 2 weeks after therapy and response is due to a cell death mechanism of response, whereby resistant cells can withstand more hypomethylation.
Issa
Jean-Pierre J
JP
Department of Leukemia and Experimental Therapeutics, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA. jpissa@mdanderson.org
Gharibyan
Vazganush
V
Cortes
Jorge
J
Jelinek
Jaroslav
J
Morris
Gail
G
Verstovsek
Srdan
S
Talpaz
Moshe
M
Garcia-Manero
Guillermo
G
Kantarjian
Hagop M
HM
D000328:Adult; D000368:Aged; D000964:Antimetabolites, Antineoplastic / Q000627:therapeutic use; D001374:Azacitidine / Q000008:administration & dosage* / Q000031:analogs & derivatives*; D001549:Benzamides; D019175:DNA Methylation; D015254:DNA Modification Methylases / Q000037:antagonists & inhibitors; D000077209:Decitabine; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D004791:Enzyme Inhibitors / Q000008:administration & dosage*; D005260:Female; D006801:Humans; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy*; D010879:Piperazines / Q000627:therapeutic use*; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D011743:Pyrimidines / Q000627:therapeutic use*
D000964:Antimetabolites, Antineoplastic; D001549:Benzamides; D004791:Enzyme Inhibitors; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D000077209:Decitabine; D000068877:Imatinib Mesylate; D015254:DNA Modification Methylases; D011505:Protein-Tyrosine Kinases; D001374:Azacitidine