Author(s): Issa JP, Gharibyan V, Cortes J, Jelinek J, Morris G,
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Abstract PURPOSE: To determine the activity of decitabine, a DNA methylation inhibitor, in imatinib-refractory or intolerant chronic myelogenous leukemia. MATERIALS AND 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). CONCLUSION: 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.
This article was published in J Clin Oncol
and referenced in Journal of Cancer Science & Therapy