Phase II study of low-dose decitabine in patients with chronic myelogenous leukemia resistant to imatinib mesylate

Jean Pierre F. Issa, Vazganush Gharibyan, Jorge Cortes, Jaroslav Jelinek, Gail Morris, Srdan Verstovsek, Moshe Talpaz, Guillermo Garcia-Manero, Hagop M. Kantarjian

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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.

Original languageEnglish (US)
Pages (from-to)3948-3956
Number of pages9
JournalJournal of Clinical Oncology
Volume23
Issue number17
DOIs
StatePublished - Dec 1 2005
Externally publishedYes

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ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Issa, J. P. F., Gharibyan, V., Cortes, J., Jelinek, J., Morris, G., Verstovsek, S., Talpaz, M., Garcia-Manero, G., & Kantarjian, H. M. (2005). Phase II study of low-dose decitabine in patients with chronic myelogenous leukemia resistant to imatinib mesylate. Journal of Clinical Oncology, 23(17), 3948-3956. https://doi.org/10.1200/JCO.2005.11.981