Originally published as JCO Early Release 10.1200/JCO.2005.11.981 on May 9 2005
Journal of Clinical Oncology, Vol 23, No 17 (June 10), 2005: pp. 3948-3956
© 2005 American Society of Clinical Oncology.
Phase II Study of Low-Dose Decitabine in Patients With Chronic Myelogenous Leukemia Resistant to Imatinib Mesylate
Jean-Pierre J. Issa,
Vazganush Gharibyan,
Jorge Cortes,
Jaroslav Jelinek,
Gail Morris,
Srdan Verstovsek,
Moshe Talpaz,
Guillermo Garcia-Manero,
Hagop M. Kantarjian
From the Department of Leukemia and Experimental Therapeutics, The University of Texas M.D. Anderson Cancer Center, Houston, TX
Address reprint requests to Jean-Pierre J. Issa, MD, Department of Leukemia, The University of Texas M.D. Anderson Cancer Center, Unit 428, 1515 Holcombe, Houston, TX 77030; e-mail: jpissa{at}mdanderson.org.
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.
Supported in part by the Leukemia SPORE grant P50CA100632 from the National Institutes of Health, the US Department of Defense grant CM020027, and a grant from Supergen (Dublin, CA). G.G.-M. is supported by an American Society of Clinical Oncology Career Development Award and the Physician-Scientist Program at The University of Texas M.D. Anderson Cancer Center.
Terms in blue are defined in the glossary, found at the end of this issue and online at www.jco.org.
Authors' disclosures of potential conflicts of interest are found at the end of this article.
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