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Phase II study of low-dose decitabine in combination with imatinib mesylate in patients with accelerated or myeloid blastic phase of chronic myelogenous leukemia†
Article first published online: 18 JAN 2007
Copyright © 2007 American Cancer Society
Volume 109, Issue 5, pages 899–906, 1 March 2007
How to Cite
Oki, Y., Kantarjian, H. M., Gharibyan, V., Jones, D., O'Brien, S., Verstovsek, S., Cortes, J., Morris, G. M., Garcia-Manero, G. and Issa, J.-P. J. (2007), Phase II study of low-dose decitabine in combination with imatinib mesylate in patients with accelerated or myeloid blastic phase of chronic myelogenous leukemia. Cancer, 109: 899–906. doi: 10.1002/cncr.22470
Presented in part at the 47th Annual Meeting of the American Society of Hematology, Atlanta, GA, December 10–13, 2005
- Issue published online: 22 FEB 2007
- Article first published online: 18 JAN 2007
- Manuscript Accepted: 15 NOV 2006
- Manuscript Revised: 30 OCT 2006
- Manuscript Received: 23 AUG 2006
- National Institutes of Health. Grant Numbers: N01-CM-62202, Leukemia SPORE Grant P50CA100632
- Department of Defense. Grant Number: W81XWH-05-1-0535
- American Society of Clinical Oncology Young Investigator Award 2005–2006
- accelerated phase;
- myeloid blastic phase;
- chronic myelogenous leukemia;
Resistance to imatinib is a frequent clinical problem in advanced phase chronic myelogenous leukemia (CML). A Phase II study was performed on low-dose decitabine, a DNA methyltransferase inhibitor, in combination with imatinib in patients with CML in accelerated phase (AP) and myeloid blastic phase (BP).
Patients received decitabine 15 mg/m2 intravenously daily, 5 days a week for 2 weeks, and imatinib 600 mg orally daily. Global DNA methylation was measured by long interspersed nucleotide element (LINE) bisulfite/pyrosequencing.
Twenty-eight patients were enrolled (25 with imatinib resistance; 18 in AP, 10 in BP). A total of 91 cycles (median, 2.5 cycles per patient) was administered. Complete hematologic responses, partial hematologic responses, and hematologic improvement were observed in 9 (32%), 1 (4%), and 2 (7%) patients. Major and minor cytogenetic responses were observed in 5 (18%) and 3 (11%) patients. The hematologic response rate was higher in patients without BCR-ABL kinase mutations (10 of 19, 53%) than in those with mutations (1 of 7, 14%). Median duration of hematologic response was 18 (range, 4 to 107+) weeks. Myelosuppression was the major adverse effect, with neutropenic fever in 9 patients (32%). LINE methylation decreased from 71.6% ± 0.9% (mean ± standard error of the mean) to 60.4% ± 2.0% on Day 5, 60.5% ± 1.8% on Day 12, and returned to 68.8% ± 1.4% at peripheral blood recovery. A decrease in LINE methylation tended to be greater in nonresponders than in responders on Days 5 and 12.
Combination therapy with decitabine and imatinib is well tolerated and active in advanced phase CML without BCR-ABL kinase mutations. Cancer 2007 © 2007 American Cancer Society.