Phase II study of low-dose decitabine in combination with imatinib mesylate in patients with accelerated or myeloid blastic phase of chronic myelogenous leukemia

Yasuhiro Oki, Hagop M. Kantarjian, Vazganush Gharibyan, Dan Jones, Susan O'Brien, Srdan Verstovsek, Jorge Cortes, Gail M. Morris, Guillerrno Garcia-Manero, Jean Pierre J. Issa

Research output: Contribution to journalArticle

104 Scopus citations

Abstract

BACKGROUND. 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). METHODS. Patients received decitabine 15 mg/m 2 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. RESULTS. 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. CONCLUSIONS. Combination therapy with decitabine and imatinib is well tolerated and active in advanced phase CML without BCR-ABL kinase mutations.

Original languageEnglish (US)
Pages (from-to)899-906
Number of pages8
JournalCancer
Volume109
Issue number5
DOIs
StatePublished - Mar 1 2007
Externally publishedYes

Keywords

  • Accelerated phase
  • Chronic myelogenous leukemia
  • Decitabine
  • Imatinib
  • Myeloid blastic phase

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Oki, Y., Kantarjian, H. M., Gharibyan, V., Jones, D., O'Brien, S., Verstovsek, S., Cortes, J., Morris, G. M., Garcia-Manero, G., & 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(5), 899-906. https://doi.org/10.1002/cncr.22470