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

Research output: Contribution to journalArticle

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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decitabine
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Cytogenetics
Methylation
DNA Methylation
Cell Death
Fever
Imatinib Mesylate

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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Phase II study of low-dose decitabine in patients with chronic myelogenous leukemia resistant to imatinib mesylate. / Issa, Jean Pierre F.; Gharibyan, Vazganush; Cortes, Jorge; Jelinek, Jaroslav; Morris, Gail; Verstovsek, Srdan; Talpaz, Moshe; Garcia-Manero, Guillermo; Kantarjian, Hagop M.

In: Journal of Clinical Oncology, Vol. 23, No. 17, 01.12.2005, p. 3948-3956.

Research output: Contribution to journalArticle

Issa, JPF, Gharibyan, V, Cortes, J, Jelinek, J, Morris, G, Verstovsek, S, Talpaz, M, Garcia-Manero, G & Kantarjian, HM 2005, 'Phase II study of low-dose decitabine in patients with chronic myelogenous leukemia resistant to imatinib mesylate', Journal of Clinical Oncology, vol. 23, no. 17, pp. 3948-3956. https://doi.org/10.1200/JCO.2005.11.981
Issa, Jean Pierre F. ; Gharibyan, Vazganush ; Cortes, Jorge ; Jelinek, Jaroslav ; Morris, Gail ; Verstovsek, Srdan ; Talpaz, Moshe ; Garcia-Manero, Guillermo ; Kantarjian, Hagop M. / Phase II study of low-dose decitabine in patients with chronic myelogenous leukemia resistant to imatinib mesylate. In: Journal of Clinical Oncology. 2005 ; Vol. 23, No. 17. pp. 3948-3956.
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T1 - Phase II study of low-dose decitabine in patients with chronic myelogenous leukemia resistant to imatinib mesylate

AU - Issa, Jean Pierre F.

AU - Gharibyan, Vazganush

AU - Cortes, Jorge

AU - Jelinek, Jaroslav

AU - Morris, Gail

AU - Verstovsek, Srdan

AU - Talpaz, Moshe

AU - Garcia-Manero, Guillermo

AU - Kantarjian, Hagop M.

PY - 2005/12/1

Y1 - 2005/12/1

N2 - 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.

AB - 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.

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