TY - JOUR
T1 - Phase II study of low-dose decitabine in combination with imatinib mesylate in patients with accelerated or myeloid blastic phase of chronic myelogenous leukemia
AU - Oki, Yasuhiro
AU - Kantarjian, Hagop M.
AU - Gharibyan, Vazganush
AU - Jones, Dan
AU - O'Brien, Susan
AU - Verstovsek, Srdan
AU - Cortes, Jorge
AU - Morris, Gail M.
AU - Garcia-Manero, Guillerrno
AU - Issa, Jean Pierre J.
PY - 2007/3/1
Y1 - 2007/3/1
N2 - 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.
AB - 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.
KW - Accelerated phase
KW - Chronic myelogenous leukemia
KW - Decitabine
KW - Imatinib
KW - Myeloid blastic phase
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U2 - 10.1002/cncr.22470
DO - 10.1002/cncr.22470
M3 - Article
C2 - 17236224
AN - SCOPUS:33847395041
SN - 0008-543X
VL - 109
SP - 899
EP - 906
JO - Cancer
JF - Cancer
IS - 5
ER -