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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.Resistance to imatinib is a frequent clinical problem in advanced phase chronic myelogenous leukemia (CML). The present study shows that a combination of low-dose decitabine, a DNA methyltransferase inhibitor, with imatinib is well tolerated and active in advanced phase CML without BCR-ABL kinase mutations.