Phase II study of low-dose decitabine in combination with imatinib mesylate in patients with accelerated or myeloid blastic phase of chronic myelogenous leukemia.
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.
Oki
Yasuhiro
Y
Department of Leukemia, University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA.
Kantarjian
Hagop M
HM
Gharibyan
Vazganush
V
Jones
Dan
D
O'brien
Susan
S
Verstovsek
Srdan
S
Cortes
Jorge
J
Morris
Gail M
GM
Garcia-Manero
Guillermo
G
Issa
Jean-Pierre J
JP
D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001374:Azacitidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D001549:Benzamides; D001752:Blast Crisis / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D019175:DNA Methylation; D000077209:Decitabine; D005260:Female; D016313:Genes, abl; D006801:Humans; D000068877:Imatinib Mesylate; D008297:Male; D008875:Middle Aged; D010879:Piperazines / Q000008:administration & dosage; D016133:Polymerase Chain Reaction; D011743:Pyrimidines / Q000008:administration & dosage; D016019:Survival Analysis; D016896:Treatment Outcome
D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D000077209:Decitabine; D000068877:Imatinib Mesylate; D001374:Azacitidine