title: Frequency and clinical significance of BCR-ABL mutations in patients with chronic myeloid leukemia treated with imatinib mesylate.
abstract: Mutations of the BCR-ABL kinase domain are a common mechanism of resistance to imatinib in chronic myeloid leukemia. We screened for mutations 171 patients failing imatinib therapy. Sixty-six mutations in 23 amino acids were identified in 62 (36%) patients not responding to imatinib. Phosphate-binding loop (P-loop) mutations were the most frequent (n=24; 36%). By multivariate analysis, factors associated with development of mutations were older age (P=0.026) prior interferon therapy (P=0.026), and accelerated phase or blast phase at time of imatinib failure (P=0.001). After a median follow-up of 38 months (range, 4-68 months) from the start of imatinib therapy, seven patients with non-P-loop and two with P-loop mutation died. By multivariate analysis, development of clonal evolution and higher percentage of peripheral blood basophils were associated with worse survival from the time of imatinib failure. Mutation status had no impact on survival. When survival was measured from the time therapy started, non-P-loop mutations together with duration of response and transformation at the time of failure to imatinib were associated with shorter survival. In conclusion, P-loop mutations were not associated with poor outcome, suggesting that the prognosis of patients who fail imatinib is multifactorial.
authors.affiliation: Department of Leukemia, The University of Texas, UT MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: E
authors.initials: E
authors.lastname: Jabbour
authors.forename: H
authors.initials: H
authors.lastname: Kantarjian
authors.forename: D
authors.initials: D
authors.lastname: Jones
authors.forename: M
authors.initials: M
authors.lastname: Talpaz
authors.forename: N
authors.initials: N
authors.lastname: Bekele
authors.forename: S
authors.initials: S
authors.lastname: O'Brien
authors.forename: X
authors.initials: X
authors.lastname: Zhou
authors.forename: R
authors.initials: R
authors.lastname: Luthra
authors.forename: G
authors.initials: G
authors.lastname: Garcia-Manero
authors.forename: F
authors.initials: F
authors.lastname: Giles
authors.forename: M B
authors.initials: MB
authors.lastname: Rios
authors.forename: S
authors.initials: S
authors.lastname: Verstovsek
authors.forename: J
authors.initials: J
authors.lastname: Cortes
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001491:Basophils / Q000473:pathology; D001549:Benzamides; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D016044:Fusion Proteins, bcr-abl / Q000235:genetics*; D006801:Humans; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000235:genetics* / Q000401:mortality; D008875:Middle Aged; D015999:Multivariate Analysis; D010879:Piperazines / Q000627:therapeutic use*; D017354:Point Mutation; D011379:Prognosis; D011743:Pyrimidines / Q000627:therapeutic use*; D015996:Survival Rate
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D016044:Fusion Proteins, bcr-abl