title: Clinical outcome of chronic myeloid leukemia imatinib-resistant patients: do BCR-ABL kinase domain mutations affect patient survival? First multicenter Argentinean study.
abstract: In imatinib-treated patients with chronic myeloid leukemia (CML), BCR-ABL mutations are the most common mechanism of resistance. Here we report the first multicenter Argentinean study investigating mutations in those patients with CML who fail or lose response to imatinib, with or without previous interferon treatment. Point mutations were detected in 36 of 154 patients by direct sequencing. In our series, the single most common mutations were G250E, E255K/V, and M351T. The presence of mutations correlated significantly with accelerated phase, lack of molecular response, and lower cytogenetic and hematological responses. While overall survival did not differ between patients with or without mutations, the probability of progression was higher in patients with mutations. Cases with non-P-loop mutations showed a significantly better overall survival from diagnosis. Multivariate analysis showed that the most significant variables related to the development of mutations were accelerated phase, duration of imatinib treatment, and time delay to starting imatinib. Our results demonstrated that mutation frequency increased with the progression of disease, and suggest that imatinib treatment should be started early.
authors.affiliation: Instituto de Investigaciones Hematológicas, Academia Nacional de Medicina, Buenos Aires, Argentina. mutaciones2@yahoo.com.ar
authors.forename: Raquel M
authors.initials: RM
authors.lastname: Bengió
authors.forename: Maria E
authors.initials: ME
authors.lastname: Riva
authors.forename: Beatriz
authors.initials: B
authors.lastname: Moiraghi
authors.forename: Emilio
authors.initials: E
authors.lastname: Lanari
authors.forename: Jorge
authors.initials: J
authors.lastname: Milone
authors.forename: Veronica
authors.initials: V
authors.lastname: Ventriglia
authors.forename: Eduardo
authors.initials: E
authors.lastname: Bullorsky
authors.forename: Miguel de
authors.initials: Md
authors.lastname: Tezanos Pinto
authors.forename: Hector
authors.initials: H
authors.lastname: Murro
authors.forename: Michele
authors.initials: M
authors.lastname: Bianchini
authors.forename: Irene
authors.initials: I
authors.lastname: Larripa
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001118:Argentina; D001549:Benzamides; D018450:Disease Progression; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D016044:Fusion Proteins, bcr-abl / Q000235:genetics*; D006801:Humans; D000068877:Imatinib Mesylate; D053208:Kaplan-Meier Estimate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000235:genetics* / Q000401:mortality; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D010879:Piperazines / Q000627:therapeutic use*; D011743:Pyrimidines / Q000627:therapeutic use*; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D016044:Fusion Proteins, bcr-abl