title: Mutation status and clinical outcome of 89 imatinib mesylate-resistant chronic myelogenous leukemia patients: a retrospective analysis from the French intergroup of CML (Fi(phi)-LMC GROUP).
abstract: The emergence of ABL point mutations is the most frequent cause for imatinib resistance in chronic myelogenous leukemia (CML) patients and can occur during any phase of the disease; however, their clinical impact remains controversial. In this study, we retrospectively analyzed the predictive impact of 94 BCR-ABL kinase domain mutations (18 T315I, 26 P-loop, 50 in other sites) found in 89 imatinib-resistant CML patients. At imatinib onset, 64% of patients (57/89) were in chronic phase (CP), 24% (21/89) in accelerated phase (AP) and 12% (11/89) in blastic phase (BP). T315I and P-loop mutations were preferentially discovered in accelerated phase of BP CML, and other types of mutations in CP (P=0.003). With a median follow-up of 39.2 months (6.3-67.2), since imatinib initiation, overall survival (OS) was significantly worse for P-loop (28.3 months) and for T315I (12.6 months), and not reached for other mutations (P=0.0004). For CP only, multivariate analysis demonstrated a worse OS for P-loop mutations (P=0.014), and a worse progression-free survival (PFS) for T315I mutations (P=0.014). Therefore, P-loop and T315I mutations selectively impair the outcome of imatinib-resistant CML patients, in contrast to other mutations, which may benefit from dose escalation of imatinib, able to improve or stabilize disease response.
authors.affiliation: Hematology Department, E. Herriot Hospital, Lyon, France.
authors.forename: F E
authors.initials: FE
authors.lastname: Nicolini
authors.forename: S
authors.initials: S
authors.lastname: Corm
authors.forename: Q-H
authors.initials: QH
authors.lastname: Lê
authors.forename: N
authors.initials: N
authors.lastname: Sorel
authors.forename: S
authors.initials: S
authors.lastname: Hayette
authors.forename: D
authors.initials: D
authors.lastname: Bories
authors.forename: T
authors.initials: T
authors.lastname: Leguay
authors.forename: L
authors.initials: L
authors.lastname: Roy
authors.forename: S
authors.initials: S
authors.lastname: Giraudier
authors.forename: M
authors.initials: M
authors.lastname: Tulliez
authors.forename: T
authors.initials: T
authors.lastname: Facon
authors.forename: F-X
authors.initials: FX
authors.lastname: Mahon
authors.forename: J-M
authors.initials: JM
authors.lastname: Cayuela
authors.forename: P
authors.initials: P
authors.lastname: Rousselot
authors.forename: M
authors.initials: M
authors.lastname: Michallet
authors.forename: C
authors.initials: C
authors.lastname: Preudhomme
authors.forename: F
authors.initials: F
authors.lastname: Guilhot
authors.forename: C
authors.initials: C
authors.lastname: Roche-Lestienne
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D001549:Benzamides; D004252:DNA Mutational Analysis; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D005602:France; D016044:Fusion Proteins, bcr-abl / Q000235:genetics*; D006801:Humans; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000175:diagnosis / Q000188:drug therapy / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D010879:Piperazines / Q000627:therapeutic use*; D017354:Point Mutation; D011237:Predictive Value of Tests; D011743:Pyrimidines / Q000627:therapeutic use*; D012189:Retrospective Studies; D015996:Survival Rate; D016896:Treatment Outcome
chemical_list: D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D016044:Fusion Proteins, bcr-abl