title: The BCR-ABLT315I mutation compromises survival in chronic phase chronic myelogenous leukemia patients resistant to tyrosine kinase inhibitors, in a matched pair analysis.
abstract: The BCR-ABL T315I mutation confers resistance to currently licensed tyrosine kinase inhibitors in chronic myelogenous leukemia. However, the impact of this mutation on survival in early stages of disease, in chronic phase, has never been detailed. Using matched pair analysis, a cohort of 64 patients with chronic phase chronic myelogenous leukemia harboring a T315I mutation and resistant to imatinib mesylate was compared to a similar cohort of 53 chronic phase patients resistant to imatinib, but with no detectable T315I mutation, in the pre-ponatinib era. These patients were matched according to age at diagnosis, interval between disease diagnosis and start of imatinib treatment, and duration of imatinib therapy. Kaplan-Meier survival analyses demonstrated the significant negative impact of the presence of the T315I mutation on overall survival (since imatinib-resistance: 48.4 months for T315I(+) patients versus not reached for T315I(-) ones; P=0.006) and failure-free survival (since imatinib-resistance: 34.7 months for T315I(+) patients versus not reached for T315I(-) patients; P=0.003). In addition, Cox proportional hazard models adjusted on overall survival demonstrated the negative influence of the T315I mutation (P=0.02, HR=2.54). These results confirm early assumptions concerning the poor prognosis of chronic phase chronic myelogenous leukemia patients with the T315I mutation who are not eligible for allogeneic transplantation, and demonstrate the need for more therapeutic options.
authors.affiliation: franck-emmanuel.nicolini@chu-lyon.fr.
authors.forename: Franck E
authors.initials: FE
authors.lastname: Nicolini
authors.forename: Amr R
authors.initials: AR
authors.lastname: Ibrahim
authors.forename: Simona
authors.initials: S
authors.lastname: Soverini
authors.forename: Giovanni
authors.initials: G
authors.lastname: Martinelli
authors.forename: Martin C
authors.initials: MC
authors.lastname: Müller
authors.forename: Andreas
authors.initials: A
authors.lastname: Hochhaus
authors.forename: Inge H
authors.initials: IH
authors.lastname: Dufva
authors.forename: Dong-Wook
authors.initials: DW
authors.lastname: Kim
authors.forename: Jorge
authors.initials: J
authors.lastname: Cortes
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Mauro
authors.forename: Charles
authors.initials: C
authors.lastname: Chuah
authors.forename: Hélène
authors.initials: H
authors.lastname: Labussière
authors.forename: Stéphane
authors.initials: S
authors.lastname: Morisset
authors.forename: Catherine
authors.initials: C
authors.lastname: Roche-Lestienne
authors.forename: Eric
authors.initials: E
authors.lastname: Lippert
authors.forename: Sandrine
authors.initials: S
authors.lastname: Hayette
authors.forename: Senaka
authors.initials: S
authors.lastname: Peter
authors.forename: Wei
authors.initials: W
authors.lastname: Zhou
authors.forename: Véronique
authors.initials: V
authors.lastname: Maguer-Satta
authors.forename: Mauricette
authors.initials: M
authors.lastname: Michallet
authors.forename: John
authors.initials: J
authors.lastname: Goldman
authors.forename: Jane F
authors.initials: JF
authors.lastname: Apperley
authors.forename: François-Xavier
authors.initials: FX
authors.lastname: Mahon
authors.forename: David
authors.initials: D
authors.lastname: Marin
authors.forename: Gabriel
authors.initials: G
authors.lastname: Etienne
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D015331:Cohort Studies; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005260:Female; D016044:Fusion Proteins, bcr-abl / Q000235:genetics*; D016313:Genes, abl; D006801:Humans; D015466:Leukemia, Myeloid, Chronic-Phase / Q000188:drug therapy* / Q000235:genetics* / Q000401:mortality; D008297:Male; D008875:Middle Aged; D009154:Mutation; D011446:Prospective Studies; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D012189:Retrospective Studies; D015996:Survival Rate; D055815:Young Adult
chemical_list: D047428:Protein Kinase Inhibitors; C406060:abl-bcr fusion protein, human; D016044:Fusion Proteins, bcr-abl