title: Factors influencing long-term efficacy and tolerability of bosutinib in chronic phase chronic myeloid leukaemia resistant or intolerant to imatinib.
abstract: The dual SRC/ABL1 tyrosine kinase inhibitor bosutinib is indicated for adults with Ph+ chronic myeloid leukaemia (CML) resistant/intolerant to prior therapy. This analysis of an ongoing phase 1/2 study (NCT00261846) assessed effects of baseline patient characteristics on long-term efficacy and safety of bosutinib 500 mg/day in adults with imatinib (IM)-resistant (IM-R; n = 196)/IM-intolerant (IM-I; n = 90) chronic phase (CP) CML. Median treatment duration was 24·8 months (median follow-up, 43·6 months). Cumulative major cytogenetic response (MCyR) rate [95% confidence interval (CI)], was 59% (53-65%); Kaplan-Meier (KM) probability of maintaining MCyR at 4 years was 75% (66-81%). Cumulative incidence of on-treatment progression/death at 4 years was 19% (95% CI, 15-24%); KM 2-year overall survival was 91% (87-94%). Significant baseline predictors of both MCyR and complete cytogenetic response (newly attained/maintained from baseline) at 3 and 6 months included prior IM cytogenetic response, baseline MCyR, prior interferon therapy and <6 months duration from diagnosis to IM treatment initiation and no interferon treatment before IM. The most common adverse event (AE) was diarrhoea (86%). Baseline bosutinib-sensitive BCR-ABL1 mutation was the only significant predictor of grade 3/4 diarrhoea; no significant predictors were identified for liver-related AEs. Bosutinib demonstrates durable efficacy and manageable toxicity in IM-R/IM-I CP-CML patients.
authors.affiliation: Universitätsklinikum RWTH Aachen, Aachen, Germany.|Department of Internal Medicine II, Hubertus Wald Tumorzentrum University Cancer Centre Hamburg, Hamburg, Germany.
authors.forename: Tim H
authors.initials: TH
authors.lastname: Brümmendorf
authors.affiliation: University of Texas MD, Anderson Cancer Center, Houston, TX, USA.
authors.forename: Jorge E
authors.initials: JE
authors.lastname: Cortes
authors.affiliation: Winship Cancer Institute of Emory University, Atlanta, GA, USA.
authors.forename: Hanna J
authors.initials: HJ
authors.lastname: Khoury
authors.affiliation: University of Texas MD, Anderson Cancer Center, Houston, TX, USA.
authors.forename: Hagop M
authors.initials: HM
authors.lastname: Kantarjian
authors.affiliation: Seoul St. Mary's Hospital, Seoul, South Korea.
authors.forename: Dong-Wook
authors.initials: DW
authors.lastname: Kim
authors.affiliation: Department of Internal Medicine II, Hubertus Wald Tumorzentrum University Cancer Centre Hamburg, Hamburg, Germany.
authors.forename: Philippe
authors.initials: P
authors.lastname: Schafhausen
authors.affiliation: Pfizer Inc, La Jolla, CA, USA.
authors.forename: Maureen G
authors.initials: MG
authors.lastname: Conlan
authors.affiliation: Pfizer Inc, Cambridge, MA, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Shapiro
authors.affiliation: Pfizer Inc, Cambridge, MA, USA.
authors.forename: Kathleen
authors.initials: K
authors.lastname: Turnbull
authors.affiliation: Pfizer Inc, Cambridge, MA, USA.
authors.forename: Eric
authors.initials: E
authors.lastname: Leip
authors.affiliation: University of Milano-Bicocca, Monza, Italy.
authors.forename: Carlo
authors.initials: C
authors.lastname: Gambacorti-Passerini
authors.affiliation: Princess Margaret Cancer Centre, Toronto, ON, Canada.
authors.forename: Jeff H
authors.initials: JH
authors.lastname: Lipton
mesh_terms: D000293:Adolescent; D000328:Adult; D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D000814:Aniline Compounds / Q000009:adverse effects / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D019008:Drug Resistance, Neoplasm; D005260:Female; D005500:Follow-Up Studies; D016044:Fusion Proteins, bcr-abl / Q000235:genetics; D006801:Humans; D000068877:Imatinib Mesylate / Q000627:therapeutic use; D053208:Kaplan-Meier Estimate; D015466:Leukemia, Myeloid, Chronic-Phase / Q000188:drug therapy* / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009570:Nitriles / Q000009:adverse effects / Q000627:therapeutic use*; D011804:Quinolines / Q000009:adverse effects / Q000627:therapeutic use*; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000814:Aniline Compounds; D000970:Antineoplastic Agents; C581634:BCR-ABL1 fusion protein, human; D009570:Nitriles; D011804:Quinolines; C471992:bosutinib; D000068877:Imatinib Mesylate; D016044:Fusion Proteins, bcr-abl
keywords: bosutinib; chronic myeloid leukaemia; second-line therapy; tyrosine kinase inhibitor