title: Long-term evaluation of cardiac and vascular toxicity in patients with Philadelphia chromosome-positive leukemias treated with bosutinib.
abstract: Vascular and cardiac safety during tyrosine kinase inhibitor (TKI) therapy is an emerging issue. We evaluated vascular/cardiac toxicities associated with long-term bosutinib treatment for Philadelphia chromosome-positive (Ph+) leukemia based on treatment-emergent adverse events (TEAEs) and changes in QTc intervals and ejection fraction in two studies: a phase 1/2 study of second-/third-/fourth-line bosutinib for Ph+ leukemia resistant/intolerant to prior TKIs (N = 570) and a phase 3 study of first-line bosutinib (n = 248) versus imatinib (n = 251) in chronic phase chronic myeloid leukemia. Follow-up time was ≥48 months (both studies). Incidences of vascular/cardiac TEAEs in bosutinib-treated patients were 7%/10% overall with similar incidences observed with first-line bosutinib (5%/8%) and imatinib (4%/6%). Few patients had grade ≥3 vascular/cardiac events (4%/4%) and no individual TEAE occurred in >2% of bosutinib patients. Exposure-adjusted vascular/cardiac TEAE rates (patients with events/patient-year) were low for second-line or later bosutinib (0.037/0.050) and not significantly different between first-line bosutinib (0.015/0.024) and imatinib (0.011/0.017; P ≥ 0.267). Vascular/cardiac events were managed mainly with concomitant medications (39%/44%), bosutinib treatment interruptions (18%/21%), or dose reductions (4%/8%); discontinuations due to these events were rare (0.7%/1.0%). Based on logistic regression modelling, performance status >0 and history of vascular or cardiac disorders were prognostic of vascular/cardiac events in relapsed/refractory patients; hyperlipidemia/hypercholesterolemia and older age were prognostic of cardiac events. In newly diagnosed patients, older age was prognostic of vascular/cardiac events; history of diabetes was prognostic of vascular events. Incidences of vascular and cardiac events were low with bosutinib in the first-line and relapsed/refractory settings following long-term treatment in patients with Ph+ leukemia. Am. J. Hematol. 91:606-616, 2016. © 2016 Wiley Periodicals, Inc.
authors.affiliation: University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Jorge E
authors.initials: JE
authors.lastname: Cortes
authors.affiliation: Winship Cancer Institute of Emory University, Atlanta, Georgia.
authors.forename: H
authors.initials: H
authors.lastname: Jean Khoury
authors.affiliation: University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Hagop
authors.initials: H
authors.lastname: Kantarjian
authors.affiliation: Universitätsklinikum RWTH Aachen, Aachen, Germany.|Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Tim H
authors.initials: TH
authors.lastname: Brümmendorf
authors.affiliation: Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Mauro
authors.affiliation: Pfizer Inc, New York, New York.
authors.forename: Ewa
authors.initials: E
authors.lastname: Matczak
authors.affiliation: Pfizer Inc, New York, New York.
authors.forename: Dmitri
authors.initials: D
authors.lastname: Pavlov
authors.affiliation: Pfizer Inc, Groton, Connecticut.
authors.forename: Jean M
authors.initials: JM
authors.lastname: Aguiar
authors.affiliation: Pfizer Inc, Groton, Connecticut.
authors.forename: Kolette D
authors.initials: KD
authors.lastname: Fly
authors.affiliation: Pfizer Inc, New York, New York.
authors.forename: Svetoslav
authors.initials: S
authors.lastname: Dimitrov
authors.affiliation: Pfizer Inc, Cambridge, Massachusetts.
authors.forename: Eric
authors.initials: E
authors.lastname: Leip
authors.affiliation: Pfizer Inc, Cambridge, Massachusetts.
authors.forename: Mark
authors.initials: M
authors.lastname: Shapiro
authors.affiliation: Princess Margaret Cancer Center, Toronto, Ontario, Canada.
authors.forename: Jeff H
authors.initials: JH
authors.lastname: Lipton
authors.affiliation: University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Jean-Bernard
authors.initials: JB
authors.lastname: Durand
authors.affiliation: University of Milano-Bicocca, Monza, Italy.
authors.forename: Carlo
authors.initials: C
authors.lastname: Gambacorti-Passerini
mesh_terms: D000293:Adolescent; D000328:Adult; D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D000814:Aniline Compounds / Q000627:therapeutic use / Q000633:toxicity*; D066126:Cardiotoxicity / Q000209:etiology*; D005260:Female; D006801:Humans; D006937:Hypercholesterolemia; D006949:Hyperlipidemias; D000068877:Imatinib Mesylate / Q000627:therapeutic use; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000150:complications* / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D009570:Nitriles / Q000627:therapeutic use / Q000633:toxicity*; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use; D011804:Quinolines / Q000627:therapeutic use / Q000633:toxicity*; D012189:Retrospective Studies; D012307:Risk Factors; D014652:Vascular Diseases / Q000139:chemically induced / Q000209:etiology*; D055815:Young Adult
chemical_list: D000814:Aniline Compounds; D009570:Nitriles; D047428:Protein Kinase Inhibitors; D011804:Quinolines; C471992:bosutinib; D000068877:Imatinib Mesylate