title: Bosutinib safety and management of toxicity in leukemia patients with resistance or intolerance to imatinib and other tyrosine kinase inhibitors.
abstract: Bosutinib is an oral, dual SRC/ABL tyrosine kinase inhibitor (TKI) with clinical activity in Philadelphia chromosome-positive (Ph(+)) leukemia. We assessed the safety and tolerability of bosutinib 500 mg per day in a phase 1/2 study in chronic-phase (CP) chronic myeloid leukemia (CML) or advanced Ph(+) leukemia following resistance/intolerance to imatinib and possibly other TKIs. Patient cohorts included second-line CP CML (n = 286), third-/fourth-line CP CML (n = 118), and advanced leukemia (n = 166). Median bosutinib duration was 11.1 (range, 0.03-83.4) months. Treatment-emergent adverse events (TEAEs) in each cohort were primarily gastrointestinal (diarrhea [86%/83%/74%], nausea [46%/48%/48%], and vomiting [37%/38%/43%]). Diarrhea presented early, with few (8%) patients experiencing grade 3/4 events; dose reduction due to diarrhea occurred in 6% of affected patients. Grade 3/4 myelosuppression TEAEs were reported in 41% of patients; among affected patients, 46% were managed with bosutinib interruption and 32% with dose reduction. Alanine aminotransferase elevation TEAEs occurred in 17% of patients (grade 3/4, 7%); among patients managed with dose interruption, bosutinib rechallenge was successful in 74%. Bosutinib demonstrated acceptable safety with manageable toxicities in Ph(+) leukemia. This trial (NCT00261846) was registered at www.ClinicalTrials.gov (this manuscript is based on a different data snapshot from that in ClinicalTrials.gov).
authors.affiliation: Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX;
authors.forename: Hagop M
authors.initials: HM
authors.lastname: Kantarjian
authors.forename: Jorge E
authors.initials: JE
authors.lastname: Cortes
authors.forename: Dong-Wook
authors.initials: DW
authors.lastname: Kim
authors.forename: H Jean
authors.initials: HJ
authors.lastname: Khoury
authors.forename: Tim H
authors.initials: TH
authors.lastname: Brümmendorf
authors.forename: Kimmo
authors.initials: K
authors.lastname: Porkka
authors.forename: Giovanni
authors.initials: G
authors.lastname: Martinelli
authors.forename: Simon
authors.initials: S
authors.lastname: Durrant
authors.forename: Eric
authors.initials: E
authors.lastname: Leip
authors.forename: Virginia
authors.initials: V
authors.lastname: Kelly
authors.forename: Kathleen
authors.initials: K
authors.lastname: Turnbull
authors.forename: Nadine
authors.initials: N
authors.lastname: Besson
authors.forename: Carlo
authors.initials: C
authors.lastname: Gambacorti-Passerini
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000814:Aniline Compounds / Q000009:adverse effects* / Q000627:therapeutic use*; D001549:Benzamides / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D064420:Drug-Related Side Effects and Adverse Reactions / Q000453:epidemiology / Q000628:therapy*; D005260:Female; D006801:Humans; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000453:epidemiology; D008297:Male; D008875:Middle Aged; D009570:Nitriles / Q000009:adverse effects* / Q000627:therapeutic use*; D010879:Piperazines / Q000627:therapeutic use*; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D011743:Pyrimidines / Q000627:therapeutic use*; D011804:Quinolines / Q000009:adverse effects* / Q000627:therapeutic use*; D028761:Withholding Treatment / Q000706:statistics & numerical data; D055815:Young Adult
chemical_list: D000814:Aniline Compounds; D001549:Benzamides; D009570:Nitriles; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D011804:Quinolines; C471992:bosutinib; D000068877:Imatinib Mesylate; D011505:Protein-Tyrosine Kinases