title: Bosutinib is active in chronic phase chronic myeloid leukemia after imatinib and dasatinib and/or nilotinib therapy failure.
abstract: Bosutinib, a dual Src/Abl tyrosine kinase inhibitor (TKI), has shown potent activity against chronic myeloid leukemia (CML). This phase 1/2 study evaluated the efficacy and safety of once-daily bosutinib 500 mg in leukemia patients after resistance/intolerance to imatinib. The current analysis included 118 patients with chronic-phase CML who had been pretreated with imatinib followed by dasatinib and/or nilotinib, with a median follow-up of 28.5 months. In this subpopulation, major cytogenetic response was attained by 32% of patients; complete cytogenetic response was attained by 24%, including in one of 3 patients treated with 3 prior TKIs. Complete hematologic response was achieved/maintained in 73% of patients. On-treatment transformation to accelerated/blast phase occurred in 5 patients. At 2 years, Kaplan-Meier-estimated progression-free survival was 73% and estimated overall survival was 83%. Responses were seen across Bcr-Abl mutations, including those associated with dasatinib and nilotinib resistance, except T315I. Bosutinib had an acceptable safety profile; treatment-emergent adverse events were primarily manageable grade 1/2 gastrointestinal events and rash. Grade 3/4 nonhematologic adverse events (> 2% of patients) included diarrhea (8%) and rash (4%). Bosutinib may offer a new treatment option for patients with chronic-phase CML after treatment with multiple TKIs. This trial was registered at www.clinicaltrials.gov as NCT00261846.
authors.affiliation: Winship Cancer Institute of Emory University, Atlanta, GA 30322, USA. hkhoury@emory.edu
authors.forename: H Jean
authors.initials: HJ
authors.lastname: Khoury
authors.forename: Jorge E
authors.initials: JE
authors.lastname: Cortes
authors.forename: Hagop M
authors.initials: HM
authors.lastname: Kantarjian
authors.forename: Carlo
authors.initials: C
authors.lastname: Gambacorti-Passerini
authors.forename: Michele
authors.initials: M
authors.lastname: Baccarani
authors.forename: Dong-Wook
authors.initials: DW
authors.lastname: Kim
authors.forename: Andrey
authors.initials: A
authors.lastname: Zaritskey
authors.forename: Athena
authors.initials: A
authors.lastname: Countouriotis
authors.forename: Nadine
authors.initials: N
authors.lastname: Besson
authors.forename: Eric
authors.initials: E
authors.lastname: Leip
authors.forename: Virginia
authors.initials: V
authors.lastname: Kelly
authors.forename: Tim H
authors.initials: TH
authors.lastname: Brümmendorf
mesh_terms: D000328:Adult; D000368:Aged; D000465:Algorithms; D000814:Aniline Compounds / Q000494:pharmacology / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001549:Benzamides; D017024:Chemotherapy, Adjuvant; D000069439:Dasatinib; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D005260:Female; D006801:Humans; D000068877:Imatinib Mesylate; D015466:Leukemia, Myeloid, Chronic-Phase / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009570:Nitriles / Q000494:pharmacology / Q000627:therapeutic use*; D010879:Piperazines / Q000008:administration & dosage; D011743:Pyrimidines / Q000008:administration & dosage; D011804:Quinolines / Q000494:pharmacology / Q000627:therapeutic use*; D013844:Thiazoles / Q000008:administration & dosage; D017211:Treatment Failure; D055815:Young Adult
chemical_list: D000814:Aniline Compounds; D000970:Antineoplastic Agents; D001549:Benzamides; D009570:Nitriles; D010879:Piperazines; D011743:Pyrimidines; D011804:Quinolines; D013844:Thiazoles; C471992:bosutinib; D000068877:Imatinib Mesylate; C498826:nilotinib; D000069439:Dasatinib