Bosutinib is active in chronic phase chronic myeloid leukemia after imatinib and dasatinib and/or nilotinib therapy failure

Blood. 2012 Apr 12;119(15):3403-12. doi: 10.1182/blood-2011-11-390120. Epub 2012 Feb 27.

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.

Publication types

  • Clinical Trial, Phase I
  • Clinical Trial, Phase II
  • Multicenter Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Algorithms
  • Aniline Compounds / pharmacology
  • Aniline Compounds / therapeutic use*
  • Antineoplastic Agents / pharmacology
  • Antineoplastic Agents / therapeutic use
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
  • Benzamides
  • Chemotherapy, Adjuvant
  • Dasatinib
  • Drug Resistance, Neoplasm / drug effects
  • Female
  • Humans
  • Imatinib Mesylate
  • Leukemia, Myeloid, Chronic-Phase / drug therapy*
  • Leukemia, Myeloid, Chronic-Phase / pathology
  • Male
  • Middle Aged
  • Nitriles / pharmacology
  • Nitriles / therapeutic use*
  • Piperazines / administration & dosage
  • Pyrimidines / administration & dosage
  • Quinolines / pharmacology
  • Quinolines / therapeutic use*
  • Thiazoles / administration & dosage
  • Treatment Failure
  • Young Adult

Substances

  • 4-methyl-N-(3-(4-methylimidazol-1-yl)-5-(trifluoromethyl)phenyl)-3-((4-pyridin-3-ylpyrimidin-2-yl)amino)benzamide
  • Aniline Compounds
  • Antineoplastic Agents
  • Benzamides
  • Nitriles
  • Piperazines
  • Pyrimidines
  • Quinolines
  • Thiazoles
  • bosutinib
  • Imatinib Mesylate
  • Dasatinib

Associated data

  • ClinicalTrials.gov/NCT00261846