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: Hagop M Kantarjian, Jorge E Cortes, Dong-Wook Kim, H Jean Khoury, Tim H Brümmendorf, Kimmo Porkka, Giovanni Martinelli, Simon Durrant, Eric Leip, Virginia Kelly, Kathleen Turnbull, Nadine Besson, Carlo Gambacorti-Passerini
• Journal: Blood (Blood) Vol. 123 Issue 9 Pg. 1309-18 (Feb 27 2014) ISSN: 1528-0020 [Electronic] United States
• PMID: 24345751 (Publication Type: Clinical Trial, Phase I, Clinical Trial, Phase II, Journal Article, Multicenter Study, Research Support, Non-U.S. Gov't)

Chemical References

• Aniline Compounds
• Benzamides
• Nitriles
• Piperazines
• Protein Kinase Inhibitors
• Pyrimidines
• Quinolines
• bosutinib
• Imatinib Mesylate
• Protein-Tyrosine Kinases

Topics

• Adolescent
• Adult
• Aged
• Aged, 80 and over
• Aniline Compounds (adverse effects, therapeutic use)
• Benzamides (therapeutic use)
• Dose-Response Relationship, Drug
• Drug Resistance, Neoplasm
• Drug-Related Side Effects and Adverse Reactions (epidemiology, therapy)
• Female
• Humans
• Imatinib Mesylate
• Leukemia, Myelogenous, Chronic, BCR-ABL Positive (drug therapy, epidemiology)
• Male
• Middle Aged
• Nitriles (adverse effects, therapeutic use)
• Piperazines (therapeutic use)
• Protein Kinase Inhibitors (therapeutic use)
• Protein-Tyrosine Kinases (antagonists & inhibitors)
• Pyrimidines (therapeutic use)
• Quinolines (adverse effects, therapeutic use)
• Withholding Treatment (statistics & numerical data)
• Young Adult