Bosutinib safety and management of toxicity in leukemia patients with resistance or intolerance to imatinib and other tyrosine kinase inhibitors

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

Research output: Contribution to journalArticle

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 patientsmanaged 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 snap shot from that in ClinicalTrials.gov).

Original languageEnglish (US)
Pages (from-to)1309-1318
Number of pages10
JournalBlood
Volume123
Issue number9
DOIs
StatePublished - Feb 27 2014
Externally publishedYes

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Safety Management
Protein-Tyrosine Kinases
Toxicity
Leukemia
Leukemia, Myeloid, Chronic Phase
Diarrhea
Safety
Philadelphia Chromosome
Chromosomes
Alanine Transaminase
Nausea
Vomiting
Imatinib Mesylate
bosutinib
Therapeutics

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

Cite this

Kantarjian, H. M., Cortes, J. E., Kim, D. W., Khoury, H. J., Brümmendorf, T. H., Porkka, K., ... Gambacorti-Passerini, C. (2014). Bosutinib safety and management of toxicity in leukemia patients with resistance or intolerance to imatinib and other tyrosine kinase inhibitors. Blood, 123(9), 1309-1318. https://doi.org/10.1182/blood-2013-07-513937

Bosutinib safety and management of toxicity in leukemia patients with resistance or intolerance to imatinib and other tyrosine kinase inhibitors. / Kantarjian, Hagop M.; Cortes, Jorge E.; Kim, Dong Wook; Khoury, H. Jean; Brümmendorf, Tim H.; Porkka, Kimmo; Martinelli, Giovanni; Durrant, Simon; Leip, Eric; Kelly, Virginia; Turnbull, Kathleen; Besson, Nadine; Gambacorti-Passerini, Carlo.

In: Blood, Vol. 123, No. 9, 27.02.2014, p. 1309-1318.

Research output: Contribution to journalArticle

Kantarjian, HM, Cortes, JE, Kim, DW, Khoury, HJ, Brümmendorf, TH, Porkka, K, Martinelli, G, Durrant, S, Leip, E, Kelly, V, Turnbull, K, Besson, N & Gambacorti-Passerini, C 2014, 'Bosutinib safety and management of toxicity in leukemia patients with resistance or intolerance to imatinib and other tyrosine kinase inhibitors', Blood, vol. 123, no. 9, pp. 1309-1318. https://doi.org/10.1182/blood-2013-07-513937
Kantarjian, Hagop M. ; Cortes, Jorge E. ; Kim, Dong Wook ; Khoury, H. Jean ; Brümmendorf, Tim H. ; Porkka, Kimmo ; Martinelli, Giovanni ; Durrant, Simon ; Leip, Eric ; Kelly, Virginia ; Turnbull, Kathleen ; Besson, Nadine ; Gambacorti-Passerini, Carlo. / Bosutinib safety and management of toxicity in leukemia patients with resistance or intolerance to imatinib and other tyrosine kinase inhibitors. In: Blood. 2014 ; Vol. 123, No. 9. pp. 1309-1318.
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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 patientsmanaged 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 snap shot from that in ClinicalTrials.gov).",
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