Long-term evaluation of cardiac and vascular toxicity in patients with Philadelphia chromosome-positive leukemias treated with bosutinib

Jorge E. Cortes, H. Jean Khoury, Hagop Kantarjian, Tim H. Brümmendorf, Michael J. Mauro, Ewa Matczak, Dmitri Pavlov, Jean M. Aguiar, Kolette D. Fly, Svetoslav Dimitrov, Eric Leip, Mark Shapiro, Jeff H. Lipton, Jean Bernard Durand, Carlo Gambacorti-Passerini

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64 Scopus citations


Vascular and cardiac safety during tyrosine kinase inhibitor (TKI) therapy is an emerging issue. We evaluated vascular/cardiac toxicities associated with long-term bosutinib treatment for Philadelphia chromosome-positive (Ph+) leukemia based on treatment-emergent adverse events (TEAEs) and changes in QTc intervals and ejection fraction in two studies: a phase 1/2 study of second-/third-/fourth-line bosutinib for Ph+ leukemia resistant/intolerant to prior TKIs (N=570) and a phase 3 study of first-line bosutinib (n=248) versus imatinib (n=251) in chronic phase chronic myeloid leukemia. Follow-up time was ≥48 months (both studies). Incidences of vascular/cardiac TEAEs in bosutinib-treated patients were 7%/10% overall with similar incidences observed with first-line bosutinib (5%/8%) and imatinib (4%/6%). Few patients had grade ≥3 vascular/cardiac events (4%/4%) and no individual TEAE occurred in >2% of bosutinib patients. Exposure-adjusted vascular/cardiac TEAE rates (patients with events/patient-year) were low for second-line or later bosutinib (0.037/0.050) and not significantly different between first-line bosutinib (0.015/0.024) and imatinib (0.011/0.017; P≥0.267). Vascular/cardiac events were managed mainly with concomitant medications (39%/44%), bosutinib treatment interruptions (18%/21%), or dose reductions (4%/8%); discontinuations due to these events were rare (0.7%/1.0%). Based on logistic regression modelling, performance status >0 and history of vascular or cardiac disorders were prognostic of vascular/cardiac events in relapsed/refractory patients; hyperlipidemia/hypercholesterolemia and older age were prognostic of cardiac events. In newly diagnosed patients, older age was prognostic of vascular/cardiac events; history of diabetes was prognostic of vascular events. Incidences of vascular and cardiac events were low with bosutinib in the first-line and relapsed/refractory settings following long-term treatment in patients with Ph+ leukemia.

Original languageEnglish (US)
Pages (from-to)606-616
Number of pages11
JournalAmerican Journal of Hematology
Issue number6
StatePublished - Jun 1 2016
Externally publishedYes

ASJC Scopus subject areas

  • Hematology


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