Bosutinib shows 'low' vascular, cardiac event risk profile

Third-generation tyrosine kinase inhibitor (TKI) study findings suggest that bosutinib is associated with a low risk of vascular and cardiac events in patients undergoing first-line or subsequent treatment for chronic myeloid leukaemia (CML).

"The results of this analysis suggest that the vascular and cardiac toxicity profile of bosutinib is distinct relative to other TKIs", write Jorge Cortes, from University of Texas MD Anderson Cancer Center in Houston, USA, and co-authors in the American Journal of Hematology.

The team collated information on treatment-emergent adverse events (TEAEs) in 570 patients who received second-, third- or fourth-line bosutinib treatment for Philadelphia chromosome-positive CML as part of a phase I/II study.

In addition, the researchers determined the incidence of TEAEs in a phase III study comparing first-line bosutinib in 248 patients with first-line imatinib in 251 patients.

Trial participants were all followed up for at least 2 years and the overall incidence of vascular TEAEs was low, with all-grade and grade 3 or more severe side effects affecting 6.8% and 3.7% of patients given bosutinib, respectively.

First-line bosutinib was associated with a lower rate of vascular TEAEs than second-line or subsequent bosutinib therapy, affecting 4.8% versus 7.7%. First-line imatinib had comparable incidence of both overall and grade 3 and more severe vascular TEAEs to that of first-line bosutinib.

Cerebrovascular TEAEs were reported in 1.8% of patients given bosutinib, again being less common in those given primary bosutinib relative to second-line or later treatment (0.8 vs 2.3%). All-grade and grade 3 or more severe cardiovascular TEAEs occurred in 3.7% and 2.3% of bosutinib-treated patients, occurring at a lower rate in first-line than later treated patients (2.4 vs 4.2%).

Serious vascular TEAEs were reported in 4.2% of bosutinib-treated patients, with grade 3 or more severe events occurring in 3.1%, most commonly coronary artery disease (0.9%) and acute myocardial infarction (0.6%).

Events were less common in newly diagnosed patients than those with refractory or relapsed disease (2.0 vs 5.1%), and there was no significant difference in the incidence or exposure-adjusted rate between the first-line bosutinib and imatinib groups.

Just 0.9% of bosutinib-treated patients discontinued treatment due to vascular TEAEs. There were nine deaths from vascular TEAEs, all of which were in patients given bosutinib as second-line or later, but just one was considered to be probably related to treatment. One first-line imatinib-treated patient also died from a vascular TEAE thought not to be associated with treatment.

Analysis showed that vascular TEAEs in patients using second-line or later bosutinib were significantly associated with an Eastern Cooperative Oncology Group performance status (ECOG PS) greater than 0 and a history of vascular disorders, while first-line bosutinib vascular TEAEs were linked to an age of at least 65 years and a history of diabetes.

Cardiac TEAEs in second-line or later bosutinib-treated patients were associated with older age, ECOG PS greater than 0, history of cardiac disorders and hyperlipidaemia, while such events in first-line bosutinib users were associated with age over 65 years.

Finally, the choice of first-line bosutinib versus imatinib did not predict the risk of vascular or cardiac TEAEs.

"This comprehensive analysis suggests that, relative to other new-generation TKIs, vascular and cardiac TEAE incidences in leukemia patients receiving bosutinib are generally low, even after long-term treatment, and not significantly different from those observed in imatinib-treated patients", the team summarises.

"Likewise, dose adjustments and discontinuations due to these events were rare; therefore, bosutinib could be considered among the treatment options for patients with cardiac or vascular comorbidities."

Nevertheless, the authors conclude that all patients should be assessed for vascular and cardiac risk factors before beginning any TKI treatment, with cardiologist evaluation where necessary.

"Close monitoring, particularly in high-risk patients, and proactive management should be standard of care before starting therapy", they emphasize.

By Lynda Williams, Senior medwireNews Reporter

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