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

Abstract

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.

Chronic myeloid leukemia: Second‐line drugs of choice

“…This same study provided the ideal framework to evaluate the safety of bosutinib as it was administered in a controlled way (i.e., vs. imatinib) in over 500 patients followed for a minimum of 5 years. Its results confirm the general safety of bosutinib especially for what pertains to cardiovascular AEs, which were very similar to those observed in patients receiving imatinib [52,72,73].…”

Tyrosine kinase inhibitor associated vascular toxicity in chronic myeloid leukemia

“…Arrow width indicates potency. See text for further discussion a phase II trial [53], and to a lesser extent, with bosutinib [54]. Manufacturer prescribing information data for ponatinib reveal much higher rates of hypertension (67 %), with up to 2 % of patients in clinical trials experiencing emergent symptomatic hypertension [34].…”

Ponatinib efficacy and safety in Philadelphia chromosome–positive leukemia: final 5-year results of the phase 2 PACE trial

“…38 With a median treatment duration of 11.1 months, vascular AEs, including hypertension, have been reported in patients treated with bosutinib, although the incidence was not different from that associated with imatinib. 39 Although the pathophysiologies underlying the vascular toxicities associated with TKIs are unclear, preexisting comorbidities, particularly cardiovascular risk factors, are associated with an increased risk of such events. 29 The finding that vascular occlusive events are observed in patients treated with different BCR-ABL1 TKIs suggests that the drugs may share a common mechanism of vascular toxicity.…”