Overestimation May Have Inaccurately Reflected Risk of AOEs With Ponatinib in Ph+ Leukemia

Take-aways

• According to results from the phase II PACE trial, treatment with ponatinib provided long-term clinical benefit to patients with relapsed Philadelphia chromosome (Ph)–positive leukemia.
• At least one-quarter of patients experienced arterial occlusive events (AOE), but rates varied depending on the approach used to define and report AOE.
• AOE rates were lower than previously reported, suggesting that overestimation may have inaccurately reflected the risk of AOE with ponatinib.

In the phase II PACE trial, arterial occlusive events (AOEs) occurred in at least 25% of trial participants with relapsed Philadelphia chromosome (Ph)–positive leukemia who received ponatinib. However, adjudication of AOEs by independent committee revealed lower rates of clinically relevant AOEs and overall serious AOEs than presented in previous reports from the PACE trial. This suggests that “earlier overestimation that may inaccurately reflect AOE risk with ponatinib,” wrote lead study author James L. Januzzi, MD, Hutter Family Professor of Medicine at Harvard Medical School.

In this report, published in the Journal of Hematology & Oncology, an independent cardiovascular adjudication committee reviewed 5-year AOE data from the PACE trial using a charter-defined process and standardized event definitions. The PACE trial included data on a total of 449 patients with CML or Ph-positive acute lymphoblastic leukemia (ALL) who were treated with ponatinib.

The adjudicated rate of AOEs was 17%, compared with the previous report of 25%. After adjudication, the only AOE reported in more than 2% of patients was peripheral arterial occlusive disease (4%). Over time, the exposure-adjusted incidence of newly occurring adjudicated AOEs decreased. In addition, the committee found higher adjudicated rates of AOEs in patients with multiple baseline cardiovascular risk factors than in those without risk factors.

“In this study, adjudication of AOEs by an independent committee of experts allowed for a clinically meaningful description of AOEs associated with ponatinib, which can help to inform healthcare providers and patients of safety risks in an accurate and objective manner,” the authors wrote.

In the future, “improved understanding of the AOE profile with ponatinib and risk factors for AOEs can help guide treatment decisions around TKI treatment,” they added.

Reference

Januzzi JL, Garasic JM, Kasner SE, et al. Retrospective analysis of arterial occlusive events in the PACE trial by an independent adjudication committee. J Hematol Oncol. 2022 Jan 6;15(1):1.