Abstract
BackgroundThe phase 2 PACE (Ponatinib Ph+ ALL and CML Evaluation) trial of ponatinib showed robust long-term benefit in relapsed Philadelphia chromosome-positive (Ph+) leukemia; arterial occlusive events (AOEs) occurred in ≥ 25% of patients based on investigator reporting. However, AOE rates vary depending on the definitions and reporting approach used.MethodsTo better understand clinically relevant AOEs with ponatinib, an independent cardiovascular adjudication committee reviewed 5-year AOE data from the PACE trial according to a charter-defined process and standardized event definitions.ResultsA total of 449 patients with chronic myeloid leukemia (CML) or Ph+ acute lymphoblastic leukemia (ALL) received ponatinib (median age 59 y; 47% female; 93% ≥ 2 prior tyrosine kinase inhibitors (TKIs); median follow-up, 37.3 months). The adjudicated AOE rate (17%) was lower than the non-adjudicated rate (i.e., rate before adjudication; 25%). The only adjudicated AOE in > 2% of patients was peripheral arterial occlusive disease (4%). Exposure-adjusted incidence of newly occurring adjudicated AOEs decreased over time. Patients with multiple baseline cardiovascular risk factors had higher adjudicated AOE rates than those without risk factors.ConclusionsThis independent adjudication study identified lower AOE rates than previously reported, suggesting earlier overestimation that may inaccurately reflect AOE risk with ponatinib. This trial was registered under ClinicalTrials.gov identifier NCT01207440 on September 23, 2010 (https://clinicaltrials.gov/ct2/show/NCT01207440).
Highlights
The phase 2 Ponatinib Ph+ ALL and CML Evaluation (PACE) (Ponatinib Ph+ acute lymphoblastic leukemia (ALL) and chronic myeloid leukemia (CML) Evaluation) trial of ponatinib showed robust longterm benefit in relapsed Philadelphia chromosome-positive (Ph+) leukemia; arterial occlusive events (AOEs) occurred in ≥ 25% of patients based on investigator reporting
All patients received ponatinib at a starting dose of 45 mg once daily; dose reductions to 30 or 15 mg qd were applied per protocol (Table 1) to manage adverse events (AEs), or implemented proactively following recommendations from the sponsor in October 2013 in response to AOEs emerging as notable AEs
CV death includes death resulting from an acute myocardial infarction (MI), sudden cardiac death, death due to heart failure (HF), death due to stroke, death due to CV procedures, death due to CV hemorrhage, death due to pulmonary embolism, and death due to other CV causes
Summary
The phase 2 PACE (Ponatinib Ph+ ALL and CML Evaluation) trial of ponatinib showed robust longterm benefit in relapsed Philadelphia chromosome-positive (Ph+) leukemia; arterial occlusive events (AOEs) occurred in ≥ 25% of patients based on investigator reporting. AOE rates vary depending on the definitions and reporting approach used. Arterial occlusive events (AOEs) were reported by investigators in 25% in the overall population (serious AOEs, 20%) and 31% in the CP-CML population (serious AOEs, 26%) in the 5-year follow-up [3]. The incidence of AOEs associated with ponatinib use has varied widely in subsequent reports. Multiple factors may contribute to variability in reported AOE rates, including differences in patient populations, as well as differences in the clinical definitions used to identify and categorize vascular occlusive events. One of the most important factors is the lack of a standardized approach for defining and capturing AOEs with BCR::ABL1 TKIs
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