1220 - Longitudinal review of cardiac events with acalabrutinib in the treatment of chronic lymphocytic leukemia (CLL) using data from 3 phase 3 randomized controlled trials (RCTs)

Introduction: The first-generation Bruton tyrosine kinase inhibitor (BTKi) ibrutinib has demonstrated notable efficacy in CLL; however, it is associated with significant cardiac toxicity, including cardiac arrhythmias (eg, atrial fibrillation), cardiac failure, and sudden death. Acalabrutinib is a selective next-generation BTKi for the treatment of CLL with a more favorable cardiovascular (CV) safety profile with fewer atrial fibrillation events versus ibrutinib. The CLL population is at higher risk for cardiac events due to advanced age, polypharmacy, significant comorbidities, and pre-existing cardiac disorders, thereby necessitating comprehensive assessment of cardiac toxicities with CLL therapies. We performed a comprehensive analysis of cardiac outcomes with acalabrutinib versus active comparators, including ibrutinib, in patients with and without CV disorders at baseline to assess the impact of CLL therapies.

Methods: Safety data were extracted from 3 phase 3 RCTs in CLL (ELEVATE-RR, ELEVATE-TN, ASCEND) utilizing 19 Standardized MedDRA Queries (SMQs; Table 1) yielding ~2400 preferred terms (PTs); a subset of specific PTs pertaining to baseline CV disorders and treatment-emergent adverse events (TEAEs) was utilized for further assessments. Exposure-adjusted incidence rates (EAIR; events/100 person-months) were reported for system organ class (SOC) “cardiac disorders” in patients overall and by number of baseline CV disorders. EAIRs for SOC “cardiac disorders” were also reported pre- and post-crossover for patients who crossed over from comparator arms (chlorambucil + obinutuzumab [ELEVATE-TN]; idelalisib + rituximab [IR] or bendamustine + rituximab [BR] [ASCEND]) to acalabrutinib monotherapy. EAIRs were also reported for SOC “cardiac disorders” overall and by number of baseline CV disorders for pooled acalabrutinib monotherapy and pooled comparator groups across the 3 RCTs.

Results: In total, 1362 patients with 3672 TEAEs were retrieved from the clinical trial database utilizing 19 SMQs. Of the 1362 patients, 404 (29.7%) had ≥1 baseline CV disorder (data by study provided in Table 1). The distribution of baseline CV disorders was similar in the acalabrutinib and comparator arms across studies. The EAIR of cardiac disorder events for each treatment arm in each study overall and by number of baseline CV disorders is shown in Table 1. In the 3 RCTs, the overall EAIR of any-grade cardiac disorder events was numerically lower in the acalabrutinib arm versus comparator arms, with no specific trend seen among patients with ≥1 baseline CV disorder. In ELEVATE-RR, the EAIR of de novo cardiac disorder events of any grade among patients without baseline CV disorders with ibrutinib was twice as high compared with acalabrutinib (0.67 vs 0.34) (Table 1). In ELEVATE-TN, EAIR of de novo cardiac disorder events of any grade was also numerically lower for acalabrutinib + obinutuzumab (0.28) and acalabrutinib monotherapy (0.25) versus chlorambucil + obinutuzumab (0.59) (Table 1). Similarly, in ASCEND, the EAIR of de novo cardiac disorder events of any grade was numerically lower for acalabrutinib (0.28) versus IR (0.44) and BR (0.54) (Table 1). In crossover patients in ELEVATE-TN (n=72), the EAIR of any-grade cardiac disorder events was lower during the post-crossover period with acalabrutinib (0.62) versus the pre-crossover period with comparator treatment (1.11). In crossover patients in ASCEND (n=80), the EAIR of any-grade cardiac disorder events was low before (0.29) and after (0.36) crossover to acalabrutinib. Based on pooled data across the 3 trials, the EAIR of cardiac disorder events overall and in patients with no baseline CV disorders was numerically lower for acalabrutinib (0.55 and 0.29) versus comparator (0.95 and 0.62) (Table 2). EAIR of fatal events was 3 to 4 times higher in the pooled comparator arms versus pooled acalabrutinib arms overall and in patients with no baseline CV disorders; the EAIR of fatal events did not increase in patients with ≥1 baseline CV disorder versus no baseline CV disorders and was low overall (Table 2).

Conclusion: The incidence of overall cardiac TEAEs across 3 phase 3 RCTs was numerically low overall with acalabrutinib compared with comparators. The current analysis does not suggest an increased risk of cardiac TEAEs and outcomes in patients treated with acalabrutinib, regardless of the presence of baseline CV disorders. The cardiac safety profile of acalabrutinib is consistent across groups with and without CV disorders at baseline and in line with acalabrutinib’s known positive safety profile.