Cardiac Events in Three Phase 3 Randomized Trials Including Acalabrutinib in Chronic Lymphocytic Leukemia.

Background: The first-generation Bruton tyrosine kinase (BTK) inhibitor ibrutinib is effective in patients with CLL but is associated with considerable cardiac toxicity. The more selective second-generation BTK inhibitor acalabrutinib has demonstrated a more favorable cardiovascular safety profile with fewer atrial fibrillation events versus ibrutinib. We performed a comprehensive analysis of cardiac outcomes with acalabrutinib versus active comparators, including ibrutinib, in patients with and without baseline cardiovascular disorders.

Materials and methods: Data from three phase 3 trials in CLL (ELEVATE-RR, ELEVATE-TN, ASCEND) were used. Exposure-adjusted incidence rates (EAIR; events/100 person-months) were reported for system organ class "cardiac disorders" in patients overall and by number of baseline cardiovascular disorders. All analyses were descriptive. No statistical comparisons were performed.

Results: In total, 1362 patients were included; 404 (29.7%) had ≥1 baseline cardiovascular disorder. The overall EAIR of any-grade cardiac disorder events was lower for acalabrutinib versus active comparator in each trial, and acalabrutinib did not increase cardiac events in patients with ≥1 baseline cardiovascular disorder. The EAIR of de novo cardiac disorder events (ie, among patients without baseline cardiovascular disorders) was also lower for acalabrutinib versus active comparator across trials (ELEVATE-RR: 0.34 vs. 0.67 [acalabrutinib vs. ibrutinib], ELEVATE-TN: 0.28 and 0.25 vs. 0.59 [acalabrutinib plus obinutuzumab and acalabrutinib vs. chlorambucil + obinutuzumab], ASCEND: 0.28 vs. 0.44 and 0.54 [acalabrutinib vs. idelalisib plus rituximab and bendamustine plus rituximab]).

Conclusions: The EAIRs of cardiac disorder events was relatively low overall with acalabrutinib versus comparators, regardless of the presence of baseline cardiovascular disorders.