Research Summary:
Covalent Bruton tyrosine kinase (BTK) inhibitors have become the preferred treatment for chronic lymphocytic leukemia (CLL). However, the first-generation BTK inhibitor ibrutinib, though effective, has been associated with cardiac toxicity, including atrial fibrillation, heart failure, and sudden death. Acalabrutinib, a second-generation, more selective BTK inhibitor, demonstrates less off-target kinase binding and has shown lower rates of atrial fibrillation and flutter compared with ibrutinib. To evaluate cardiac safety, this analysis by O’Quinn et al1 examined data from three Phase III randomized trials in CLL (ELEVATE-RR, ELEVATE-TN, and ASCEND) comparing acalabrutinib regimens with active comparators (ibrutinib, obinutuzumab plus chlorambucil, idelalisib plus rituximab, or bendamustine plus rituximab). Each study included patients with treatment-naïve (TN) or relapsed/refractory (R/R) CLL requiring therapy, defined by the International Workshop on CLL criteria. Acalabrutinib was administered at 100mg twice daily until disease progression or unacceptable toxicity, alone or with obinutuzumab (ELEVATE-TN). Exposure-adjusted incidence rates (EAIRs) were calculated for treatment-emergent cardiac disorders overall and by number of baseline cardiovascular disorders. EAIRs were assessed for individual trials, pooled treatment groups, and patients who crossed over from comparator to acalabrutinib therapy.
A total of 1,362 patients with 3,672 treatment-emergent adverse events (TEAEs) were analyzed, including 599 treated with acalabrutinib monotherapy, 178 with acalabrutinib plus obinutuzumab, and 585 with active comparators. Among all patients, 404 (29.7%) had at least one cardiovascular disorder at baseline. Median treatment exposure was longer for BTK inhibitor arms, which were administered continuously, compared to the chemoimmunotherapy regimens. Across all three studies, the overall EAIR of any-grade cardiac disorder events was numerically lower with acalabrutinib compared with each comparator arm. The EAIR of Grade 3 or greater cardiac disorder events was generally similar between groups, and fatal event rates were lowest among BTK inhibitor treatments.
Among patients without baseline cardiovascular disorders, the EAIR of de novo cardiac disorder events was consistently lower with acalabrutinib than with comparators. In ELEVATE-RR, the EAIR was 0.34 for acalabrutinib versus 0.67 for ibrutinib. In ELEVATE-TN, the rates were 0.28 and 0.25 for acalabrutinib plus obinutuzumab and acalabrutinib monotherapy, respectively, compared with 0.59 for chlorambucil plus obinutuzumab. In ASCEND, rates were 0.28 for acalabrutinib versus 0.44 and 0.54 for idelalisib plus rituximab and bendamustine plus rituximab, respectively.
In pooled analyses, the EAIR of any-grade cardiac disorder events was 0.55 for pooled acalabrutinib monotherapy compared with 0.95 for pooled comparators, and the fatal-event EAIR was 0.02 versus 0.08, respectively. Atrial fibrillation was the most frequent cardiac disorder, with pooled EAIRs of 0.20 for acalabrutinib versus 0.41 for comparators. The pooled de novo cardiac disorder EAIR was 0.29 for acalabrutinib versus 0.62 for comparators, and fatal-event rates were lower with acalabrutinib as well (0.02 vs. 0.06). The EAIR of fatal events did not increase among patients with one or more baseline cardiovascular disorders compared to those without baseline cardiovascular disorder. When stratified by treatment setting, the EAIR of cardiac disorder events was lower for acalabrutinib-treated patients with TN CLL (0.44) compared to those with R/R CLL (0.61) and patients who received comparators (TN: 1.28, R/R: 0.91). Grouped analyses showed lower EAIRs of arrhythmia and hypertension events with acalabrutinib versus comparators in both populations.
In crossover analyses, patients switching from comparator therapy to acalabrutinib experienced stable or reduced cardiac event rates. In ELEVATE-TN, the EAIR of any-grade cardiac disorder event overall decreased from 1.11 precrossover to 0.62 postcrossover, and among patients with one or more baseline cardiovascular disorders, from 0.67 to 0.22. In ASCEND, EAIRs were similar precrossover and postcrossover (0.29 vs. 0.36). Although Grade 3 or greater events increased slightly after crossover in ASCEND, the number of events was small, and no fatal events occurred.
Limitations of this study included lack of statistical comparisons, potential differences in the classification of cardiac events, and the equal weighing of cardiovascular disorders of varying severity.
Overall, the analysis demonstrated that acalabrutinib was not associated with an increased risk of cardiac disorder events compared with other standard CLL therapies. Differences between treatment arms diminished as baseline cardiovascular disorders increased, reflecting smaller sample sizes in those subgroups. The general CLL population, which is characterized by older age and higher comorbidity burden, carries elevated cardiovascular risk, making these findings clinically relevant for treatment selection. The lower rates of atrial fibrillation and cardiac failure with acalabrutinib compared with ibrutinib align with prior findings from ELEVATE-RR. Furthermore, the pooled exposure-adjusted data reinforce the favorable cardiac safety profile of acalabrutinib in the treatment of TN and R/R CLL.
Reference
- O’Quinn R, Corry AJ, Bajwa N, et al. Cardiac events in three Phase III randomized trials including acalabrutinib in chronic lymphocytic leukemia. Clin Lymphoma Myeloma Leuk. 2025;25(11):819–828.e5