Acalabrutinib Associated With Fewer Cardiac Toxicities Than Ibrutinib in CLL Treatment

Patients with chronic lymphocytic leukemia (CLL) who received acalabrutinib (Calquence) reported a fewer number of cardiac toxicities than patients receiving other treatments such as ibrutinib (Imbruvica), according to findings from a longitudinal study. These findings were consistent among patients with and without preexisting cardiovascular disorders at baseline.

Key Findings

Data presented at the 2023 International Workshop on CLL demonstrated that the exposure-adjusted incidence rates (EAIR; effects/100 person-months) of cardiac disorder events observed were consistently lower in the acalabrutinib arm vs the comparator arms across the 3 individual trials regardless of grade. Although no distinct trend was noted among patients who presented with 1 or more baseline cardiovascular disorders, the number of events in this subgroup was limited.

In the pooled comparator group (n = 585), EAIRs of any grade of cardiac disorder events were approximately twice as high vs the pooled acalabrutinib group (n = 599).

Analysis of cardiac disorder events in patients who crossed over from other treatments to acalabrutinib in the phase 3 ELEVATE-TN trial (n =72; NCT02475681) demonstrated a lower EAIR of any-grade cardiac disorder events during the post-crossover period with acalabrutinib vs the pre-crossover period with comparator treatment.

“This analysis does not suggest an increased risk of cardiac treatment-emergent adverse effects [TEAEs] and outcomes in acalabrutinib-treated patients, regardless of the presence of baseline cardiovascular disorders,” Rupal O’Quinn, MD, of Perelman School of Medicine, and colleagues wrote in a poster presentation on the data.

Although the first-generation BTK inhibitor ibrutinib has shown significant efficacy in the treatment of patients with CLL, it is associated with notable cardiac toxicity, including cardiac arrhythmias, cardiac failure, and sudden death. In contrast, the next-generation BTK inhibitor acalabrutinib offers a more favorable cardiovascular safety profile with fewer atrial fibrillation events compared with ibrutinib due to its selectivity. Given that the CLL patient population is inherently at higher risk for cardiac events due to factors like advanced age, polypharmacy, substantial comorbidities, and pre-existing cardiac conditions, a comprehensive evaluation of cardiac toxicities associated with CLL therapies is imperative.

Methodology

In this longitudinal review, investigators conducted a comprehensive assessment of cardiac outcomes with acalabrutinib vs active comparator drugs, such as ibrutinib in patients with and without cardiovascular disorders at baseline. The analysis evaluated how CLL therapies affect cardiac health.

Safety data were gathered from 3 randomized phase 3 studies: ELEVATE-RR (NCT02477696), ELEVATE-TN, and ASCEND (NCT02970318). Regarding patients’ treatment regimen, those on ELEVATE-RR received acalabrutinib or ibrutinib; those on ELEVATE-TN were treated with acalabrutinib with or without obinutuzumab (Gazyva) vs obinutuzumab plus chlorambucil; and patients in ASCEND received acalabrutinib vs idelalisib (Zydelig) plus rituximab (Rituxan) or bendamustine plus rituximab.

A total of 19 standardized MedDRA queries with approximately 2400 preferred terms (PTs) were used to identify patients based on patient medical history and TEAEs. For additional analysis, a subset of 89 PTs was used to identify the number of baseline cardiovascular disorders.

EAIRs were reported for system organ class (SOC) “cardiac disorders” among all patients and stratified by the count of baseline cardiovascular disorders in each individual trial. EAIRs for SOC cardiac disorders were also reported pre- and post-crossover for patients who switched from comparator arms to acalabrutinib monotherapy in ELEVATE-TN and ASCEND. For the third analysis group, EAIRs were also reported for SOC “cardiac disorders” overall and by number of baseline disorders for pooled acalabrutinib monotherapy and pooled comparator groups across the 3 randomized controlled trials.

A total of 1,362 patients who experienced 3,672 TEAEs were identified from the clinical trial database. Demographic and baseline characteristics were similar between the acalabrutinib and comparator arms in all 3 trials. Across all trials, 404 patients (29.7%) presented with at least 1 baseline cardiovascular disorder. The distribution of these baseline cardiovascular disorders was also comparable between the acalabrutinib and comparator arms across the various studies. Specifically, 599 patients received acalabrutinib monotherapy, 178 were treated with acalabrutinib plus obinutuzumab, and 585 were treated with various comparators, including ibrutinib and other anticancer agents.

Within the ELEVATE-TN and ASCEND trials, 72 patients who initially received obinutuzumab plus chlorambucil and 80 patients who were treated with idelalisib plus rituximab or bendamustine plus rituximab later transitioned to acalabrutinib monotherapy. Notably, the median duration of exposure to BTK inhibitors administered continuously exceeded that of the comparator treatments across all studies.

Additional Findings

Regarding the EAIRs for de novo cardiac disorder events in patients without any baseline cardiovascular disorders, the results varied by trial. In ELEVATE-RR, the EAIR associated with ibrutinib was 2-times higher than that observed with acalabrutinib (0.67 vs. 0.34).

Meanwhile, the EAIR in ELEVATE-TN was numerically lower for both acalabrutinib plus obinutuzumab (0.28) and acalabrutinib monotherapy (0.25) vs chlorambucil plus obinutuzumab (0.59). In the ASCEND trial, acalabrutinib demonstrated a numerically lower EAIR (0.28) vs idelalisib plus rituximab (0.44) and bendamustine plus rituximab (0.54). These findings suggest a potentially favorable cardiovascular safety profile associated with acalabrutinib.

Pooled analysis revealed that the EAIR of any-grade cardiac disorder events among patients without any baseline cardiovascular disorders was numerically lower in the pooled acalabrutinib group (0.29) vs the comparator group (0.62). Patients in the pooled acalabrutinib group with a baseline number of 1, 2 and 3 or more cardiovascular disorders experienced any-grade EAIRs of 0.16, 0.05, and 0.05, respectively. Corresponding any-grade EAIRs in the pooled comparator arm were 0.22, 0.07, and 0.04.

The most frequently occurring any-grade cardiac disorder PT in both groups was atrial fibrillation (acalabrutinib group, 0.20; comparator group, 0.41). Other common any-grade PTs included palpitations (0.08; 0.12), cardiac failure (0.04; 0.08), tachycardia (0.04; 0.08), angina pectoris (0.06; 0.05), sinus tachycardia (0.01; 0.05), chronic cardiac failure (0.01; 0.04), myocardial ischemia (0.01; 0.04), acute myocardial infarction (0.01; 0.03), arrythmia (0.02; 0.03) atrial flutter (0.01; 0.03), cardiac arrest (0.00; 0.03), coronary artery disease (0.00; 0.03), mitral valve incompetence (0.00; 0.03), myocardial infarction (0.01; 0.03), pericarditis (0.00; 0.03), and sinus bradycardia (0.03; 0.03)

Notably, the EAIR of fatal events within the cardiac disorder category was 3- to 4-times higher in the pooled comparator group vs the pooled acalabrutinib group. However, the incidence of fatal events did significantly increase in patients with 1 or more baseline cardiovascular disorder compared with those without baseline cardiovascular disorders (0.01 vs 0.06). Within the subgroup of patients without baseline cardiovascular disorders, the EAIR of fatal events was 3-times higher in the pooled comparator group compared with the pooled acalabrutinib group. The overall incidence of fatal events remained low.

In the ELEVATE-TN trial (n = 72), the EAIR of grade 3 or greater events remained similar pre- and post-crossover, and only one fatal event occurred during the post-crossover period. However, among patients with no cardiovascular disorders at baseline, the EAIRs were similar pre- and post-crossover (0.44 vs 0.40). Conversely, the EAIR among those who had one or more any-grade cardiovascular disorder at baseline was higher pre- vs post-crossover. Those with 1, 2, and 3 or more events before crossover had an EAIR of 0.67, 0.0 and 0.0 vs 0.13, 0.09, and 0.0, respectively, after crossover.

In the ASCEND trial (n = 80) the EAIR of any-grade cardiac disorder events remained low both before and after the crossover to acalabrutinib. Although the EAIR of grade 3 or greater effects numerically increased post- vs pre-crossover (0.18 vs 0.19), no fatal effects were reported. For those with baseline cardiovascular effects, results were consistent regardless of the number of cardiovascular disorders present. Prior to crossover, patients with 1, 2, and 3 or more events at baseline had EAIRs of 0.0, 0.0, and 0.10. The corresponding EAIR for all 3 categories after crossover was 0.06.

“The results may help to inform treatment decisions for patients with CLL, particularly if they also have heart disease or are at higher risk of heart disease,” study investigators concluded.

Reference

O’Quinn R, Corry AJ, Bajwa N, et al. Longitudinal review of cardiac events with acalabrutinib in the treatment of chronic lymphocytic leukemia (CLL) using data from 3 phase 3 randomized controlled trials. Presented at: 2023 International Workshop on CLL; October 6-9, 2023; Boston, Massachusetts. Abstract 1552457.