Second-Generation BTK Inhibitors Exhibit Lower Incidence of Cardiac AEs in B-Cell Malignancies

Second-generation BTK inhibitors were associated with a significantly lower incidence of atrial fibrillation (AF), total cardiac adverse effects (AEs), and heart failure compared with first-generation agents in patients with B-cell hematologic malignancies, including chronic lymphocytic leukemia, mantle cell lymphoma, and Waldenström macroglobulinemia, according to data from a meta analysis presented at the 2024 ASH Annual Meeting.

Presenting study author Ali Mushtaq, MD, and colleagues wrote in a poster presentation of the data that treatment with second-generation BTK inhibitors in patients with higher cardiovascular risk is recommended, noting that close monitoring is needed if they are treated with ibrutinib (Imbruvica). The authors added that the risks of coronary artery disease (CAD), ventricular tachycardia, sudden cardiac death, and hypertension were similar between first- and second-generation BTK inhibitors.

Findings from the retrospective study showed that AF occurred in 15.65% of patients treated with a first-generation BTK inhibitor (n = 19746) vs 5.63% of patients treated with second-generation BTK inhibitors (n = 2501; odds ratio [OR], 2.829; 95% CI, 1.772-4.517).

“A meta analysis [conducted] in 2016 showed there was a higher incidence of AF of [approximately] 3.5 fold with the use of ibrutinib compared [with] other therapies,” Mushtaq said in a poster presentation of the meta-analysis. “Although [the 2016 study] did not compare [ibrutinib] to second-generation BTK inhibitors, which were not introduced at the time, they saw that ibrutinib alone increased this risk.”

Mushtaq is a second-year resident in the Department of Internal Medicine at the Cleveland Clinic in Ohio.

Baseline Patient Characteristics and Additional Data

The meta analysis included data from 11 studies that featured patients treated with a first-generation BTK inhibitor or a second-generation BTK inhibitor, including acalabrutinib (Calquence), zanubrutinib (Brukinsa), or pirtobrutinib (Jaypirca).

Main outcomes evaluated during the meta analysis were the incidence of AF, CAD, and total cardiac AEs, based on MedDRA cardiac system organ class terms.

Among patients from the first-generation BTK inhibitor arm, the mean age was 65.95 years (standard deviation [SD], 9.55), 65.05% of patients were male, 82.6% were White, 7.0% were Asian, and 86.93% had an ECOG performance status of 0 or 1. In the second-generation BTK inhibitor arm, the mean age was 66.51 years (SD, 9.25), 62.71% of patients were male, 84.17% were White, 7.35% were Asian, and 87.8% had an ECOG performance status of 0 or 1.

Additional cardiac AE data showed that 14.78% of patients in the first-generation arm experienced general cardiac AEs vs 12.64% of patients in the second-generation arm (OR, 1.397; 95% CI, 1.039-1.878). The rates of CAD were 4.91% and 4.49%, respectively (OR, 1.02; 95% CI, 0.715-1.455), and the rates of other arrhythmias were 8.91% vs 12.97%, respectively (OR, 0.659; 95% CI, 0.436-0.996).

Bleeding events were reported in 23.42% of patients in the first-generation arm vs 18.9% of patients in the second-generation arm (OR, 1.526; 95% CI, 1.041-2.238). The rates of heart failure were 4.83% and 2.54%, respectively (OR, 1.376; 95% CI, 1.016-1.863). Additionally, 1.23% of patients in the first-generation arm experienced cerebrovascular events vs 1.13% of patients in the second-generation arm (OR, 1.797; 95% CI, 0.951-3.394). Ventricular tachycardia was reported in 0.96% of patients in the first-generation group vs 1.10% of patients in the second-generation group (OR, 1.965; 95% CI, 0.74-5.222).

“If we can improve the selectivity of the second-generation BTK inhibitors and reduce off-target effects, we can potentially lower this cardiotoxicity, and that's what we see in our study,” Mushtaq concluded. “What we want to show is that the second-generation BTK inhibitors are lowering the effect of not just AF but also other cardiovascular outcomes. If patients are going to continue ibrutinib, it’s important that we have closer monitoring for these patients.”

Reference

Mushtaq A, Ahmed E, Aljumaa R, et al. Cardiac safety profiles of first-generation vs. second-generation BTK inhibitors: a meta-analysis.Blood. 2024;144(suppl 1):3017. doi:10.1182/blood-2024-202096