Cardiovascular events and bleeding in patients with chronic lymphocytic leukemia treated with first- and second-generation Bruton tyrosine kinase inhibitors

Introduction. Therapy with Bruton tyrosine kinase inhibitors is associated with an increased risk of cardiovascular complications including atrial fibrillation and arterial hypertension and elevated risk of bleeding events. However, there is still little data regarding both the real-world frequency and phenotypic presentation of cardiovascular complications during BTK inhibitor therapy, as well as the long-term prognosis of patients experiencing these events.

Aim. To compare the incidence of cardiovascular complications and hemorrhagic events, and to evaluate their prognostic significance in patients with chronic lymphocytic leukemia (CLL) receiving ibrutinib versus acalabrutinib.

Materials and Methods. This retrospective study included 710 patients with CLL: 605 patients received ibrutinib, 69 received acalabrutinib and 36 received ibrutinib and were subsequently switched to acalabrutinib for various reasons. A comparative analysis was performed between the groups of patients treated with either ibrutinib or acalabrutinib. To eliminate the influence of age and sex as major risk factors for cardiovascular complications, a matching-adjusted indirect comparison (MAIC) was conducted, with patients in the groups matched for age and sex. The primary endpoint of the study was atrial fibrillation (AF). Additionally, the following events were recorded: decompensated heart failure (HF), arterial hypertension (AH) and bleeding. To evaluate outcomes, a composite endpoint of prognostic events was used, comprising thrombotic complications, clinically significant bleeding, and cardiovascular death. The incidence of AF, AH and HF was assessed among surviving patients.

Results. Acalabrutinib was associated with an eightfold reduction in the risk of new-onset AF (22 % for ibrutinib vs. 3.4 % for acalabrutinib; OR 0.12; 95 % CI: 0.02–0.54; р = 0.006). The incidence of AH and HF was comparable between the two drugs. Comparative analysis revealed a five-fold reduction in the risk of prognostic events in patients receiving acalabrutinib (RR 0.214; 95 % CI: 0.051–0.907; р = 0.036). When evaluating the structure of prognostic events, the differences between groups were driven by a higher incidence of thrombotic complications: ischemic stroke (10 % with ibrutinib vs. 1.5 % with acalabrutinib; p = 0.033) and venous thrombosis (15 % with ibrutinib vs. 6 % with acalabrutinib; р = 0.061), while the incidence of bleeding remained comparable.

Conclusion. Patients receiving acalabrutinib exhibited an eight-fold reduction in the risk of developing AF. When assessing the long-term prognosis, acalabrutinib therapy was associated with a five-fold decrease in the risk of prognostic events due to a lower incidence of thrombotic complications, while the frequency of bleeding remained comparable.

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