Bruton tyrosine kinase inhibitor-related atrial fibrillation and its implications in the treatment of B-cell lymphoma

Abstract

Adverse events of atrial fibrillation (AF) have been commonly reported in lymphoma patients in treating Bruton's tyrosine kinase inhibitors (BTKi). The incidence rate of AF can vary depending on the specific types of BTKi and the patient population. Totally 45 published studies have revealed that the overall incidence rate of AF is 5% (95% CI 4%-7%). By performing a subtype single-rate analysis, the second-generation BTKi shows a lower AF incidence rate and lower cardiovascular toxicity. In the subtype single-rate analysis, we conclude the different AF incidence rates of Ibrutinib (10%, 95% CI 7%-13%), Acalabrutinib (4%, 95% CI 1%-6%), Orelabrutinib (0%, 95% CI 0%-1%), and Zanubrutinib (0%, 95% CI 0%-1%). The comprehensive analysis of AF inspires us to better predict and manage AF and other cardiovascular events in treating lymphoma. Meticulous evaluation, collaboration between cardiologists and hematologists, and discovery of new biomarkers are essential for its management.

Keywords: Bruton tyrosine kinase inhibitors; Ibrutinib; atrial fibrillation; cardiovascular toxicity; lymphoma.

Figure 1

Flow diagram of the study. The diagram of the study shows the inclusion and exclusion criteria and a specific number of studies we obtained from different sources. We set atrial fibrillation and corresponding BTK inhibitors as keywords to exclude non-clinical trial studies and reviews. Eventually, 45 studies in different BTK inhibitors were taken into further research.

Figure 2

Forest plots of the included studies of atrial fibrillation or flutter occurrence rate and sub-type analysis. Through the single-rate analysis of AF incidence, we determined the AF incidence rates for Ibrutinib (10%, 95% CI 7%–13% in random effects model), Acalabrutinib (4%, 95% CI 1%–6% in random effects model), Orelabrutinib (0%, 95% CI 0%–1% in common effects model), Zanubrutinib (0%, 95% CI 0%–1% in common effects model), and overall AF incidence rate (5%, 95% CI 4%–7% in random effects model).

Figure 3

The risk factors, adverse events, and interventions of BTKi-related atrial fibrillation in the treatment of lymphoma. BTK inhibitors are related to different cardiovascular adverse events including AF (5%), hypertension (14.8%), and heart failure (4.6%). It is related to different receptors like BTK, EGFR, and TEC expressed by myocardial cells and vascular endothelial cells. Risk factors and evaluation methods like CHA2DS2-VASc and HAS-BLED are taken to evaluate its interventions. Dosage adjustment or anticoagulants are common clinical measures, and a healthy lifestyle and continuous monitoring are advised to manage risk factors, hypertension, and diabetes. Patients with an AF history are highly risky for BTKi-related AF and require special monitoring and decisions.