Incidence of Atrial Fibrillation (AF) in Chronic Lymphocytic Leukemia (CLL) Patients: A Real-World Retrospective Comparison of Ibrutinib and Acalabrutinib
Authors: Murru Roberta , Innocenti Idanna , Galitzia Andrea , Tomasso Annamaria , Chessa Caterina , Murineddu Marco , Fresa Alberto , Oggianu Valeria , Autore Francesco , Mosca Antonio , Caocci Giovanni , Palmas Angelo D. , La Nasa Giorgio , Laurenti Luca 
Published: December 2024

Background: Bruton tyrosine kinase inhibitors (BTKi), such as ibrutinib and acalabrutinib, are pivotal in treating chronic lymphocytic leukemia (CLL). However, they exhibit different risks of atrial fibrillation (AF), greater in the first year of treatment. Data from real-world settings are scarce, particularly in evaluating differences in AF incidence. Additionally, literature data are mostly on relapsed/refractory (RR) patients. This study aimed to compare the incidence of AF between these drugs in a real-life setting, assessing the impact of treatment and patient characteristics on AF risk.

Methods: A retrospective analysis was conducted, in three Italian centers, on 184 CLL patients treated, for at least six months, with ibrutinib (n° 104) or acalabrutinib (n° 80), between 2014 and 2023 and 2020 to 2023, respectively. Patient demographic, biological, and clinical data were collected, including age, sex, baseline cardiovascular conditions, echocardiographic findings, and prior treatment history. The incidence of AF was assessed at various time points using the Kaplan-Meier method. Log-rank tests were used to compare groups. Multivariable Cox regression analyses were conducted to identify predictors of AF.

Results: The gender distribution was similar between groups, with an expected higher percentage of males overall. Patients on acalabrutinib were older at treatment initiation (mean age 72.8 years) compared to those on ibrutinib (mean age 69.2 years) (p=0.01). Patients on acalabrutinib had fewer previous treatment lines, with 77.5% treatment-naïve (TN) in the acalabrutinib group versus 39.4% in the ibrutinib group (p&lt;0.001).The median follow-up was 40.9 months for ibrutinib and 15.6 months for acalabrutinib. Echocardiographic findings revealed no significant differences in valvular insufficiency, atrial dilatation, or other abnormalities between the groups. Prior history of arrhythmia was comparable. Overall, 24 AF events occurred during the follow-up: 19 in patients on ibrutinib and 5 on acalabrutinib, accounting for 5 cases per 100 patient-years in both groups (p=0.98). At six months, the cumulative incidence of AF was 1.6% for acalabrutinib and 5.8% for ibrutinib, increasing to 4.4% and 9.2% at 12 months, and to 8.9% and 16% at 24 months, respectively (p=0.36). Treatment was temporarily interrupted in 6 cases of AF occurrence and permanently discontinued in 4; all patients received full anticoagulation after AF occurrence. Significant predictors for AF included dilated atria, a previous history of arrhythmia, and the number of previous treatments, which markedly increased AF risk and retained their significance in multivariable analysis (p=0.001, p=0.021, and p=0.006, respectively). Haemorrhage occurred in 38 patients (7 on anticoagulation due to AF), mostly of limited grade (median grade 2 CTCAE, range 1-5), with one fatal case in a patient on acalabrutinib. Given the unbalanced distribution in the number of previous treatment lines between acalabrutinib and ibrutinib, we focused distinctively on TN and RR patients. For treatment-naïve patients, the cumulative incidence of AF was 1.6% at both six and twelve months and 4.5% at 24 months for acalabrutinib, while for ibrutinib it was 2.4%, 5.1%, and 11.2%, respectively (p=0.36). Among RR patients the cumulative incidence of AF was 0%, 14.3%, and 28.6% for acalabrutinib, and 8%, 11.4%, and 19.1% for ibrutinib, respectively (p=0.526). AF occurrence did not negatively impact overall survival, which was comparable between the two groups.

Conclusions: Although the cumulative incidence of AF was slightly higher in the ibrutinib group, the lack of significant differences suggests that the inherent risk of AF may be comparable for both drugs, particularly in the TN setting, according to a specific class-effect profile. Indeed, significant predictors for AF include atrial dilatation, prior history of arrhythmia, and the number of prior treatments, but not the specific BTKi molecule. This study highlights the need for further research with balanced follow-up periods, baseline characteristics and larger sample sizes, to fully understand the long-term risks of AF associated with BTKi and to guide more personalized patient management strategies.