Age and Sex Modify Atrial Fibrillation Risk in BTK Inhibitor-Treated CLL

Among patients with chronic lymphocytic leukemia (CLL) receiving Bruton tyrosine kinase inhibitors (BTKis), the risk of atrial fibrillation (AF) increased with advancing age and was consistently higher in males than in females, according to findings published in Leukemia & Lymphoma.¹

In this retrospective analysis, investigators applied propensity score matching to the TriNetX database, a global federated health research network including both academic medical centers and community hospitals, to construct balanced cohorts of male and female patients with CLL who had received ibrutinib (Imbruvica; n = 5312) or acalabrutinib (Calquence; n = 3110). Outcomes assessed during the first 3 years of BTKi therapy included new-onset AF, hypertension (HTN), and all-cause mortality.

Across both BTKis, the rate of AF during the 3-year observation window rose with increasing patient age and was higher among males than females at every age stratum examined. For ibrutinib-treated patients, the divergence between the highest- and lowest-risk subgroups was particularly pronounced. Nearly 1 in 3 males aged 75 years or older developed AF over 3 years of follow-up compared with fewer than 1 in 10 females aged 18 to 74 years, representing a substantial gradient in absolute risk that has practical implications for clinical decision-making.

The pattern with acalabrutinib followed a similar directional trend, with older males appearing more susceptible to AF than younger females, although the magnitude of these differences across subgroups was not identical to ibrutinib. This finding is consistent with the known pharmacological profile of acalabrutinib, which demonstrates greater BTK selectivity and a generally more favorable cardiovascular toxicity profile than ibrutinib, but suggests that age- and sex-mediated risk stratification remains relevant even with next-generation BTKis.

The study also evaluated HTN and all-cause mortality as secondary outcomes, providing a broader cardiovascular risk profile for each age-sex subgroup within both treatment cohorts.

“These findings are relevant to decision-making about CLL therapy options and, for patients commencing BTKi, determining appropriate cardiovascular assessments before and during therapy,” study authors Abdulrahman Majrashi et al wrote in the publication.¹

Considering Cardiovascular Health in CLL Treatment

The authors noted that these findings should be factored into BTKi selection and management decisions in CLL. In patients who are male and aged 75 years or older, the markedly elevated AF risk identified in the analysis—particularly with ibrutinib—may support preferential use of a more selective second-generation BTKi where clinically appropriate.

For instance, a systematic review demonstrated a lower odds of developing AF with zanubrutinib (Brukinsa), another second-generation BTKi, compared with acalabrutinib, although zanubrutinib was associated with higher odds of severe HTN.² Another study showed the clinical value of zanubrutinib in reducing AF risk vs both ibrutinib and acalabrutinib in patients with B-cell malignancies.³ These findings highlight the importance of weighing competing cardiovascular toxicities when individualizing BTKi therapy.

Accordingly, the differential risks may warrant a more rigorous baseline cardiovascular workup and intensified cardiac monitoring during treatment. Conversely, younger female patients appear to carry substantially lower BTKi-associated AF risk, which may inform more streamlined monitoring strategies in this population.

The investigators also emphasized that these considerations are relevant not only to treatment selection, but also when weighing BTKis against alternative CLL therapies with differing cardiovascular toxicity profiles such as the BCL2 inhibitor venetoclax (Venclexta)-based regimens, particularly in older male patients with preexisting cardiovascular comorbidities.

Taken together, the data reinforce an individualized approach to CLL management that integrates patient-specific cardiovascular risk factors alongside disease biology, treatment history, and patient preference.

REFERENCES

1. Majrashi A, Shantsila A, Gue YX, Williams S, Lip GYH, Pettitt AR. Effect of age and sex on cardiovascular outcomes among patients with chronic lymphocytic leukemia treated with Bruton tyrosine kinase inhibitors: a propensity matched analysis. Leuk Lymphoma. Published online April 11, 2026. doi:10.1080/10428194.2026.2653123

2. Alqassas I, Foroutan F, Lu R, et al. Cardiovascular risk of Bruton’s tyrosine kinase inhibitors: a systematic review and network meta-analysis. J Am Coll Cardiol. 2025;85(12):2506. doi:10.1016/s0735-1097(25)02990-0

3. Munir T, Sportoletti P, Mohseninejad L, et al. Number of patients needed to treat to prevent one atrial fibrillation event with zanubrutinib versus ibrutinib and acalabrutinib in B-cell malignancies. Blood. 2025;146(Supplement 1):8024-8024. doi:10.1182/blood-2025-8024