Balancing Efficacy and Safety in BTKi Therapy

Bruton tyrosine kinase inhibitors (BTKis) have reshaped treatment for chronic lymphocytic leukemia (CLL), yet cardiovascular (CV) toxicity remains a significant concern with long-term use.1 In a comprehensive expert opinion review published in the European Journal of Haematology, cardio-oncology and hematology specialists evaluate the latest evidence and outline practical strategies to reduce cardiovascular risks associated with BTKi therapy, particularly among older adults with multiple comorbidities and preexisting heart disease.

First-generation ibrutinib has established itself as a backbone for CLL treatment, but the risk of CV complications remains substantial. Data indicate that ibrutinib is associated with a more than fourfold higher risk of CV events, including atrial fibrillation (AF), ventricular arrhythmias (VA), heart failure, and hypertension, compared to untreated CLL cohorts. A pharmacovigilance cohort of 86,370 patients treated with a BTKi reported an overall CV event rate of 10.2% with ibrutinib, 5.7% with acalabrutinib, and 4.7% with zanubrutinib (P = .011). AF occurred in 5.1%, 2.1%, and 1.8%, respectively.

The authors emphasized the importance of multidisciplinary care at diagnosis, especially in elderly patients or those with CV disease, even if asymptomatic, to optimize outcomes and minimize treatment discontinuation. | Image credit: sovova - stock.adobe.com

Extended ambulatory monitoring in 98 patients with CLL revealed arrhythmias developed in 72%, including 16% with incident AF and 14% with ventricular tachycardia. AF burden ≥ 10% was associated with a threefold higher risk of major adverse cardiovascular events (MACE) (HR, 3.12; P = .005) and mortality (HR, 2.97; P = .007). In addition, a U.S. analysis of 1,476 patients suggests “that while the overall incidence of AF was comparable between the two agents, zanubrutinib with respect to acalabrutinib may exhibit an increase in late-­onset AF at longer follow-­up intervals,” the specialists noted. The study reported AF rates of 3.1% at 9 months, 4.2% at 12 months, and 4.0% at 15 months for acalabrutinib, and 2.7%, 4.2%, and 6.1% at the same time points for zanubrutinib.

Hypertension is also a concern. In 562 ibrutinib-treated patients, 78.3% developed new or worsened hypertension over a median 30-month follow-up, while 17.7% experienced grade ≥ 3 elevations (>160/100 mm Hg). A meta-analysis confirmed a 2.82-fold increased risk (P < .001) compared with controls. Comparative trials report grade ≥ 3 hypertension in roughly 9% with acalabrutinib vs 23% with ibrutinib, while zanubrutinib rates (24%) were similar to ibrutinib.

The review attributes AF primarily to off-target Tec kinase inhibition and to PI3K–Akt signaling blockade, which prolong cardiac action potentials and trigger depolarization events. Ibrutinib-mediated interference with HER2-dependent cardiomyocyte stress pathways may further predispose to contractile dysfunction and heart failure, whereas endothelial nitric oxide inhibition contributes to hypertension.

Across studies, the rate of sudden death in ibrutinib-treated patients ranged from 0.49 to 0.788 per 100 patient-years, roughly double that seen in comparators. In contrast, pooled analyses of acalabrutinib trials (n = 1299) show sudden death or VA in 1.2% of patients (0.35 per 100 patient-years).

Useful tools such as the Cumulative Illness Rating Scale and CLL Comorbidity Index help predict overall survival and event-­free survival but lack specificity for BTKi-related toxicities. Older adults, who constitute most patients with CLL, also face amplified risk of toxicities due to multiple comorbidities and polypharmacy that may increase CV risk.2,3 The authors note, “To mitigate these risks and optimize patient outcomes, the integration of CV risk stratification and the adoption of a multidisciplinary care approach are essential, particularly in this vulnerable patient population.”1

Management strategies focus on a thorough baseline evaluation, including electrocardiogram, blood pressure, and echocardiography for patients aged 65 years or with known heart disease, which is recommended before initiating BTKi therapy. Close monitoring during the first 6 months is critical, as most severe cardiac events occur early. The noncovalent BTKi pirtobrutinib shows early promise for patients intolerant to prior covalent BTKi therapy. Early-phase studies show that 75% of patients who discontinued prior covalent BTKis due to AF did not experience recurrence with pirtobrutinib, and discontinuations for cardiac events were rare (5.2%).

The authors provide an expert opinion review and demonstrate that second-generation BTKis have reduced but not eliminated CV toxicity. Ultimately, they emphasize, “Collaborations between oncology and cardiology specialists will be critical to developing comprehensive, multidisciplinary care models.” They further recommend initiating such collaboration at diagnosis, especially in elderly patients or those with CV disease, even if asymptomatic, to optimize outcomes and minimize treatment discontinuation.

References

1. Oliva S, Molica S. Cardiovascular challenges in chronic lymphocytic leukemia (CLL) patients undergoing Bruton tyrosine kinase (BTK) inhibitor therapy. Eur J Haematol. Published online October 21, 2025. doi:10.1111/ejh.70047

2. Rotbain EC, Rostgaard K, Andersen MA, et al. Healthcare utilization and comorbidity in chronic lymphocytic leukemia. Clin Epidemiol. 2021;13:1155-1165. doi:10.2147/CLEP.S337495

3. Brieghel C, Lacoppidan T, Packness E, et al. Polypharmacy independently predicts survival, hospitalization, and infections in patients with lymphoid cancer. Hemasphere. 2025;9(7):e70172. doi:10.1002/hem3.70172