Age, BTKi Use May Contribute to Cardiovascular Risk in CLL

Cardiovascular adverse events are a considerable problem for patients being treated for chronic lymphocytic leukemia (CLL), but the existing data on the issue are limited and heterogeneous. Those are among the takeaways of a new literature review published in the journal Critical Reviews in Oncology/Hematology.1

The authors noted that the treatment options for people with CLL have expanded significantly in recent years, with the list of options now including Bruton tyrosine kinase inhibitors (BTKis), the B-cell lymphoma 2 (BCL-2) inhibitor venetoclax (Venclexta; Abbvie and Genentech), and anti-CD20 monoclonal antibodies like rituximab (Rituxan; Genentech and Biogen), ofatumumab (Kesimpta; Novartis), and obinutuzumab (Gazyva; Genentech).

It was difficult to generate strong conclusions from the existing data due to the “sparse and heterogeneous” nature of the cardiovascular data reported in the trials. | Image credit: Tima - stock.adobe.com

However, the authors noted that many of these newer therapies—and BTKis in particular—come with cardiovascular risks.2

“Although BTKis have demonstrated superior progression-free survival outcomes when compared with chemoimmunotherapy in CLL, they have been associated with a risk of adverse CV (cardiovascular) outcomes, such as atrial fibrillation, heart failure, and hypertension,” they noted.

The authors added that, since most people with CLL are diagnosed at an older age, the cardiovascular adverse effects are a particularly worrisome concern, as those patients are also more likely to have multiple comorbidities.

Previous studies have looked at the cardiovascular risks associated with certain classes of therapies, but the authors of the new report said there has not been a comprehensive assessment of cardiovascular outcomes in patients with CLL that compares all of the available therapies.

They therefore conducted a systematic literature review of interventional trials and a targeted literature review of observational studies related to cardiovascular outcomes in patients with CLL. They found a total of 55 interventional trials and 8 pooled analyses for their systematic review and 24 observational studies for their targeted review. All of the studies were published between January 2012 and June 2023. 

The investigators found a mix of results. Interventional trials tended to have limited data related to cardiovascular disease, and what data were available were heterogeneous in nature. For instance, some trials only reported adverse events if they were grade 3 or higher.

Atrial fibrillation was the most consistently reported significant cardiovascular adverse event across the trials, and the incidence of atrial fibrillation was highest among patients receiving the first-generation BTKi ibrutinib (Imbruvica Pharmacyclics and Johnson & Johnson) at 19.9-80.8 cases per 1000 patient years. Other arrhythmias, including tachycardias and bradycardias, were also reported, but the authors said the reporting was inconsistent and the grade of the adverse events was not always available.

Heart failure was less common. Any-grade heart failure rates ranged from 0 to 6.9% across trials that reported heart failure data (the median follow-up ranged from 16.1 to 70 months). Yet, as with atrial fibrillation, the authors said it was difficult to summarize the data because grades were reported heterogeneously and some trials segmented out heart failure into categories like “cardiac failure” and “cardiac failure acute.”

Myocardial infarction rates ranged from 0 to 2.7%, with a median follow-up of 16.1 to 41.6 months. The targeted literature review suggested that cardiovascular risk increased with age and that ibrutinib therapy brought a higher risk of cardiovascular adverse events than chemotherapy.

Given that patients with CLL are typically diagnosed at an older age, by which time many patients have multiple comorbidities, the authors said it was likely that the cardiovascular risk identified in these studies was linked with multiple causal factors.

The investigators said it was difficult to generate strong conclusions from the existing data due to the “sparse and heterogeneous” nature of the cardiovascular data reported in the trials.

“Future research efforts should consistently collect and report baseline CV comorbidities and outcomes, particularly in diseases that predominantly impact older patients with multiple comorbidities,” they wrote.

References

1. Chen YC, Miranda P, Barqawi YK, et al. Cardiovascular safety outcomes of chronic lymphocytic leukemia treatments: A systematic and targeted literature review. Crit Rev Oncol Hematol. Published online August 5, 2025. doi:10.1016/j.critrevonc.2025.104877

2. Fleming MR, Xiao L, Jackson KD, Beckman JA, Barac A, Moslehi JJ. Vascular impact of cancer therapies: the case of BTK (Bruton tyrosine kinase) inhibitors. Circ Res. 2021;128(12):1973-1987. doi:10.1161/CIRCRESAHA.121.318259