Baseline Cardiovascular Assessment, Monitoring Are Crucial With BTK Inhibitors in CLL and Other Hematologic Malignancies

BTK inhibitors were associated with a clinically meaningful incidence of cardiovascular adverse effects (CVAEs), including hypertension, atrial fibrillation, and hemorrhage, according to findings from a meta analysis presented at the 2025 SOHO Annual Meeting, evaluating 5 BTK inhibitors across 25 clinical trials conducted between 2015 and 2024.1

The analysis included 2,956 patients treated with ibrutinib (Imbruvica), acalabrutinib (Calquence), zanubrutinib (Brukinsa), pirtobrutinib (Jaypirca), or nemtabrutinib in phase 1 through phase 4 studies, which included patients with chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), mantle cell lymphoma, and marginal zone lymphoma. Using a random-effects model, investigators calculated pooled event rates and 95% confidence intervals to estimate the overall incidence and spectrum of CVAEs.

Findings demonstrated that ibrutinib (n = 442) was associated with the highest cardiovascular toxicity, with hypertension observed in 20% (95% CI, 3%-29%) of patients and atrial fibrillation in 8.9% (95% CI, 6.0%-13.2%). In comparison, acalabrutinib (n = 1001) demonstrated a lower rate of hypertension at 11% (95% CI, 7%-17%); hemorrhage was reported 14% (95% CI, 0%-95%) of patients, and 14% (95% CI, 1%-75%) experienced bleeding. Zanubrutinib (n = 938) was associated with a hypertension rate of 10% (95% CI, 6%-17%) and a hemorrhage rate of 34% (95% CI, 16%-59%) of patients. Pooled data across all BTK inhibitors indicated an overall incidence of 14% (95% CI, 11%-17%) for hypertension, 6% (95% CI, 5%-8%) for atrial fibrillation, and 28% (95% CI, 15%-47%) for hemorrhage.

“BTK inhibitors are associated with a clinically meaningful incidence of CVAEs, particularly hypertension, atrial fibrillation, and hemorrhage,” lead study author Norayr Mkrtchyan, a medical student at the School of Medicine at the University of California, Davis, Sacramento, and colleagues wrote in a poster presentation of the data. “Although rates are lower than those historically seen with ibrutinib, baseline cardiovascular risk assessment and close monitoring remain important with second-generation BTK inhibitors.”

How Was the Meta Analysis Designed?

The study employed a systematic review and meta-analysis approach to evaluate the incidence and spectrum of CVAEs associated with BTK inhibitors.

A systematic literature review identified 25 monotherapy trials conducted between 2015 and 2024 that investigated five BTK inhibitors: ibrutinib, pirtobrutinib, zanubrutinib, nemtabrutinib, and acalabrutinib. The pooled dataset included a total of 2,956 patients. Among the included studies, there were 3 phase 1, 9 phase 2, 7 phase 3, and 6 phase 4 trials. Specifically, ibrutinib was evaluated in 5 trials (n = 442), pirtobrutinib in 1 trial (n = 323), zanubrutinib in 8 trials (n = 938), nemtabrutinib in 2 trials (n = 242), and acalabrutinib in 9 trials (n = 1001).

The meta analysis was conducted using the R meta package, applying a random-effects model to calculate pooled proportions and 95% confidence intervals. Statistical heterogeneity across studies was assessed using the I² statistic.

The primary outcome was the pooled incidence of CVAEs, including atrial fibrillation, hypertension, hemorrhage, angina, bleeding, and cardiovascular insufficiency. Secondary analyses assessed individual drug-level cardiovascular risk patterns.

What Were the Limitations of the Study? Are There Future Steps Planned for this Analysis?

Study authors highlighted several key limitations that should be considered when interpreting the findings. First, there was substantial heterogeneity across the included trials, which may be attributed to differences in study design, patient populations, treatment durations, and, notably, non-standardized reporting of CVAEs. This variability may have influenced the pooled incidence rates and limited the precision of cross-trial comparisons.

Additionally, the availability of trial data for newer BTK inhibitors, such as pirtobrutinib and nemtabrutinib, was limited. Pirtobrutinib was the BTK inhibitor most recently approved in the United States, earning accelerated approval from the FDA in 2023 for the treatment of adult patients with CLL or SLL who have received at least 2 prior lines of therapy, including a BTK inhibitor and a BCL2 inhibitor.2 The small number of studies and patient samples for these agents restricts the generalizability of the results, making it difficult to draw definitive conclusions regarding their cardiovascular safety profiles.1 As these agents gain wider clinical use, further investigation with larger, standardized datasets will be necessary to clarify their long-term cardiovascular risks relative to first- and second-generation BTK inhibitors.

“[Moving forward, it will be important to conduct] analysis of real-world data to view CVAEs in [broader] and more diverse patient populations,” Mkrtchyan added.

References

1. Mkrtchyan N, Dermarderosian A, Jones D, et al. Exploring side effect profile of Bruton tyrosine kinase inhibitors on the cardiovascular system. Presented at: 2025 SOHO Annual Meeting; September 4-7, 2025; Houston, TX. Abstract CLL-1240.
2. FDA grants accelerated approval to pirtobrutinib for chronic lymphocytic leukemia and small lymphocytic lymphoma. FDA. December 7, 2023. Accessed October 13, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-pirtobrutinib-chronic-lymphocytic-leukemia-and-small-lymphocytic