Acalabrutinib Shows Low Cardiac Toxicity in Clinical, Real-World Data

A new cumulative analysis of clinical trial and post-marketing data is emphasizing a favorable cardiovascular safety profile associated with acalabrutinib in patients with chronic lymphocytic leukemia (CLL). The data, detailed in HemaSphere, showed low rates of cardiac failure in both controlled and real-world settings.1

Despite overall low rates, the study emphasizes that patients with CLL at a high cardiovascular risk, especially those with atrial fibrillation, should be monitored closely during treatment. Still, these findings support acalabrutinib as a safer BTKi alternative when cardiac risk is a concern.

The analysis combined data from 3 major CLL clinical trials—ELEVATE-TN, ELEVATE-RR, and ASCEND—and postmarketing surveillance from a global database. | Image credit: laszlo - stock.adobe.com

Together with other second-generation Bruton tyrosine kinase inhibitors (BTKis), acalabrutinib is designed to be more selective, thus reducing the risk of off-target effects, such as cardiac toxicity, one of the most well-known side effects of the earlier BTKi ibrutinib.

The authors suggested that reduced off-target kinase inhibition with acalabrutinib may account for its more favorable cardiac profile. Inhibition of the PI3K-Akt pathway, which plays a cardioprotective role, has been implicated in BTKi-related cardiotoxicity, a mechanism more strongly associated with ibrutinib.

Cardiac safety, in particular, is a critical consideration in CLL, a disease that mostly affects older adults, often with pre-existing cardiovascular conditions. Data from a previous study have indicated that approximately 1 in 3 patients with CLL present with cardiovascular disease at the time of diagnosis and treatment initiation.2

The analysis combined data from 3 major clinical trials—ELEVATE-TN, ELEVATE-RR, and ASCEND—and postmarketing surveillance from a global database.1

Across the 3 trials, approximately 600 patients received acalabrutinib alone, with exposure-adjusted incidence rates (EAIRs) of cardiac failure compared to those receiving ibrutinib or chemoimmunotherapy (e.g., bendamustine plus rituximab or obinutuzumab plus chlorambucil). In all studies, acalabrutinib-treated patients had numerically lower EAIRs of cardiac failure of any grade and of grade ≥3 compared with comparator arms. When data were pooled across the 3 trials, the EAIR of cardiac failure for acalabrutinib alone was 0.04 per 100 patient-months, confirming the low observed rates.

A sensitivity analysis excluding non-specific terms like “peripheral edema” still showed consistent results, suggesting a true reduction in true cardiac failure events with acalabrutinib.

These data align with earlier pooled trial data of 762 patients, where overall cardiac failure incidence was 0.8% (any grade) and 0.4% (grade ≥3). Notably, this study provides the first cumulative assessment specifically using the Standardized MedDRA Query for cardiac failure.

The postmarketing data showed 727 cardiac failure–related events out of 33,588 patient-years of exposure with acalabrutinib. The EAIR for all-grade cardiac failure was 0.008 per 100 patient-months.

While many events were labeled under broader terms such as “peripheral swelling,” serious events like congestive heart failure and pulmonary edema were rare. Importantly, these findings held even in older, comorbid patients outside the strict eligibility criteria of clinical trials, noted the researchers.

Comparing acalabrutinib’s cardiac failure risk against ibrutinib and chemoimmunotherapy with data from the ELEVATE-RR trial, the EAIR of heart failure was lower with acalabrutinib than with ibrutinib (2.3% vs 3.4% for any grade; 1.9% vs 3.0% for grade ≥3).

Chemoimmunotherapy comparators, such as bendamustine and rituximab, both of which carry known cardiac risks, also showed higher cardiac failure rates compared with acalabrutinib in their respective trials.

"Based on results from this analysis of clinical trials and real-world safety data, the risk of cardiac failure with acalabrutinib monotherapy in patients with CLL/SLL appears to be low," the authors concluded. "Patients at high risk for developing cardiac failure should still be monitored closely while receiving BTKi therapy, especially given the association of these treatments with an increased incidence of atrial fibrillation, which may further increase cardiac failure risk."

References

1. Ghia P, Bajwa N, Corry AJ. Cumulative review of cardiac failure with acalabrutinib in the treatment of chronic lymphocytic leukemia using data from clinical trials and postmarketing experience. HemaSphere. Published online April 22, 2025. doi:10.1002/hem3.70130

2. Larrson K, Mattsson M, Ebrahim F, Glimelius I, Höglund M. High prevalence and incidence of cardiovascular disease in chronic lymphocytic leukaemia: a nationwide population-based study. Br J Haematol. Published online June 9, 2020. doi:10.1111/bjh.16859