Lower Risk of Cardiovascular Events With Acalabrutinib vs Ibrutinib in CLL in Real-World Study

Building on clinical data, findings from patients receiving treatment with Bruton tyrosine kinase inhibitors (BTKis) in the real world are highlighting an improved heart-related safety profile associated with acalabrutinib (Calquence; AstraZeneca) compared with its earlier counterpart ibrutinib among patients with chronic lymphocytic leukemia (CLL).

Newer, more selective BTKis, such as acalabrutinib and zanubrutinib (Brukinsa; BeiGene), have demonstrated greater tolerability than ibrutinib. Improvements in cardiovascular safety have been demonstrated in several clinical trials, including in the phase 3 ELEVATE-RR trial (NCT02477696) comparing acalabrutinib and the first-generation BTKi.

Among patients in the real-world setting, acalabrutinib was associated with reduced risks of AF or flutter and a reduced risk of hypertension. | Image credit: inthasone - stock.adobe.com

Now, real-world findings are confirming what researchers have found in a clinical setting, with lower rates of certain cardiovascular side effects seen in patients with CLL who were part of a global collaborative network. The study, published in Pharmacology Research & Perspectives, assessed outcomes among approximately 900 patients over a 3-year period.

“By utilizing a large population-level dataset, our study showed that acalabrutinib produces less [atrial fibrillation] and [hypertension] compared to ibrutinib; in doing so, it confirms the findings of the ELEVATE-RR trial in a real-world setting,” the researchers wrote.

Initial data from the ELEVATE-RR trial, published in 2021, showed a lower rate of cardiovascular events with acalabrutinib compared with ibrutinib, including atrial fibrillation (AF) or flutter (9.4% vs 16%, respectively; P = .02).² A 2023 post hoc analysis from the trial confirmed the earlier findings, showing lower rates of cardiovascular events, including AF, hypertension (HTN), and bleeding.³ 

Among patients in the real-world setting, acalabrutinib was associated with a 41% reduced risk of AF or flutter (HR, 0.59; 95% CI, 0.43-0.83; P = .002) and a 35% reduced risk of HTN (HR, 0.65; 95% CI, 0.53-0.81; P < .05). Rates of AF/flutter for the acalabrutinib and ibrutinib were 5.8% and 11.7%, respectively, and rates of HTN were 15% and 26.3%, respectively.

Patients receiving the 2 treatments had similar characteristics, which included age, gender, ethnicity, and coexisting conditions.

Across other outcomes, including heart failure (4.6% vs 5% [HR, 1.13; 95% CI, 0.74-1.73; P = .5]), ventricular arrhythmia (1.1% vs 1.6% [HR, 0.65; 95% CI, 0.27-1.56; P = .3]), bleeding events (2.8% vs 4.7% [HR, 0.76; 95% CI, 0.46-1.25; P = .2]), and all-cause mortality (9% vs 11.9% [HR, 0.98; 95% CI, 0.73–1.30; P = .8]), no significant differences were observed between the 2 BTKis.

Based on their findings, the researchers highlighted the importance of accounting for cardiovascular and bleeding risk when deciding between BTKis.

Notably, available data on zanubrutinib leave a less clear picture of the relative risk of certain cardiovascular side effects, such as HTN, compared with ibrutinib.

“Interestingly, in the ALPINE trial [NCT03734016], which compared ibrutinib with the more selective second-generation BTKi, zanubrutinib, the rate of new-onset HTN was similar in the two treatment arms, whereas grade 3 HTN occurred slightly more frequently in the zanubrutinib arm (14.8% and 11.1%),” wrote the researchers. “ In contrast, in the ASPEN trial, which compared ibrutinib with zanubrutinib in patients with Waldenstrom's macroglobulinemia (WM), a lower incidence of HTN was observed in the zanubrutinib group, but not until at least months of follow-up.”

References

1. Majrashi A, Gue YX, Shantsila A, et al. A comparative analysis of cardiovascular events associated with acalabrutinib versus ibrutinib in chronic lymphocytic leukemia: insights from a global federated network. Pharmacol Res Perspect. 2025;13(3):e70113. doi:10.1002/prp2.70113
2. Byrd JC, Hillmen P, Ghia P, et al. Acalabrutinib versus ibrutinib in previously treated chronic lymphocytic leukemia: results of the first randomized phase III trial. J Clin Oncol. 2021;39(31):3441-3452. doi:10.1200/JCO.21.01210
3. Seymour JF, Byrd JC, Ghia P, et al. Detailed safety profile of acalabrutinib vs ibrutinib in previously treated chronic lymphocytic leukemia in the ELEVATE-RR trial. Blood. 2023;142(8):687-699. doi:10.1182/blood.2022018818