Comparing CV Safety and Exploratory Bleeding Outcomes of BTK Inhibitors in Mantle Cell Lymphoma

Bruton tyrosine kinase (BTK) inhibitors have become a mainstay of treatment for relapsed or refractory (R/R) mantle cell lymphoma (MCL), but cardiovascular and bleeding toxicities complicate agent selection.¹ Ibrutinib (Imbruvica; Janssen), the first covalent BTK inhibitor approved for MCL, has long been linked to atrial fibrillation/flutter, hypertension, and bleeding, while second-generation agents acalabrutinib and zanubrutinib were engineered for greater kinase selectivity.²

(Of note, Janssen voluntarily withdrew ibrutinib from the US market in MCL in April 2023.³)

Although head-to-head safety data exist that evaluate BTK inhibitors in chronic lymphocytic leukemia (CLL), direct comparative safety data among ibrutinib, acalabrutinib (Calquence; AstraZeneca), and zanubrutinib (Brukinsa; BeOne Medicines), “specifically in mantle cell lymphoma remain limited,” according to authors led by Anna Homeniuk, MD, a current resident in internal medicine at UPMC Central Pennsylvania, in Harrisburg.⁴

Writing this week in Cancer Medicine, the authors set out to address this gap in real-world evidence using the TriNetX Global Collaborative Network. They built 3 mutually exclusive propensity-score matched cohorts of MCL patients who were treated with ibrutinib, acalabrutinib, or zanubrutinib, excluding anyone with a recorded exposure to an alternate BTK inhibitor.

After 1:1 matching based on demographics, comorbidities, cardiovascular risk factors, anthracycline exposure, and antithrombotic use, the matched groups included the following:⁴

• 738 patients per arm for acalabrutinib versus ibrutinib,
• 522 per arm for zanubrutinib versus ibrutinib, and
• 532 per arm for acalabrutinib versus zanubrutinib.

The primary outcome was newly recorded atrial fibrillation/flutter over 365 days, with heart failure as a secondary outcome and gastrointestinal (GI) bleeding as an exploratory endpoint, plus 180-day sensitivity analyses.⁴

Second-Generation BTK Inhibitors Are Safer

The central finding was a consistent cardiovascular safety advantage for the newer agents, acalabrutinib and zanubrutinib:⁴

• Newly recorded atrial fibrillation/flutter occurred in 4.5% of acalabrutinib patients versus 12.0% of ibrutinib patients, for a risk ratio (RR) of 0.371 and a hazard ratio (HR) of 0.387),
• Newly recorded atrial fibrillation/flutter was seen in 5.0% of zanubrutinib patients versus 12.3% of ibrutinib patients (RR 0.408, HR 0.421).
• Rates were similar between the 2 second-generation drugs, 4.0% versus 5.7% (RR 0.704).
• Results were consistent with the 180-day sensitivity analyses. The authors wrote, “The atrial fibrillation/flutter signal with ibrutinib was already evident within the first 6 months of therapy and persisted through the 365-day analysis window.”
• Heart failure, by contrast, did not differ significantly across any comparison, with wide confidence intervals crossing the null in every pairwise analysis.

GI bleeding, evaluated using a specific hemorrhage-code composite rather than a broad diagnosis code, was higher with ibrutinib than acalabrutinib, 4.3% versus 2.2%, and numerically higher with ibrutinib than zanubrutinib, 4.7% versus 3.3%, though the latter difference was not statistically significant.

Matched output for acalabrutinib versus zanubrutinib bleeding was unavailable, so the authors describe the bleeding findings overall as “exploratory and incomplete across all 3 pairwise comparisons.”

“The clearest comparative safety distinction among these agents in real-world mantle cell lymphoma is the higher arrhythmia signal observed with ibrutinib,” the authors wrote.

They explained the biology behind this result. “Ibrutinib inhibits BTK but also has off-target activity against other kinases, including TEC-family kinases, which may contribute to cardiac electrophysiologic and platelet effects,” they wrote. By contrast, “Second-generation inhibitors such as acalabrutinib and zanubrutinib were designed with greater kinase selectivity, which may contribute to lower observed cardiovascular toxicity.”

The findings align with results from 2 key trials in CLL: ELEVATE-RR, which compared acalabrutinib with ibrutinib,⁵ and ALPINE, which compared zanubrutinib vs. ibrutinib.⁶ Both trials found lower atrial fibrillation/flutter rates with the newer agents.

Clinically, the authors suggest these results “may support preferential consideration of second-generation covalent BTK inhibitors in patients with baseline cardiovascular risk, anticipated anticoagulation needs, older age, or frailty.”⁴ However, the authors cautioned that “efficacy expectations, access, prior therapy, and disease biology remain central to sequencing decisions.” They emphasized that treatment choice should remain individualized.⁴

Limitations Are Noted

The authors noted several limitations. As a retrospective analysis derived from electronic health records, the study can show association but not causation, and the mutually exclusive cohort design necessarily excluded patients who later switched BTK inhibitors; thus, it excluded some at highest risk for treatment-related toxicity. The authors acknowledge that “the findings apply to mutually exclusive single-BTK-inhibitor exposure cohorts and should not be interpreted as an intention-to-treat analysis of all patients initiating a BTK inhibitor.”⁴

Clinical variables such as MIPI score, TP53 status, prior transplant, and dose intensity were unavailable for matching, and no competing-risk model accounted for death or progression. In addition, follow-up was capped at 365 days.

Nonetheless, the authors say their findings support “individualized BTK inhibitor selection in mantle cell lymphoma, particularly among patients with baseline cardiovascular risk,” pending confirmation in prospective, patient-level studies.⁴

References

1. Phillips T, Di M, Miller TA, et al. Real-world comparative effectiveness of Bruton tyrosine kinase inhibitors in relapsed/refractory mantle cell lymphoma. Blood Adv. 2026;10(5):1457-1468. doi: 10.1182/bloodadvances.2025017160
2. Sestier M, Hillis C, Fraser G, Leong D. Bruton's tyrosine kinase Inhibitors and cardiotoxicity: More than just atrial fibrillation. Curr Oncol Rep. 2021;23(10):113. doi: 10.1007/s11912-021-01102-1.
3. Update on IMBRUVICA® (ibrutinib) US accelerated approvals for mantle cell lymphoma and marginal zone lymphoma indications. News release. The Janssen Pharmaceutical Companies of Johnson & Johnson. April 7, 2023. Accessed August 5, 2026. https://www.jnj.com/media-center/press-releases/update-on-imbruvica-ibrutinib-u-s-accelerated-approvals-for-mantle-cell-lymphoma-and-marginal-zone-lymphoma-indications
4. Homeniuk A, Sandhu A, Abdalla L, Atrash A. Comparative cardiovascular safety and exploratory bleeding outcomes of ibrutinib, acalabrutinib, and zanubrutinib in mantle cell lymphoma: a propensity score-matched real-world analysis,” Cancer Med. 2026;15(8):e72111, https://doi.org/10.1002/cam4.72111.
5. 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.
6. Brown JR, Eichhorst B, Hillmen P, et al. Zanubrutinib or ibrutinib in relapsed or refractory chronic lymphocytic leukemia. N Engl J Med. 2023;388(4):319-332. doi: 10.1056/NEJMoa2211582.