Comparative Cardiac Safety of Covalent and Non-Covalent Bruton Tyrosine Kinase Inhibitors in Mantle Cell Lymphoma – A Multi-Center Retrospective Cohort Study

A Anand¹; S Biswas²; K Anmol³; S Sapkota⁴; Y Srivastava²

¹ Jacobi Medical Center / Albert Einstein College of Medicine, Bronx, NY, USA
² Ivano-Frankivsk National Medical University, Ivano-Frankivsk, Ukraine
³ University of Michigan Health Sparrow, Lansing, MI, USA
⁴ Baptist Memorial Hospital–North Mississippi, Oxford, MS, USA

Second-generation BTK inhibitors (BTKi), including acalabrutinib and zanubrutinib, and the non-covalent BTKi pirtobrutinib are increasingly used in mantle cell lymphoma (MCL). Much of their safety data has been extrapolated from trials in other B-cell malignancies, including ELEVATE-RR, ALPINE, and ASPEN. We evaluated the comparative cardiovascular, infectious, and bleeding risks of BTKi therapy in patients with MCL in a real-world setting.

To compare the 1-year risks of cardiac, infectious, and major bleeding events among different BTKi regimens in patients with MCL.

Design: Multicenter retrospective cohort study using the TriNetX Global Collaborative Network.

Population: Adults with MCL diagnosed between 2018 and 2025.

Exposure: Patients were stratified by first BTKi exposure with no prior exposure to an alternative BTKi agent within 1 year before the index date.

Comparisons following 1:1 PSM:

1. Acalabrutinib vs ibrutinib

2. Zanubrutinib vs ibrutinib

3. Acalabrutinib vs zanubrutinib

4. Pirtobrutinib vs pooled second-generation BTKi

PSM factors: Demographics, comorbidities, and prior medication use.

Primary outcome: Composite of atrial fibrillation, hypertension, heart failure, and ventricular arrhythmia.

Secondary outcomes: Infections (sepsis, invasive fungal infection, herpes zoster) and major bleeding (intracranial hemorrhage, gastrointestinal bleeding) within 1 year of BTKi initiation.

Post-PSM matched cohort sizes (per comparison):

• Acalabrutinib vs ibrutinib: 531 vs 531

• Zanubrutinib vs ibrutinib: 254 vs 254

• Acalabrutinib vs zanubrutinib: 475 vs 475

• Pirtobrutinib vs pooled second-generation BTKi: 190 vs 190

Comparison	Cardiac composite HR (95% CI)	Infections HR (95% CI)	Major bleeding HR (95% CI)
Acalabrutinib vs ibrutinib	0.86 (0.73–1.02)	0.88 (0.67–1.16)	0.82 (0.53–1.29)
Zanubrutinib vs ibrutinib	0.95 (0.75–1.20)	0.83 (0.56–1.23)	0.97 (0.54–1.73)
Acalabrutinib vs zanubrutinib	0.84 (0.71–1.00)	0.97 (0.72–1.31)	0.70 (0.42–1.14)
Pirtobrutinib vs pooled 2nd-generation BTKi	1.33 (1.00–1.77)	1.56 (1.03–2.36)	1.66 (0.78–3.56)

HR >1 favors the comparator; HR <1 favors the first agent.

Acalabrutinib vs ibrutinib: No significant differences in cardiac, infectious, or major bleeding outcomes.

Zanubrutinib vs ibrutinib: No significant differences in cardiac, infectious, or major bleeding outcomes.

Acalabrutinib vs zanubrutinib: No significant differences in cardiac, infectious, or major bleeding outcomes.

Pirtobrutinib vs pooled second-generation BTKi: Higher infections (HR 1.56, 95% CI 1.03–2.36) and borderline increased cardiac outcomes (HR 1.33, 95% CI 1.00–1.77), without a significant difference in major bleeding (HR 1.66, 95% CI 0.78–3.56).

Second-generation BTKi did not demonstrate significantly improved cardiovascular, infectious, or bleeding safety profiles compared with ibrutinib in patients with MCL within 1 year of therapy initiation.

Pirtobrutinib was associated with higher cardiac and infectious complications compared with pooled second-generation BTKi, although interpretation is limited by the smaller sample size and shorter follow-up.

We thank the TriNetX team and participating institutions for providing access to the real-world data used in this study.

1. Shadman M, et al. ELEVATE-RR: Acalabrutinib in relapsed/refractory CLL. N Engl J Med. 2020;382:2185–2196.

2. Tam CS, et al. ALPINE: Zanubrutinib vs ibrutinib in R/R CLL/SLL. Lancet Oncol. 2022;23:1031–1043.

3. Fraser G, et al. ASPEN: Pirtobrutinib in previously treated B-cell malignancies. Blood. 2021;138:203.

Aditya Anand, MD
Internal Medicine Resident
Jacobi Medical Center / Albert Einstein College of Medicine
Email: ananda5@nychhc.org