Real-World Data Shows Less Afib, All-Cause Mortality With Zanubrutinib Than Ibrutinib in B-Cell Malignancies

Bruton tyrosine kinase (BTK) inhibitors are now cornerstone treatments for a range of B-cell malignancies, from chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) to mantle cell lymphoma (MCL). However, the arrival of these agents was associated with well-documented cardiovascular toxicities. This was especially true with the first agent, ibrutinib (Imbruvia; Janssen/AbbVie), with which patients experienced atrial fibrillation/flutter (AF/AFL) major bleeding events, and ventricular arrhythmia.¹

In both the ALPINE trial in CLL/SLL² and the ASPEN trial in Waldenström macroglobulinemia,³ ratesof AF/AFL were higher with ibrutinib than with zanubrutinib.^2,3

The emergence of second-generation BTK inhibitors, such as zanubrutinib (Brukinsa; BeOne Medicines) raised the possibility of achieving comparable anti-tumor efficacy with a more favorable cardiovascular safety profile. A new study published this month in the American Journal of Cardiology in May 2026, directly compares the real-world cardiovascular outcomes of these 2 agents in a large, propensity-matched patient cohort.⁴

Zanubrutinib is FDA-approved in multiple indications: for adults with CLL/SLL, for Waldenström’s macroglobulinemia (WM), relapsed/refractory mantle cell lymphoma (MCL), relapsed/refractory marginal zone lymphoma (MZL), and, in combination with obinutuzumab, relapsed/refractory follicular lymphoma. In MCL, it is a preferred treatment option (Category 2A) in the NCCN guidelines for relapsed/refractory MCL. Sponsors of ibrutinib voluntarily withdrew approval of ibrutinib’s accelerated approval in MCL and MZL in April 2023.⁵

Who Are the Patients in This Study?

The researchers conducted a retrospective, multicenter cohort study using data from the TriNetX Global Collaborative Network, a large real-world database. The study enrolled adults aged 18 years and older diagnosed with 1 of 5 B-cell malignancies: CLL /SLL, MCL, follicular lymphoma, WM, or MZL. All patients were initiating treatment with either zanubrutinib or ibrutinib.

To ensure comparability between groups, patients with pre-existing atrial fibrillation or flutter (AF/AFL) were excluded from the analysis. Rigorous propensity score matching was applied on a 1:1 ratio across 41 clinical and demographic covariates, resulting in 3447 well-balanced pairs. The primary analysis window was the 12 months following initiation of a BTK inhibitor, and outcomes were evaluated using Cox proportional hazard models, with statistical significance set at P < .05.

What Was the Surprising Finding About Survival?

The study found that compared with ibrutinib users, patients treated with zanubrutinib demonstrated a 53% lower risk of developing new-onset atrial fibrillation or flutter (HR = 0.47; 95% CI: 0.38–0.58; P < .001). This is a clinically meaningful reduction, given that AF/AFL is among the most common and troublesome adverse effects associated with BTK inhibitor therapy. Zanubrutinib was also associated with a 21% lower risk of major bleeding events (HR = 0.79; 95% CI: 0.68–0.91; P = .001), which carries significant implications for patient safety and quality of life.

Finally, results showed a dramatic reduction in all-cause mortality among zanubrutinib users, who had a 73% lower risk of death compared to those on ibrutinib (HR = 0.27; 95% CI: 0.15–0.48; P < .001). Study authors said the magnitude of this mortality benefit warrants further investigation to understand the underlying mechanisms.

The cohorts showed no statistically significant differences in several other serious cardiovascular endpoints, including intracranial hemorrhage, ischemic stroke, myocardial infarction, ventricular arrhythmias, new-onset heart failure, and new-onset hypertension.

What Do These Findings Mean?

Having a large-world analysis offers evidence that zanubrutinib offers a safer option for patients over ibrutinib, particularly with respect to cardiovascular effects such as AF/AFL, and major bleeding. The finding that zanubrutinib offered an overall survival benefit merits further study.

The authors conclude that when cardiovascular safety is a priority—such as in older patients or those with underlying cardiac risk factors—zanubrutinib should be the preferred BTK inhibitor. These real-world data support findings from clinical trial data as well as evolving treatment guidelines that favor second-generation BTK inhibitors in appropriate patient populations, the authors concluded.

References

1. Brown JR, Moslehi J, O'Brien S, et al. Characterization of atrial fibrillation adverse events reported in ibrutinib randomized controlled registration trials. Haematologica. 2017 Oct;102(10):1796-1805. doi: 10.3324/haematol.2017.171041
2. Tam CS, Shadman M, Ong SY, et al. Zanubrutinib versus ibrutinib in patients with relapsed/refractory chronic lymphocytic leukemia and small lymphocytic lymphoma: health-related quality of life in a subgroup of Chinese patients in the ALPINE trial. Curr Med Res Opin. 2026;42(1):139-146. doi: 10.1080/03007995.2026.2623629.
3. Dimopoulos MA, Opat S, D'Sa S, et al. Zanubrutinib versus ibrutinib in symptomatic Waldenström macroglobulinemia: final analysis from the randomized phase III ASPEN study. J Clin Oncol. 2023;41(33):5099-5106. doi: 10.1200/JCO.22.02830.
4. Qamar U, Imtiaz Z, Jan MH, et al. Comparative risk of adverse cardiovascular outcomes with zanubrutinib vs ibrutinib in B-cell malignancies: A large real-world propensity-matched analysis. Am J Cardiol. 2026:S0002-9149(26)00318-8. doi: 10.1016/j.amjcard.2026.04.064.
5. Lipfert C, Kim MS, Haslam A, Prasad VK. Recall of ibrutinib and issues with therapeutic approval. BMJ Oncol. 2024;3(1):e000418. doi: 10.1136/bmjonc-2024-000418.