Zanubrutinib Demonstrates Favorable Tolerability in R/R CLL/SLL

Zanubrutinib (Brukinsa; BeOne) is associated with low rates of treatment discontinuation and atrial fibrillation in patients with relapsed or refractory (R/R) chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL), supporting its tolerability in clinical trial settings, according to a new systematic review and meta-analysis. The authors, however, note that long-term and real-world safety monitoring remains necessary.

The findings, published in Pharmaceuticals,¹ offer the first dedicated quantitative synthesis of zanubrutini’s safety profile in this patient population.

Zanubrutinib is a next-generation Bruton’s tyrosine kinase (BTK) inhibitor approved in the US, China, and the European Union for the treatment of CLL and in the US and China for SLL.² It was designed to improve on the selectivity limitations of first-generation agents like ibrutinib (Imbruvica; Pharmacyclics/Johnson&Johnson), which inhibits numerous off-target kinases, including TEC family kinases, EGFR, and Src family kinases, and has been associated with cardiovascular toxicities such as atrial fibrillation and hypertension. Zanubrutinib’s higher BTK selectivity was intended to reduce these off-target effects while maintaining therapeutic efficacy.

The investigators searched PubMed, Scopus, Web of Science, and MEDLINE for clinical trials published through August 2025 that reported treatment-emergent adverse events (TEAEs) in patients with R/R CLL/SLL receiving zanubrutinib. Pooled incidence estimates were calculated using a random-effects model (DerSimonian and Laird method). Four studies met the inclusion criteria: the phase 3 ALPINE trial (NCT03734016), a phase 1/2 multicenter open-label study conducted in Japan (NCT04172246), a phase 2 single-arm US trial enrolling patients intolerant of prior BTK inhibitors (NCT04116437), and a phase 2 multicenter study from China (NCT03206918). Together, these trials encompassed 508 patients, with median follow-up durations ranging from 15.1 to 34.5 months.

What the Results Say

Most patients in the pooled analysis (98.5%) experienced at least 1 TEAE, a finding the authors described as expected in heavily pretreated populations. Adverse events of at least grade 3 occurred in 67.0% of patients, and serious AEs were reported in 32.2%.

Despite the high overall incidence of AEs, treatment discontinuation due to toxicity was noticeably low, occurring in just 7.2% of patients. Further, AE-related mortality was observed in 7.1% of patients, although the authors noted significant heterogeneity in this estimate across studies, likely reflecting differences in patient comorbidity burden and disease stage.

Among hematological AEs, neutropenia was the most common (32.1%), followed by anemia (26.7%). Bleeding events of any grade occurred in 51.9% of patients, but most of these were mild to moderate, with major bleeding leading to discontinuation or death being a rare outcome. Nonhematological adverse events included upper respiratory tract infections (27.2%), pneumonia (19.4%), and hypertension (16.4%). Atrial fibrillation, a toxicity of particular concern with ibrutinib, occurred in only 2.9% of patients, with no significant heterogeneity observed across studies.

Real-World Implications

The authors contextualized zanubrutinib’s safety profile against that of earlier BTK inhibitors. In the RESONATE (NCT01578707) and RESONATE-2 (NCT01722487) ibrutinib trials, hypertension was reported in 20% to 26% of patients and atrial fibrillation in 11% to 16%, with treatment discontinuation due to AEs reaching 12% to 28% at extended follow-up. By comparison, the ALPINE trial showed that patients with R/R CLL who received zanubrutinib had fewer discontinuations due to AEs (15% vs 22%) and fewer instances of atrial fibrillation or flutter (5% vs 13%) relative to ibrutinib.

The authors attributed zanubrutinib’s more favorable cardiovascular profile to its reduced binding to off-target kinases. When tested against a panel of 370 kinases, zanubrutinib inhibited only 7 off-target kinases compared with 17 for ibrutinib and 15 for acalabrutinib.

The review’s authors acknowledged several limitations to their analysis, including the small number of included studies, inconsistent AE reporting across trials, and follow-up periods that may be insufficient to capture long-term or delayed toxicities, such as secondary malignancies or late cardiac events. The majority of included trials were also open-label and single-arm, which may introduce selection and reporting bias.

The authors concluded that zanubrutinib represents a well-tolerated option for patients with R/R CLL, particularly those with preexisting cardiovascular comorbidities or those who are intolerant of earlier BTK inhibitors. “While nearly all patients experience at least 1 AE, severe or treatment-limiting toxicities remain infrequent,” they said, “and treatment discontinuations due to adverse events are low.”

Still, they also call for larger randomized trials with extended follow-up to further characterize zanubrutinib’s long-term safety.

References

1. Hetta HF, Salama A, Aljuaid TA, et al. Is Brukinsa (zanubrutinib) a safer Bruton's tyrosine kinase (BTK) inhibitor in relapsed or refractory chronic lymphocytic leukemia? a systematic review and meta-analysis. Pharmaceuticals (Basel). 2026;19(3):467. doi:10.3390/ph19030467
2. Brukinsa (zanubrutinib). Prescribing information. BeOne; 2025. Accessed April 3, 2026. https://brukinsahcp.com/