In CLL, Zanubrutinib Shows Better Safety Profile Than Ibrutinib

Zanubrutinib demonstrated a more favorable safety profile than ibrutinib for patients with chronic lymphocytic leukemia (CLL), with fewer serious adverse events (SAEs) and lower rates of treatment discontinuation due to toxicity, according to a study published in Hematological Oncology.¹

Specifically, patients on zanubrutinib experienced fewer hematologic toxicities such as neutropenia and had a reduced incidence of cardiovascular complications like atrial fibrillation and hypertension, making it a potentially safer alternative, especially for patients with a higher risk for treatment-related complications.

Zanubrutinib demonstrated a more favorable safety profile than ibrutinib for patients with CLL. | Image credit: Rawpixel.com – stock.adobe.com

The prospective cohort study included 200 patients with CLL, with 100 receiving ibrutinib and the other 100 receiving zanubrutinib. Researchers tracked AEs, SAEs, and treatment discontinuation rates over the study period. While both of the Bruton's tyrosine kinase (BTK) inhibitors demonstrated comparable efficacy in disease management, there were some notable differences in their safety profiles.

In the study, fewer patients in the zanubrutinib group experienced severe AEs (4% vs 9%) and SAEs (8% vs 17%) compared with the ibrutinib group, though neither of these P values were statistically significant, warranting further research.

Neutropenia—a condition that increases infection risk—was only reported in the ibrutinib group (3%), while no cases occurred in the zanubrutinib group (P = .081). According to the study authors, while this was not statistically significant, it is still clinically meaningful, especially for patients who are older or frailer and need to maintain neutrophil counts.

Treatment’s Effect on Cardiovascular Health

One key finding from the study was the impact of treatment choice on cardiovascular health. Patients who received ibrutinib had higher rates of atrial fibrillation and hypertension, both of which are known limitations of ibrutinib therapy.² In contrast, zanubrutinib was associated with fewer cardiovascular complications, reinforcing its potential advantage for patients at higher risk for these events.¹ However, it’s important to note that more patients in the ibrutinib group had cardiovascular disease, atrial fibrillation, and hypertension at baseline, which could skew results in this area.

According to the authors, these findings echo those of previous studies suggesting zanubrutinib's more selective BTK inhibition may reduce off-target toxicities compared with ibrutinib, such as cardiovascular complications and bleeding events.

Complication Rates and Genetic Factors

Despite its overall favorable safety profile, zanubrutinib was associated with a slightly higher complication rate in certain patient subgroups, particularly those without refractory disease and those with impaired performance status.

Among patients with nonrefractory CLL, complications were more frequent in the zanubrutinib group (11.4%) than the ibrutinib group (5.26%). Additionally, for patients with an Eastern Cooperative Oncology Group (ECOG) performance status of 2, those receiving zanubrutinib had higher complication and SAE rates (13.88%) than those treated with ibrutinib (2.77%). However, for patients with an ECOG status of 3, complication and SAE rates were similar between the treatment groups (5.47%). None of these findings reached statistical significance.

The study also showed that patients with TP53 mutations or chromosome 17p deletions had higher odds of experiencing SAEs regardless of treatment choice, but they were more pronounced in the zanubrutinib arm. (8.46% vs 3.85%).

“These findings align with prior studies highlighting the heightened vulnerability of this subgroup to treatment-related complications,” the authors said. “Importantly, zanubrutinib exhibited a more favorable safety profile, with significantly fewer cardiovascular complications and lower rates of treatment discontinuation compared to ibrutinib. This advantage is consistent with findings from the ALPINE trial.”

While the results suggest zanubrutinib may be the preferable option for many CLL patients, the researchers noted that treatment decisions should be individualized. Ibrutinib may still be a viable—and even preferred—choice for patients with lower performance status or those less susceptible to cardiovascular risks.

“These findings highlight the importance of personalized treatment approaches in the management of CLL, taking into account the individual patient's clinical characteristics, comorbidities, and risk factors,” the authors said.

References

1. Fan F, Liu X, Su Z, et al. Comparative safety of ibrutinib versus zanubrutinib in patients with chronic lymphocytic leukemia: a prospective cohort study.  Hematol Oncol. 2025;43(2):e70041. doi:10.1002/hon.70041
2. Caldeira D, Alves D, Costa J, Ferreira JJ, Pinto FJ. Ibrutinib increases the risk of hypertension and atrial fibrillation: systematic review and meta-analysis.  PLoS One. 2019;14(2):e0211228. doi:10.1371/journal.pone.0211228