Comparative Safety of Ibrutinib Versus Zanubrutinib in Patients With Chronic Lymphocytic Leukemia: A Prospective Cohort Study

ABSTRACT This study compares the safety profiles of two Bruton's tyrosine kinase (BTK) inhibitors, Ibrutinib and Zanubrutinib, in patients with chronic lymphocytic leukemia (CLL). While Ibrutinib has transformed CLL treatment, it is associated with significant adverse events (AEs). Zanubrutinib, a second‐generation BTK inhibitor, offers potential for improved safety. In this prospective study, 200 CLL patients were enrolled, with 100 receiving Ibrutinib and 100 receiving Zanubrutinib. Baseline characteristics such as age, sex, body mass index (BMI), Eastern Cooperative Oncology Group (ECOG) performance status, and genetic factors were evaluated. AEs and serious AEs (SAEs) were tracked and graded using the Common Terminology Criteria for Adverse Events (CTCAE). Multivariate logistic regression models were conducted to determine predictors of SAE and AEs grade ≥ 3. Adjusted odds ratio (aOR) and 95% confidence interval (CI) were reported. The mean ages of the Ibrutinib and Zanubrutinib groups were 49.65 and 49.16 years, respectively ( p = 0.285). The Zanubrutinib group had a higher percentage of patients with worse ECOG status (71% vs. 57%, p = 0.039). Fewer Zanubrutinib patients experienced severe AEs (4% vs. 9%, p = 0.152) or SAEs (8% vs. 17%, p = 0.054). Neutropenia occurred only in the Ibrutinib group (3%). Subgroup analysis showed a higher complication rate with Zanubrutinib in non‐refractory patients (11.40% vs. 5.26%, p = 0.065). Stage III CLL was a protective factor of grade ≥ 3 AEs (aOR = 0.007; 95% CI: 0.0003–0.1829) and SAE (aOR = 0.015; 95% CI: 0.001–0.177). While ECOS status (2 vs. 3) resulted in reduced risk of SAE, chromosome 17p deletion emerged as the main risk factor of SAE (aOR = 6.40; 95% CI: 1.33–30.79). Zanubrutinib demonstrated a more favorable safety profile than Ibrutinib, with fewer severe adverse events. It may be a safer alternative for CLL patients, particularly those at higher risk for complications from BTK inhibitors. However, these differences stemmed from variability in baseline clinical characteristics rather than the interventions themselves.