Real-World Safety and Effectiveness of Zanubrutinib versus Ibrutinib in CLL: The CLL-ZANU2024 Italian Cohort Open Access

• In a large real-world Italian cohort, zanubrutinib showed significantly lower treatment discontinuation rates compared with ibrutinib.

• Zanubrutinib-treated patients experienced fewer off-target AEs supporting its preferential use than Ibrutinib in CLL with comorbidities.

Bruton tyrosine kinase inhibitors (BTKis) have dramatically changed the therapeutic landscape of chronic lymphocytic leukemia (CLL), with ibrutinib, first-in-class, demonstrating durable efficacy even in high-risk patients. However, off-target adverse events (AEs) have raised concerns, prompting the development of more selective second-generation BTKi, as zanubrutinib, designed to improve tolerability while maintaining efficacy. Despite encouraging results from clinical trials, real-world data comparing zanubrutinib with ibrutinib remain limited. In this multicenter, retrospective study, we analyzed 934 CLL patients treated outside clinical trials, including 393 receiving zanubrutinib and 541 receiving ibrutinib. We evaluated time to treatment discontinuation (TTD) and time to next treatment or death (TTNTD) in both the overall cohort and a propensity score-matched population. Zanubrutinib-treated patients experienced lower 12-month discontinuation rates (overall:12.6% versus 21.4%; matched:12.4% versus 20.2%) and higher 12-month TTNTD rates (overall:91.9% versus 83.0%; matched:93.2% versus 83.4%). Multivariable analyses confirmed zanubrutinib as an independent predictor of longer TTD and TTNTD, while high-risk features, including age, relapsed/refractory disease, Binet stage C, TP53 disruption, ECOG 2-3, and congestive heart failure, were consistently associated with poorer outcomes. AEs leading to discontinuation, particularly atrial fibrillation, bleeding, and infections, were less frequent with zanubrutinib, reflecting its favorable safety profile. These findings provide real-world evidence that zanubrutinib offers more durable disease control and improved persistence compared with ibrutinib, reinforcing its clinical value as a preferred second-generation BTKi. Nevertheless, the relatively short follow-up for zanubrutinib warrants cautious interpretation of long-term outcomes and underscores the need for ongoing observation to fully characterize its durability and safety.