Enrica Antonia Martino, Annalisa Pitino, Ernesto Vigna, Raffaella Pasquale, Isacco Ferrarini, R. Moia, Andrea Visentin, A. Sanna, Marina Pamponet Motta, Massimo Moratti, Paolo Sportoletti, Annalisa Chiarenza, Alessandro Maggi, Valentina Zammit, Michele Merli, Idanna Innocenti, C. Giordano, Laura Nocilli, Massimiliano Postorino, Caterina Stelitano, Andrea Ferrario, A. M. Frustaci, Marcello Riva, Sara Pepe, Adalberto Ibatici, Stefania Scardino, Paola Anticoli Borza, Laura Ballotta, Salvatrice Mancuso, Francesco Malaspina, Anna Mele, Sara Galimberti, Gioacchino Catania, Annamaria Giordano, Ilaria Angeletti, Luana Schiattone, Elsa Pennese, Rosanna Maria Miccolis, Angelo Famà, Giulio Giordano, Catello Califano, Bruzzese Antonella, Santino Caserta, Giuliana Farina, Pietro Bulian, Giacomo Loseto, Barbara Pocali, Vanessa Innao, Piero Galieni, Vincenzo Fraticelli, Candida Vitale, Azzurra Romeo, Marco Rossi, Ilaria Scortechini, Federico Vozella, Luigi Malandruccolo, Marzia Varettoni, Lucia Morello, Giuseppe Pietrantuono, Esmeralda Conte, Martina Cantelli, Roberta Murru, Daniele Caracciolo, Enrico Derenzini, Valentina Martina, Roberto Marasca, Maria Ilaria Del Principe, Amalia Figuera, Francesco Angotzi, Marta Gina Coscia, Nicola Di Renzo, Luca Laurenti, Nicola Amodio, Pellegrino Musto, Francesco Di Raimondo, Arcangelo Liso, Alessandra Tedeschi, Livio Trentin, Gianluca Gaidano, Francesca Romana Mauro, Giovanni Tripepi, Fortunato Morabito, Valter Gattei, Gentile Massimo
ABSTRACT: 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 BTKis, such 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 patients with CLL 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. Patients who were treated with zanubrutinib experienced lower 12-month discontinuation rates (overall: 12.6% vs 21.4%; matched: 12.4% vs 20.2%) and higher 12-month TTNTD rates (overall: 91.9% vs 83.0%; matched: 93.2% vs 83.4%). Multivariable analyses confirmed zanubrutinib as an independent predictor of longer TTD and TTNTD, whereas high-risk features, including age, relapsed/refractory disease, Binet stage C, TP53 disruption, Eastern Cooperative Oncology Group 2 to 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.