Real-world safety and effectiveness of zanubrutinib vs ibrutinib in CLL: the CLL-ZANU2024 Italian cohort

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.

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Journal
Blood Advances
Published
2026-01-07
DOI
https://doi.org/10.1182/bloodadvances.2025018757
Primary Topic
Chronic Lymphocytic Leukemia Research
Type
article
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article

Real-world safety and effectiveness of zanubrutinib vs ibrutinib in CLL: the CLL-ZANU2024 Italian cohort

Elsa Pennese, Ilaria Angeletti, Laura Nocilli, A. Sanna et al.
Blood Advances
Chronic Lymphocytic Leukemia Research
article

Real-world safety and effectiveness of zanubrutinib vs ibrutinib in CLL: the CLL-ZANU2024 Italian cohort

Elsa Pennese, Ilaria Angeletti, Laura Nocilli, A. Sanna, Giulio Giordano, A. M. Frustaci, Nicola Di Renzo, Esmeralda Conte, Anna Maria Mele, Francesca Romana Mauro, Amalia Figuera, Barbara Pocali, Marcello Riva, Francesco Di Raimondo, Luana Schiattone, Arcangelo Liso, Laura Ballotta, Valentina Martina, Caterina Cecilia Stelitano, Stefania Scardino, Paola Anticoli Borza, Rosanna Maria Miccolis, Federico Vozella, Santino Caserta, Valentina Zammit, Lucia Morello, Roberto Marasca, R. Moia, Marco Rossi, Luigi Malandruccolo, Vincenzo Fraticelli, Angelo Famà, C. Giordano, Francesco Malaspina, S. Pepe, Marina Pamponet Motta, Pellegrino Musto, Ilaria Scortechini, Francesco Angotzi, idanna innocenti, G. Loseto, Daniele Caracciolo, L. Trentin, Annalisa Pitino, Marta Gina Coscia, Bruzzese Antonella, R. Murru, Gioacchino Catania, Andrea Visentin, Alessandra Tedeschi, Gentile Massimo, Gianluca Gaidano, Valter Gattei, Martina Cantelli, Massimo Moratti, Giuseppe Pietrantuono, Maria Ilaria Del Principe, Fortunato Morabito, Ernesto Vigna, Michele Merli, Marzia Varettoni, Salvatrice Mancuso, Raffaella Pasquale, Annamaria Giordano, Enrica Antonia Martino, Massimiliano Postorino, Adalberto Ibatici, Azzurra Romeo, Pietro Bulian, Candida Vitale, Paolo Sportoletti, Vanessa Innao, Piero Galieni, Isacco Ferrarini, Enrico Derenzini, Andrea Ferrario, Giuliana Farina, Annalisa Chiarenza, Alessandro Maggi, Luca Laurenti, Catello Califano, Giovanni Tripepi, Nicola Amodio, Sara Galimberti
article en

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.

Blood AdvancesVol. 10(5)
Università Cattolica del Sacro Cuore (IT), University of Pisa (IT), University of Rome Tor Vergata (IT), University of Verona (IT), Marche Polytechnic University (IT), Università degli Studi del Piemonte Orientale “Amedeo Avogadro” (IT), University of Molise (IT), University of Padua (IT), University of Trieste (IT), University of Pavia (IT), University of Perugia (IT), Azienda Ospedaliera San Giovanni Addolorata (IT), Ospedale di Circolo e Fondazione Macchi (IT), Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico (IT), Accademia di Belle Arti di Frosinone (IT), Magna Graecia University (IT), University of Catania (IT), Azienda Ospedaliera Citta' della Salute e della Scienza di Torino (IT), Ospedale Maggiore (IT), Ospedale Antonio Cardarelli (IT), ASL Roma (IT), Ospedale "Santa Maria delle Croci" di Ravenna (IT), Centro di Riferimento Oncologico della Basilicata (IT), Azienda Socio Sanitaria Territoriale Grande Ospedale Metropolitano Niguarda (IT), Azienda Universitaria Ospedaliera Consorziale - Policlinico Bari (IT), Innovation Engineering (Italy) (IT), Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IT), Azienda ospedaliera "Bianchi-Melacrino-Morelli" (IT), Azienda Ospedaliera di Cosenza (IT), Azienda Socio Sanitaria Territoriale degli Spedali Civili di Brescia (IT), Azienda Ospedaliero Universitaria di Sassari (IT), Ospedale di Santo Spirito (IT), Fatebenefratelli Hospital (IT), Azienda Ospedaliero Universitaria Ospedali Riuniti (IT), Azienda Ospedaliero-Universitaria di Modena (IT), Department of Health (ES), Azienda Ospedaliera S.Giuseppe Moscati (IT), Azienda Ospedaliero-Universitaria Careggi (IT), CTO Andrea Alesini (IT), Federico II University Hospital (IT), Azienda Ospedaliera Sant'Andrea (IT), Ospedale Santa Maria della Misericordia di Udine (IT), Azienda Socio Sanitaria Territoriale Lariana (IT), Centro di Riferimento Oncologico (IT), Policlinico Universitario di Catania (IT), Istituto Tumori Bari (IT), Ospedale Annunziata di Cosenza (IT), Azienda Ospedaliero-Universitaria "Renato Dulbecco" (IT), Nini Hospital (LB), Guglielmo da Saliceto Hospital (IT), Ospedale Santa Maria Goretti (IT), Campus Bio Medico University Hospital (IT), Azienda di Rilievo Nazionale ed Alta Specializzazione (IT), Ospedale Policlinico San Martino (IT), Azienda USL di Pescara (IT), Ospedale Sant'Anna (IT), Policlinico San Matteo Fondazione (IT), Ospedale San Bortolo (IT), Ospedale Vito Fazzi (IT), Istituti di Ricovero e Cura a Carattere Scientifico (IT), ASM Terni (Italy) (IT), National Research Council (IT), Department of Public Health (US), Fondazione Vincenzo Pansadoro (IT), Azienda Ospedaliera Nazionale SS. Antonio e Biagio e Cesare Arrigo (IT), La Maddalena (IT), Azienda Ospedaliera Universitaria Pisana (IT), Azienda Ospedaliera Ospedali Riuniti Papardo Piemonte (IT), University of Calabria (IT), University of Turin (IT), University of Bari Aldo Moro (IT), University of Reggio Calabria (IT), European Institute of Oncology (IT), Sapienza University of Rome (IT), University of Palermo (IT)
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