Ernesto Vigna, Enrica Antonia Martino, Annalisa Pitino, 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, R. 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, R. Murru, Daniele Caracciolo, Enrico Derenzini, Valentina Martina, Roberto Marasca, Maria Ilaria Del Principe, Amalia Figuera, Francesco Angotzi, Marta Gina Coscia, Nicola Di Renzo, L. Laurenti, Nicola Amodio, Pellegrino Musto, F. Di Raimondo, Arcangelo Liso, Alessandra Tedeschi, Livio Trentin, Gianluca Gaidano, Francesca Romana Mauro, Giovanni Tripepi, Andrea Corsonello, Fortunato Morabito, Valter Gattei, Gentile Massimo
The management of chronic lymphocytic leukemia (CLL) in older patients requires careful balancing of therapeutic efficacy with the risks of treatment intolerance. Frailty assessment is increasingly recognized as a critical determinant of clinical outcomes, but its specific role in guiding therapy with second-generation Bruton tyrosine kinase inhibitors remains poorly defined. We conducted a prospective, multicenter investigation of 326 consecutive CLL patients aged 65 years or older who received zanubrutinib across 52 Italian centers, aiming to evaluate whether the Clinical Frailty Scale (CFS) could predict treatment discontinuation in real-world practice. The cohort was characterized by advanced age (median 78.1 years, range 65.1-94.5), with over half of the patients presenting with Binet stage C disease. Two-thirds were treated in the frontline setting, while the remainder received zanubrutinib as salvage therapy. After a median follow-up of 8 months, 48 patients (14.7%) discontinued treatment, most commonly due to toxicity or disease progression. Receiver operating characteristic curve analysis identified a CFS of 3 as the optimal threshold for predicting discontinuation, with an area under the curve of 0.65 (95% CI 0.56-0.73, p < 0.001). At 12 months, the discontinuation rate was significantly higher among patients with a CFS > 3 (29.2%) compared with those with a CFS ≤ 3 (8.8%) (p < 0.001); among conventional prognostic variables, only relapsed/refractory disease demonstrated an independent association with TTD. These findings highlight the CFS as a simple yet powerful clinical tool that provides incremental prognostic information beyond standard disease-related factors. Incorporating frailty assessment into treatment planning may enhance patient selection and optimize therapeutic strategies for elderly CLL patients in daily practice.