Baseline Characteristics from CLL-ZANU2024, an Italian Non-Interventional Study Assessing the Real-World Use of Zanubrutinib in the Treatment of Patients with Chronic Lymphocytic Leukemia (CLL)
Authors: Martino Enrica Antonia , Pasquale Raffaella , Ferrarini Isacco , Moia Riccardo , Visentin Andrea , Sanna Alessandro , Motta Marina , Moratti Massimo , Sportoletti Paolo , Chiarenza Annalisa , Maggi Alessandro , Zammit Valentina , Merli Michele , Innocenti Idanna , Giordano Claudia , Nocilli Laura , Postorino Massimiliano , Stelitano Caterina , Ferrario Andrea , Frustaci Annamaria , Scardino Stefania , Anticoli Borza Paola , Ballotta Laura , Mancuso Salvatrice , Musuraca Gerardo , Mele Anna , Galimberti Sara , Catania Gioacchino , Giordano Annamaria , Angeletti Ilaria , Schiattone Luana , Pennese Elsa , Miccolis Rosanna , Fama Angelo , Giordano Giulio , Califano Catello , Vigna Ernesto , Bruzzese Antonella , Farina Giuliana , Bulian Pietro , Loseto Giacomo , Pocali Barbara , Innao Vanessa , Galieni Piero , Fraticelli Vincenzo Ludovico , Vitale Candida , Romeo Azzurra Anna , Rossi Marco , Scortechini Ilaria , Vozzella Federico , Malandruccolo Luigi , Derenzini Enrico , di Martina Valentina , Marasca Roberto , Del Principe Maria Ilaria , Coscia Marta , Di Renzo Nicola , Laurenti Luca , Neri Antonino , Musto Pellegrino , Di Raimondo Francesco , Tedeschi Alessandra , Trentin Livio , Gaidano Gianluca , Morabito Fortunato , Gattei Valter , Gentile Massimo 
Published: December 2024

Introduction: Zanubrutinib, a selective second-generation irreversible Bruton Tyrosine Kinase (BTK) inhibitor, received European Medicines Agency (EMA) approval in November 2022 for the chronic lymphocytic leukemia (CLL) treatment and Agenzia Italiana del Farmaco (AIFA)

reimbursement as monotherapy in October 2023. Despite this, further evaluation of Zanubrutinib in real-world post-marketing settings is necessary. The CLL-ZANU2024 study, an Italian, observational, multicenter, longitudinal secondary data usage analysis, aims to address this need by retrospectively examining a cohort of CLL patients who initiated Zanubrutinib between October 2023 and June 2024, regardless of their treatment status at the time of inclusion.

Methods: CLL-ZANU2024 study started in May 2024 (first-patient in), and aimed to enroll CLL patients (pts) across 52 Italian sites. The study provides the first Italian real-world data on Zanubrutinib use in CLL. The primary end-point of this study was to evaluate the time to treatment

discontinuation (TTD) and reasons for discontinuation in pts with CLL, both overall and according to treatment lines. Pts will be prospectively observed for up to 5 years since the last patient's index date or until study withdrawal (consent withdrawal, physician's choice, loss to follow-up or death), whichever occurs first, regardless of Zanubrutinib discontinuation. All visits and assessments are conducted as per site clinical practice. Descriptive statistics is used for baseline characteristics.

Results: As of June 2024, 203 pts were identified and included for demographic and baseline characteristics analysis. The median age was 75.9 years (range 45.8-94.5), and 129 pts (63.2%) were male. Zanubrutinib was first treatment in 128 (62.7%) pts (treatment-naïve, TN) pts and subsequent therapy in 77 (37.3%) pts (refractory/relapsed, RR). The median time from diagnosis to Zanubrutinib initiation was 2.2 years (range 0.2-18.4) in TN pts and 8.8 years (range 1.5-33) in RR pts. Binet classification at treatment start was: A stage (24 pts; 11.8%), B stage (71 pts; 34.8%), C stage (109 pts; 53.4%). Del(17p), del(11q), TP53 mutational status and IGHV mutational status data were available in 179 (87.9%), 171 (83.8%), 177 (86.8%) and 176 (86.3%) pts, respectively. Del(17p) was reported in 29 pts (16.2%; 16 TN, 13 RR), del(11q) in 30 pts (17.5%; 18 TN, 12 RR), TP53 mutations in 32 pts (15.7%; 16 TN, 16 RR). IGHV was unmutated in 122 pts (68.9%; 86 TN, 36 RR). In 169 cases in which del(17p) and TP53 mutation data were simultaneously available, concomitant TP53 mutations and del(17p) were observed in 15/169 (8.9%) pts while del(17p)-only cases and TP53-mutated-only cases were 1/169 (8.9%) and 12/169 (7.1%), respectively. Elevated LDH (&gt;250 U/L) and beta-2-microglobulin (≥ 5 mg/L) levels were found in 93 pts (45.6%) and 65 pts (31.9%), respectively. Bulky lymph nodes (diameter &gt;10 cm) were observed in 17 pts (8.3%). According to a recently reported scoring system generated for ibrutinib-treated pts, (PMID:

33580969), at Zanubrutinib start pts were stratified at high- (27 pts; 16%), intermediate- (44 pts; 26%) or low- (98 pts; 58%) risk of progression. The majority of pts (n=170, 83.3%) received an initial dose of 320 mg/day, as per the Summary of Product Characteristics (SmPC).

Conclusions: This preliminary report indicates that the demographic characteristics of the enrolled in this study was similar to previously reported cohorts for CLL pts receiving therapy in both clinical trials and real-world settings. Future reports will focus on Zanubrutinib TTD, reasons of discontinuation, and time to next treatment.