Background: The next-generation Bruton's Tyrosine Kinase inhibitor (BTKi) Zanubrutinib (ZAN) was FDA approved in 2021 and reimbursed in Italy for patients with Waldenström macroglobulinemia (WM), both in the relapsed/refractory (RR) setting and for treatment-naïve (TN) patients (pts) ineligible for chemoimmunotherapy (CIT). Initially available through a Compassionate Use Program (CUP, October 2020–September 2022), it has been commercially available (Com-U) since October 2022. Data on ZAN in clinical practice are scarce, limited to small cohorts treated within CUP, and not representative of the current patient population often represented by heavily pretreated pts. The aim of this study is to evaluate treatment management, safety and outcomes of pts with WM receiving ZAN in CUP or Com-U in Italy.

Methods: FIL_BRUCE (NCT06441214) is a retrospective-prospective multicenter study conducted according to the Declaration of Helsinki. Eligible pts were ≥18 years and had to have received ZAN outside of clinical trial in CUP or Com-U in Italy. ZAN was administered continuously at 320 mg/daily or 160 mg twice daily. Primary objective was treatment management defined as: definitive (Tox-DTD) and temporary discontinuation due to toxicity; permanent (PDR) and temporary dose reduction. Secondary objectives included safety (adverse events, AEs graded per CTCAE v 5.0) and efficacy (overall response rate [ORR]; partial remission [PR]; very good partial remission [VGPR]; complete remission [CR]; progression free survival [PFS]; event free survival [EFS, event: progression, death, Tox-DTD]; overall survival [OS]).

Results: From October 2020 to July 2025, 99 pts have been enrolled across 15 centers: 11 in CUP and 88 in Com-U. Median age for the overall population was 77 years (range 70-85); 63 pts were R/R with a median of 1 prior line. Five pts (8%) switched to ZAN due to ibrutinib intolerance. Median CIRS was 4 (range 2-6). Cardiac comorbidity or hypertension were present at baseline in 19.2% and 35.4% of pts, respectively; 7.1% had baseline neutropenia. Median number of concomitant medications among 60 pts was 3 (range 1-12). In 36 TN, comorbidity burden was the main reason for choosing ZAN over CIT. Overall, 58/67 (87%) had MYD88L265P and 8/25 (32%) CXCR4 mutations. At data cut-off, a total of 90 pts had received at least 1 dose of ZAN and were evaluated for treatment management and safety. After a median ZAN exposure of 12 months, 80 (89%) remain on treatment. Overall, 4 pts discontinued ZAN due to progression (PD, 4,4%) and 6 (6.7%) due to AEs (Tox-DTD), with a median time to Tox-DTD of 4 months. Reason for Tox-DTD were: major infection (1 pt), gastrointestinal toxicity (1), skin toxicity (1), cerebrovascular disease (1), cerebral hemorrhage (1) and acute renal failure (1). 23 pts (25.6%) temporary discontinued ZAN for a median of 13 consecutive days. PDR occurred in 10 pts (11.1%), after a median time of 6 months (main reason: neutropenia). 8 pts (8.9%) temporary reduced ZAN for a median of 58 days (mainly for neutropenia, pneumonia, gastrointestinal AE). A total of 37 patients (41%) reported at least one adverse event, 20 (17.8%) of grade ≥3, mostly infections. As regards adverse events of special interest for BTKi: any grade atrial fibrillation/flutter occurred in 5 pts (5.6%); 1 (1.1%) had grade 5 hemorrhage; 2 (2.2%) presented grade 3-4 hypertension. Overall, 6 pts died due to: PD (3 pts), cerebrovascular disease (2), acute renal failure (1). Of 90 pts receiving ≥1 ZAN dose, 68 reached first specified response assessment at 3 months. Of these 61 responded to treatment with an ORR of 89.7% (TN: 100%, R/R: 85.1%) and major response rate of 75% (including 23.5% VGPR/CR); 4 pts (5.8%) had a stable disease. After a median follow-up of 15 months, 12-months PFS, EFS and OS were 92%, 89% and 95%, respectively. One case of DLBCL transformation was recorded after 9 months of treatment. Two non-melanoma skin cancers were reported at 11 and 17 months after ZAN initiation. Overall 4 pts started a subsequent line after ZAN.Conclusion: In this real word cohort, including pts treated within CUP, ZAN efficacy was comparable to the pivotal trial in terms of ORR and response quality, with similar outcomes in TN and R/R pts. Even in a very elderly and comorbid population, ZAN showed a favorable safety profile, with no new safety signals observed. Enrollment is ongoing to prospectively confirm its effectiveness and tolerability in routine care.

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2025
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