Real world outcomes of zanubrutinib monotherapy for CLL/SLL focusing on treatment discontinuation and BTKi switching: A single center retrospective analysis

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Abstract Introduction: Zanubrutinib as a second generation bruton tyrosin kinase inhibitor (BTKi) has become the standard of care for both frontline and relapsed/refractory chronic lymphocytic leukemia (CLL) /small lymphocytic lymphoma (SLL) in China regardless of TP53 mutation or fitness status. As it has a better safety profile in clinical trials over first-generation ibrutinib in CLL/SLL, patients on zanubrutinib may enjoy fewer adverse events (AE) and longer event-free survival. The objective of this study was to assess the real-world efficacy and treatment persistence of single agent zanubrutinib in CLL/SLL patients. Methods: This was a retrospective observational study of adult patients with CLL/SLL who initiated single agent zanubrutinib treatment between December 2020 and April 2024 in West China Hospital, Sichuan University, which was from the comparably underdeveloped Western China region. The end of follow-up was March 1, 2025. Duration of treatment, reasons for discontinuation, dose reduction, real-world event free survival (rwEFS) and outcomes of patients switched from ibrutinib were reported. Results: A total of 91 patients were enrolled with 49 male patients (53.8%). 39.6% (36/91) patients received zanubrutinib as first line (1L) treatment while 60.4% (55/91) were second line (2L) users. The median age of diagnosis was 59 years (range, 26 - 85). 25% (17/68) patients had a smoking history. Hypertension was documented in 5.4% (3/74) patients. 78 (84.8%) patients were diagnosed as CLL while 14 (15.2%) patients were SLL. At baseline, among 55 patients with intact staging data, 20% (11/55) were staged as Binet A, with 36% (19/55) as Binet B and 45% (25/55) as Binet C. The cytogenetic and molecular characteristics were as follows: mutated IGHV at 34.1% (14/41), unmutated IGHV at 65.9% (27/41), del17p at 21.1% (7/33) and TP53 mutation at 37.5% (9/24). Dose reductions were documented in 24.2% (22/91) patients. Only 31.8% (7/22) dose reductions were caused by intolerable AEs. The others were attributed to personal preferences. Treatment discontinuation was documented in 18.7% (17/91) patients. 64.7% (11/17) treatment discontinuations were caused by economic or personal reasons, with 17.6% (3/17) by intolerable AEs 11.2% (2/17) by progression of disease (PD) and only 1 death from COVID19 infection. 94.1% (16/17) treatment discontinuations occurred within the first 2 years on zanubrutinib. The median time on zanubrutinib treatment prior to discontinuation was 8.0 months (range, 1.0 - 29.0). No patient discontinued zanubrutinib due to cardiovascular AE. Until the cut-off date, the median follow-up was 23.0 months (95%CI: 20.0 - 26.0). The median rwEFS was not reached. The estimated 48-months rwEFS rate was 77%. There was no significant difference in rwEFS between 1L and 2L subgroups (p=0.39). Overall survival was also not reached. Only two cases of Richter transformation (RT) occurred. Noticeably, among the 2L subgroup 34.5% (19/55) patients were switched from previous ibrutinib treatment. The reasons for BTKi switch were as follows: 57.9% (11/19) for AEs (including 3 skin rash, 2 infection, 1 pleural infusion, 3 myelosuppression and 2 bleeding cases), 21.1% (4/19) for PD, 10.5% (2/19) for inadequate efficacy (stable disease) and 10.5% (2/19) for economic considerations. After switching to zanubrutib, 54.5% (6/11) AEs were recovered and 45.5% (5/11) were improved to lower degrees. Among the 6 patients with PD or SD after ibrutinib, 4 patients (66.7%) responded to zaubrutinib with only 1 PD and 1 RT in the follow-up. Conclusion: Our findings suggest that the real-world efficacy and safety profile of zanubrutinib for CLL/SLL is consistent with previous clinical trials. Real-world data support zanubrutinib continuous treatment as a preferred regimen for CLL/SLL patients. Discontinuation of zanubrutinb due to PD or AE is not common. Economic burden is the main reason for dose reduction or the treatment discontinuation. For patients who cannot tolerate ibrutinib or have inadequate response to ibrutinib, switching to zanubrutinib could be a desirable option which could alleviate most ibrutinib-related AEs with further improvement of response in certain patients. Future validation is warranted to fully elucidate the long-term benefits of zanubrutinib in the management of CLL/SLL.

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