Efficacy and safety of zanubrutinib combined with reduced-dose bendamustine and Rituximab for eldly Mantle Cell Lymphoma: A retrospective analysis

Abstract BR regimen was a common treatment for elderly patients with mantle cell lymphoma, however, infection and treatment tolerability remain a clinical challenges for those eldly MCL patients. We investigated the application of reduced-dose Bendamustine Combined with Rituximab and Zanubrutinib to provide the treatment evidence for clinical practice. This was a retrospective analysis and all patients receive Bendamustine (70 mg/m2,d1-2) , Rituximab(375mg/m2,d1) and Zanubrutinib (160mg bid) for 6 cycles, every 28 days as a cycle. If the treatment is effective, patients receive Zanubrutinib (160mg bid) for at least 2 years as maintenance therapy. Minimal residual disease was assessed by NGS in blood, and immunological function assessment was performed. A total of 23 patients have been enrolled as of July 2025. Among them, The median age was 68.0 years, with a male predominance (68.2%). Blastoid morphology was observed in 21.7% of cases. The Ki-67 index was ≥30% in 73.9% of patients, and advanced disease stages (IVA and IVB) accounted for 91.3% of cases. The MIPI risk categories were evenly distributed, with 34.8% each in high and intermediate risk groups. 26.1% patients had TP53 aberration and 17.4% were complex karyotype. The complete response rate at 6 course was 73.9% and the overall response rate was 91.3%. As of the follow-up through July 2025, the median progression-free survival (PFS) was is NA [25 - NA, 95% CI] months, and the median overall survival (OS) was not reached. The 24-month PFS and OS rates were 75.4% [59%-96.8%, 95% CI]and 90.7% [79.2%-100%, 95% CI]. Among 16 patients evaluable for MRD, the undetectable MRD (uMRD) rate was 88% (14/16) in the end-of-induction therapy. After six cycles of zanubrutinib maintenance therapy, the uMRD rate increased to 94% (15/16) in the evaluable cohort. Furthermore, longitudinal monitoring of five patients with available serial samples demonstrated sustained MRD negativity at 24 months post-maintenance initiation. Immune function monitoring showed a significant decline in CD4⁺ T-cell and NK-cell counts after three induction cycles, with both reaching their nadir by the end of induction therapy. After 6 months of maintenance treatment, the above indicators began to gradually rebound and 12 months of maintenance treatment, the vast majority of patients' CD4 ⁺ T cells recover to ≥ 200 cells/μ L, and NK cells also return to the normal range. Despite dose reduation, the most frequent treatment-emergent adverse events (TEAEs) were hematological toxicities, with leukopenia occurring in 65.2% of patients (grade ≥3: 34.8%) and thrombocytopenia in 34.8% (grade ≥3: 17.4%). Infectious complications included COVID-19 (13.0% all-grade; fatal in 4.3%) and lung infections (13.0% all-grade; grade ≥3: 8.7%). Conclusions Our results provide preliminary evidence that Zanubrutinib combined reduced-dose Bendamustine with Rituximab plus Zanubrutinib maintenance therapy is an active regimen for eldly MCL, which provides an additional treatment option for clinical practice.