Efficacy and safety of zanubrutinib-containing regimens in patients with newly diagnosed Mantle Cell Lymphoma: Interim results from a Phase II investigator-initiated study

Abstract Background: First-line treatments such as intensive immunochemotherapy followed by autologous stem cell transplantation (ASCT) provide favorable outcomes in fit younger mantle cell lymphoma (MCL) patients. However, elderly patients and younger high-risk patients (e.g., TP53 mutation, high Ki-67, blastoid morphology) face therapeutic challenges with no consensus frontline regimen. Zanubrutinib, a selective BTK inhibitor, demonstrates improved safety and tolerability. Combining it with anti-CD20 antibodies may enhance efficacy. This study evaluates zanubrutinib-containing regimens in elderly and younger high-risk treatment-naïve MCL patients. Methods: This multicenter, investigator-initiated, prospective study stratified patients into two cohorts based on age and biological risk: an elderly cohort (n=21; age ≥65 years) and a younger high-risk cohort (n=20; age <65 years with at least one high-risk feature, including TP53 mutation, blastoid/pleomorphic variant, high-risk sMIPI score [6–11 points], or Ki-67 >30%). Elderly cohort (n=21): Patients received zanubrutinib 160 mg orally BID combined with rituximab 375 mg/m² intravenously on day 1 of each 21-day cycle for 12 cycles as induction therapy, followed by zanubrutinib maintenance until disease progression or unacceptable toxicity. Younger high-risk cohort (n=20): Patients received zanubrutinib 160 mg BID in combination with the R-BAC regimen (rituximab 375 mg/m² on day 1, bendamustine 70 mg/m² on days 2–3, and cytarabine 500 mg/m² on days 2–4), administered every 28 days for 6 cycles as induction therapy. Patients achieving complete remission (CR) or partial remission (PR) and meeting criteria for ASCT underwent ASCT consolidation, followed by zanubrutinib maintenance therapy. Patients ineligible for transplantation continued zanubrutinib monotherapy until disease progression or unacceptable toxicity. Results: From October 2023 to May 2025, 23 patients with newly diagnosed MCL were enrolled, of whom 22 were evaluable for efficacy. Of these, 9 (39.1%) were allocated to the elderly cohort and 13 (60.9%) to the younger high-risk cohort. The elderly cohort had a median age of 71 years (range, 66–82), comprising 7 males and 2 females. High-risk simplified MIPI (sMIPI ≥6) was observed in 4 patients (44.4%), bone marrow involvement in 4 (44.4%), Ki-67 >30% in 4 (44.4%), and TP53 mutation or deletion in 1 (11.1%). The younger high-risk cohort had a median age of 59 years (range, 43–63), with 11 males and 2 females. High-risk sMIPI was identified in 53.8% (7/13), bone marrow involvement in 84.6% (11/13), Ki-67 >30% in 53.8% (7/13), and blastoid variant in 7.7% (1/13). The elderly cohort had an overall response rate (ORR) of 100.0% (95% CI: 66.4%–100.0%) and a CR rate of 88.9% (8/9; 95% CI: 51.8%–99.7%). Among five patients evaluable for minimal residual disease (MRD), four were MRD-negative at cycle 4, resulting in an MRD negativity rate of 80.0% (4/5), including one patient with a TP53 mutation. At a median follow-up of 11.5 months(as of May 2025), the 1-year progression-free survival (PFS) rate was 85.7% (95% CI: 51.8%–99.7%), with one patient experiencing disease progression at 10 months. In the younger high-risk cohort, ORR was 100.0% (95% CI: 75.3%–100.0%), and the CR rate was 84.6% (11/13; 95% CI: 54.6%–98.1%). Among eight patients assessed for MRD after 2 cycles, 87.5% (7/8) were MRD-negative, including one with blastoid morphology. At a median follow-up of 10.7 months (as of May 2025), no events occurred within 12 months; one patient progressed later at 14.9 months. Median duration of response (DoR) was not reached in either cohort; 81.8% (n=18) maintained response ≥6 months. Grade 3–4 adverse events (AEs) occurred mainly in younger high-risk patients, including neutropenia (38.5%), anemia (15.4%), thrombocytopenia (23.1%), and pneumonia (23.1%), mostly related to R-BAC and all manageable. No grade 3–4 AEs were observed in elderly patients. Common grade 1–2 AEs included arrhythmia and rash, each occurring in 1 of 9 patients (11.1%).No deaths were reported. Conclusions: In treatment-naïve elderly MCL patients, zanubrutinib combined with rituximab demonstrated favorable efficacy and safety, warranting further investigation. For younger high-risk patients, zanubrutinib combined with R-BAC showed encouraging efficacy and high MRD negativity rates in a small cohort, suggesting its potential to improve prognosis and showing promise as a first-line treatment option for this population.