Real-world study of rituximab, methotrexate, and zanubrutinib (R-MZ) in the treatment of newly diagnosed primary central nervous system lymphoma

Abstract Objective: Primary central nervous system lymphoma (PCNSL) is a rare subtype of extra-nodal non-Hodgkin lymphoma and and there is currently no defined standard treatment for newly diagnosed PCNSL except for the high-dose methotrexate (HD-MTX). The first-generation Bruton's tyrosine kinase inhibitor (BTKi) ibrutinib demonstrated an overall response rate (ORR) of 51.9–89% and a median progression-free survival (PFS) of 4.6–4.8 months in relapsed/refractory PCNSL, highlighting the potential of BTKi in PCNSL therapy. Zanubrutinib, a second-generation BTKi, exhibits improved selectivity for tyrosine kinases and enhanced blood-brain barrier penetration. This trial investigates the safety and efficacy of rituximab, methotrexate, and zanubrutinib (R-MZ) therapy in patients with newly diagnosed PCNSL. Methods: From October 2020 to February 2025, a total of 35 patients with PCNSL from three centers received six cycles of the R-MZ regimen (375 mg/m2 rituximab, 3.5 g/m2 methotrexate and 160mg zanubrutinib twice daily, every 3 weeks). Subsequently, patients underwent autologous hematopoietic stem cell transplantation (auto-HSCT), 2 years of zanubrutinib maintenance therapy or observation. The primary endpoint of this study was the objective response rate (ORR) after 6 cycles, with secondary endpoints including progression-free survival (PFS), overall survival (OS), and safety. Results: With a median follow-up of 22 months, the ORR after six treatment cycles was 88.6% (31/35), including a CR rate of 80% (28/35). 34.3% (12/35) of patients experienced progressive disease (PD) during follow-up. Median OS was 43 months and median PFS was 29 months. Among patients with objective response, 2 patients underwent auto-HSCT consolidation, and 11 patients received zanubrutinib maintenance. In contrast, 18 patients received no consolidation/maintenance therapy due to financial constraints or advanced age. Patients receiving either auto-HSCT or maintenance therapy showed significantly superior PFS versus observation (not reached vs 22 months; p=0.012). Regarding safety, 71.4% (25/35) experienced adverse events, most commonly leukopenia (28.5%), infections (20%), and elevated serum creatinine (11%). The majority of adverse events (AEs) were grade 1-2, with two treatment-related deaths reported. Conclusion: The R-MZ regimen demonstrates promising efficacy as induction therapy for PCNSL, with high initial response rates observed in this study. However, these findings reinforce the critical role of consolidative strategies or sustained maintenance therapy, to achieve durable disease control in this challenging malignancy.