Zanubrutinib, rituximab, and high-dose methotrexate as first-line treatment in newly diagnosed primary central nervous system lymphoma （zana）: A prospective, single-arm study

Abstract

Abstract Background Primary central nervous system lymphoma (PCNSL) is a rare, aggressive extranodal non-Hodgkin lymphoma with limited therapeutic options and suboptimal long-term survival. High-dose methotrexate (HD-MTX) remains the backbone of frontline therapy; however, relapses are frequent and outcomes remain unsatisfactory. Zanubrutinib, a next-generation Bruton tyrosine kinase (BTK) inhibitor, demonstrates favorable CNS penetration and promising activity in CNS lymphomas. We conducted a prospective study to evaluate the efficacy and safety of a zanubrutinib, rituximab, and HD-MTX (ZRM) regimen in newly diagnosed PCNSL patients.Methods This prospective, single-arm study (NCT05896007) was conducted at Shanghai Ruijin Hospital, enrolling patients aged 18–80 years with histologically confirmed, newly diagnosed PCNSL and measurable CNS lesions. Patients received intravenous rituximab (375 mg/m² on day 0), HD-MTX (3.5 g/m² on day 1) or temozolomide (TMZ; 150 mg/m², days 1–5 for MTX-intolerant patients), and continuous oral zanubrutinib (160 mg twice daily) in 28-day cycles. The planned treatment consisted of 6 induction cycles. Patients who achieve a partial or complete response were required to continue zanubrutinib maintenance therapy for at least one year. The primary endpoint was 2-year progression-free survival (PFS). Secondary endpoints included overall survival (OS), overall response rate (ORR), complete response (CR) rate, safety, and tolerability. Adverse events (AEs) were graded using CTCAE v5.0. Response assessments were performed by MRI or PET-CT scan according to IPCG criteria.Results Between 2023-07-13 and 2025-07-13, 29 patients were enrolled. Four patients received autologous stem cell transplantation (ASCT) following induction remission. Accordingly, all 29 patients were assessed for end-of-induction efficacy, whereas the per-protocol 2-year PFS and OS analyses were restricted to the 25 patients who did not undergo transplantation. The median age was 60 years (range: 43–75), with 56% male. Objective response rate (ORR) was 89.7 % ( 26 / 29 ), with a complete response (CR) rate of 89.7% (26/29). At a median follow-up of 16.2 months, the estimated 2-year progression-free survival (PFS) and overall survival (OS) were 82.8% (95% CI, 68.7–98.8) and 95.2% (95% CI, 86.6–100), respectively. Treatment was generally well tolerated. The most common Grade ≥3 AEs included leukopenia (17.2%), neutropenia (17.2%), and thrombocytopenia (17.2%). No treatment-related atrial fibrillation, bleeding, or invasive fungal infections were observed. Swimmer plot analysis revealed that 2 patients with confirmed responses (CR or PR) maintained their remission for over 16 months at data cutoff.Conclusion The combination of zanubrutinib, rituximab, and HD-MTX as first-line therapy for newly diagnosed PCNSL demonstrates promising efficacy and manageable toxicity. These findings support zanubrutinib as a promising BTK inhibitor backbone for PCNSL and warrants further investigation in larger, multi-center studies.