Background: Central nervous system diffuse large B-cell lymphoma (CNS DLBCL) is a relatively rare extranodal non-Hodgkin lymphoma with high malignancy and poor prognosis. At present, the combined chemotherapy regimen based on high-dose methotrexate has been established as the first-line standard treatment regimen for CNS DLBCL. Studies have shown that most CNS DLBCLs are activated B-cell type diffuse large B-cell lymphomas (ABC-DLBCL), usually carrying mutations in MYD88 and CD79B. These molecular characteristics provide potential targets for targeted therapy. At present, a number of studies have shown that BTK inhibitors have significant anti-tumor activity in patients with ABC-DLBCL, especially those with both MYD88 and CD79B mutations. However, the efficacy and safety of the treatment regimen of zanubrutinib combined with rituximab and high-dose methotrexate in patients with CNS DLBCL need to be further verified through large-scale clinical trials.

Objective: To investigate the efficacy and safety of zanubrutinib combined with rituximab and high-dose methotrexate regimen in the treatment of patients with CNS DLBCL.

Methods: The clinical data of patients with CNS DLBCL who received zanubrutinib combined with R + HD-MTX treatment in the Affiliated Hospital of Southwest Medical University from November 2023 to July 2025 were analyzed.

Results: A total of 7 patients were included, with a median age of 51 (38-67) years, including 2 males (28.6%) and 5 females (71.4%). There were 1 case (14.3%) of GCB subtype and 6 cases (85.7%) of non-GCB subtype. There was 1 patient (14.3%) with CD79B gene mutation, 3 patients (42.9%) with MYD88 gene mutation, and 1 patient (14.3%) with both CD79B and MYD88 gene mutations. Among them, 3 cases (42.9%) were primary central nervous system diffuse large B-cell lymphoma, and 4 cases (57.1%) were secondary central nervous system diffuse large B-cell lymphoma. One patient (14.3%) had received hematopoietic stem cell transplantation before, and the median number of treatment lines was 2. Efficacy was evaluated by PET/CT. All patients received zanubrutinib combined with rituximab and high-dose methotrexate regimen for at least 2 cycles, with a median of 4 cycles. The objective response rate (ORR) of the 7 patients was 100%, 6 patients (85.7%) achieved CR, and 1 patient (14.3%) achieved PR. Hematological adverse events (AEs) of grade ≥ 3 included neutropenia (57.1%) and thrombocytopenia (28.6%). Non-hematological AEs included pulmonary infection (42.9%), nausea (42.9%), diarrhea (14.3%), and liver and kidney function damage (42.9%). No atrial fibrillation or renal failure occurred in all patients.

Conclusion: The zanubrutinib combined with R + HD-MTX regimen shows good efficacy and controllable safety in patients with CNS DLBCL, which may improve the prognosis of patients and is worthy of further research.

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2025
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