Objective <p>Limited treatment options for primary central nervous system lymphoma (PCNSL) highlight the need for alternative therapies. This study evaluated orelabrutinib (O) and rituximab (R), plus high-dose methotrexate (M) (ORM), as a potential induction therapy for newly diagnosed PCNSL.</p> Methods <p>Patients received six cycles of 150&#xa0;mg/day orelabrutinib, 375&#xa0;mg/m² rituximab, plus 3.5&#xa0;g/m² methotrexate every 3&#xa0;weeks, followed by autologous hematopoietic stem cell transplantation and orelabrutinib maintenance. The primary endpoint was the overall response rate (ORR) at the end of induction therapy. Secondary endpoints included progression-free survival (PFS), overall survival (OS), and safety.</p> Results <p>From October 21, 2020, to October 22, 2024, 28 patients were treated and evaluated for efficacy and safety analyses. At the end of induction therapy, the ORR was 71.4% (95% CI, 51.3–86.8), including 16 (57.1%) complete and 4 (14.3%) partial responses. At a median follow-up of 21.6&#xa0;months, the median PFS was 35.3&#xa0;months (95% CI, 8.4–not evaluable), and the median OS was not reached, with PFS and OS rates of 64.3% and 96.3% at 1&#xa0;year, 64.3% and 90.9% at 2&#xa0;years, and 45.9% and 82.7% at 3&#xa0;years, respectively. All 28 (100%) patients experienced treatment-related adverse events (TRAEs) of any grade. Grade 3 TRAEs occurred in seven (25.0%) patients, including five (17.9%) leukopenia, one (3.6%) thrombocytopenia, and one (3.6%) diarrhea. No other Bruton’s tyrosine kinase inhibitor-related off-target toxicities (e.g., atrial fibrillation/flutter) or TRAE-related deaths were observed.</p> Conclusion <p>The ORM induction regimen showed anti-tumor activity with a favorable safety profile, offering a potential therapeutic strategy for newly diagnosed PCNSL.</p> <p>Clinical trial registration:&#xa0;ClinicalTrials.gov: NCT05600660.</p>