Effectiveness and safety of orelabrutinib combined with rituximab, temozolomide, methotrexate, and cytarabine in intensive chemotherapy-unfit patients with PCNSL in China.

[BACKGROUND] Primary central nervous system lymphoma (PCNSL) is a rare and aggressive lymphoma subtype. Orelabrutinib (O), a novel and potent second-generation Bruton tyrosine kinase inhibitor, has shown impressive efficacy in PCNSL. This study aimed to evaluate the effectiveness and safety of the O-based regimen in the treatment of intensive chemotherapy-unfit patients with newly diagnosed PCNSL.

[METHODS] In this single-center, retrospective case series, we consecutively included 10 patients with PCNSL who were unfit for intensive chemotherapy, defined as an Eastern Cooperative Oncology Group performance status score of ≥ 3, a Karnofsky Performance Status score of ≤ 70, or a Sequential Organ Failure Assessment score of ≥ 2. All patients received the O-based regimen, including the combination of O, rituximab (R), and temozolomide (T; ORT), with or without methotrexate (M) or cytarabine (A; ORT-M/A), followed by ORT maintenance. The effectiveness outcomes were overall response rate (ORR), progression-free survival (PFS), and overall survival (OS).

[RESULTS] Following ORT-M/A treatment, six patients achieved a complete response (60.0% [95% CI 26.2-87.8]) and four achieved a partial response, yielding an ORR of 100.0% (95% CI 69.2-100.0). As of the data cutoff (September 7, 2025), the median follow-up of 23.7 months (range, 9.2-40.2). The corresponding 24-month PFS rate and 36-month OS rate were 80.0% (95% CI 51.6-100.0) and 90.0% (95% CI 73.2-100.0), respectively. The most common grade 3-4 treatment-related adverse events (AEs) were thrombocytopenia (100.0%) and leukopenia (90.0%). No serious AEs or treatment-related deaths were observed.

[CONCLUSION] The ORT-M/A chemotherapy regimen was efficacious and well-tolerated in our patients with PCNSL. This retrospective study provided a potential therapeutic strategy for PCNSL patients who are unfit for intensive chemotherapy and warrant further investigation.