A total of six cycles of the R-PMDT regimen (rituximab, pirtobrutinib, high-dose methotrexate, dexamethasone, and thiotepa) will be administered to patients with newly diagnosed primary central nervous system lymphoma (PCNSL). The primary objective is to assess the overall response rate (ORR) of R-PMDT. Secondary objectives include evaluating the complete response rate, progression-free survival (PFS), overall survival (OS), and safety.

In this prospective, multicenter, open-label, single-arm phase 2 clinical trial, eligible patients with newly diagnosed primary central nervous system lymphoma (PCNSL) will receive six cycles of the R-PMDT regimen. The R-PMDT regimen is administered as follows: rituximab (R, 375 mg/m²) is given as an intravenous infusion on day 0; methotrexate (M, 3.5 g/m²) is administered as a 3-hour intravenous infusion on day 1, with dose adjustment based on pre-treatment creatinine clearance; dexamethasone (D, 20 mg) is given intravenously on days 1-4; thiotepa (T, 30 mg/m²) is administered intravenously on day 1; and pirtobrutinib (P, 200 mg once daily) is taken orally on days 4-21. After completion of six cycles, depending on the investigator's decision, patients may receive consolidation or maintenance therapy, including but not limited to autologous hematopoietic stem cell transplantation, radiotherapy, or pirtobrutinib maintenance. The primary objective is to assess the overall response rate (ORR) of R-PMDT. Secondary objectives include evaluation of the complete response rate, progression-free survival (PFS), overall survival (OS), and safety.

Inclusion Criteria:

• Newly diagnosed primary central nervous system diffuse large B-cell lymphoma
• Adequate hematologic function: ANC ≥1.0×10⁹/L, PLT ≥75×10⁹/L
• Adequate hepatic function: ALT/AST ≤3×ULN; total bilirubin ≤1.5×ULN
• Adequate renal function: serum creatinine ≤2×ULN or CrCl ≥40 mL/min
• LVEF ≥55% by echocardiography
• Baseline oxygen saturation >92% on room air
• Expected survival ≥3 months

Exclusion Criteria:

• Prior anti-lymphoma therapy other than corticosteroids.
• Uncontrolled significant cardiovascular or cerebrovascular disease.
• Uncontrolled active systemic bacterial, fungal, or viral infection.
• Active hepatitis B and/or active hepatitis C (HCV RNA positive). Patients with positive hepatitis B surface antigen and/or core antibody but HBV-DNA < 1000 IU/mL may be included and should receive concurrent oral antiviral prophylaxis against HBV reactivation.
• Hypersensitivity to any study drug or its components.
• Other active malignancy, except for adequately controlled non-melanoma skin cancer, in situ carcinoma, or malignancy that has been in complete remission for ≥5 years.
• Pregnant or lactating women. Fertile patients unwilling to use effective contraception.
• Other conditions deemed inappropriate by the investigator.