A Multicenter, Prospective Clinical Trial With a Concurrent Control Evaluating Methotrexate Combined With Rituximab,Sintilimab and Pirtobrutinib vs. Investigator-Selected Standard of Care in Treatment-Naive PCNSL

Primary Central Nervous System Lymphoma (PCNSL) is a rare extranodal non-Hodgkin lymphoma with poor prognosis, characterized by MYD88 L265P/CD79B mutations and PD-L1/PD-L2 overexpression. Current first-line therapies based on high-dose methotrexate (HD-MTX) have limitations including high recurrence rates, poor blood-brain barrier penetration, and significant toxicity. Pirtobrutinib, a highly selective reversible BTK inhibitor, exhibits superior CNS penetration and safety profiles compared to covalent BTK inhibitors. Sintilimab (anti-PD-1) enhances anti-tumor immunity by blocking PD-1/PD-L1 axis. This study evaluates the efficacy and safety of the quadruple combination (methotrexate+rituximab + sintilimab + pirtobrutinib ) in treatment-naive PCNSL, with a concurrent control cohort providing comparative evidence.

Inclusion criteria

• Age >= 18 years.
• Voluntarily signed informed consent.
• ECOG Performance Status 0-3.
• Expected survival > 3 months.
• Histopathologically confirmed Diffuse Large B-Cell Lymphoma (DLBCL) restricted to the CNS or eyes (PCNSL).
• Measurable lesion on contrast-enhanced MRI (>10x10 mm) or positive CSF cytology for leptomeningeal disease.
• No prior systemic treatment for lymphoma (corticosteroids excepted).
• Adequate bone marrow and organ function (ANC >=1.5x10^9/L, PLT >=80x10^9/L, Hb >=80 g/L; Bilirubin <=1.5xULN, AST/ALT <=2.5xULN; Creatinine <=1.5xULN or CrCl >=60 mL/min) .
• Stable controlled comorbidities allowed (e.g., hypertension with blood pressure <=160/100 mmHg, type 2 diabetes with HbA1c <=8%, mild coronary heart disease without myocardial infarction in the past 6 months).
• Basic communication ability to complete PROs questionnaires (no severe cognitive impairment).
• Reproductive-aged females and males with childbearing potential: No pregnancy plans during the study and 3 months after treatment discontinuation; use effective contraception (abstinence, physical contraception, or hormonal contraceptives initiated >=3 months before first dose). Males prohibited from donating sperm during treatment and 3 months after discontinuation.
• For Observational Cohort (Palliative Care Subgroup only): Pathologically confirmed DLBCL restricted to the CNS or eyes; Follow-up available for efficacy assessment (at least one CR evaluation) .

Exclusion criteria

1.Prior treatment with PD-1/PD-L1 inhibitors or CTLA4 monoclonal antibodies. Uncontrolled active infection. 2.Uncontrolled or significant cardiovascular diseases: 3.Congestive heart failure (NYHA class III/IV),

• myocardial infarction, unstable angina within 6 months before first dose; arrhythmia requiring treatment; LVEF <50%.
• Primary cardiomyopathy.
• History of clinically significant QTc prolongation, second-degree type II/third-degree atrioventricular block, or QTc interval (Fridericia method) >470 msec (females) / >480 msec (males).
• Atrial fibrillation (EHRA grade ≥2b).
• Refractory hypertension. 4.Active hepatitis B/C infection (HBV-DNA ≥ detection limit, HCV RNA positive) or syphilis. (Exceptions: HBV-DNA < detection limit, cured HCV).

5.HIV infection. 6.Prior organ transplantation or allogeneic stem cell transplantation. 7.Pregnant or lactating females. 8.Prior/current pulmonary fibrosis, interstitial pneumonia, pneumoconiosis, or radiation pneumonitis (unsuitable for study per investigator).

9.Autoimmune diseases requiring systemic treatment within 2 years. 10.For Observational Cohort (Palliative Care Subgroup only): Incomplete clinical data (e.g., no pathological report, inability to perform MRI/PET-CT assessment).