R-MA-PD-1 Versus R-MA in Treatment-naive Primary CNS Lymphoma

Primary central nervous system lymphoma is a rare, aggressive non-Hodgkin lymphoma, predominantly diffuse large B-cell lymphoma. High-dose methotrexate-based chemotherapy is the standard induction, but the optimal combination remains to be defined. Building on a prior single-arm phase II study of penpulimab plus R-MA (NCT05347641), this randomized controlled study evaluates whether adding the PD-1 inhibitor penpulimab to R-MA improves efficacy in treatment-naive PCNSL.

Induction (both arms, every 21 days x 6 cycles):

• Rituximab 375 mg/m2 (Day 0)
• Methotrexate 3.5 g/m2 (Day 1)
• Cytarabine (Ara-C): age <60 or ECOG ≤2: 2 g/m2 q12h Day 2-3; age ≥60 or ECOG >2: 1 g/m2 q12h Day 2 (from cycle 2)
• Experimental arm only: Penpulimab 200 mg (Day 5)

Consolidation (response- and age-adapted): patients <60 years achieving PR/CR proceed to autologous stem cell transplantation (thiotepa + busulfan); patients ≥60 years or ASCT-ineligible receive penpulimab maintenance (CR) or whole-brain radiotherapy 36 Gy plus penpulimab maintenance (PR). Experimental-arm responders receive 8 cycles of penpulimab maintenance.

Sample size: 58 participants (29 vs 29), based on 2-year PFS of 39% (R-MA) versus 70% (R-MA-PD-1), two-sided alpha 0.05, power 80%, 18-month enrollment, 30-month follow-up, 10% dropout (PASS 15.0).

Inclusion criteria

• Fully understands the study and voluntarily signs informed consent.
• Age 18 to 80 years.
• Treatment-naive, pathologically (immunophenotypically) confirmed PCNSL (per 2016 WHO classification).
• Diffuse large B-cell lymphoma originating in the CNS without other organ involvement, confirmed by PET-CT or contrast-enhanced CT.
• Expected survival more than 3 months.
• Laboratory: creatinine clearance ≥50 mL/min (Cockcroft-Gault); INR ≤1.5 x ULN or aPTT ≤1.5 x ULN (INR 2-3 allowed if on warfarin); LVEF ≥50%.
• GFR ≥60 mL/min.
• Participants of childbearing potential must agree to use effective contraception during the study and for 30 days after the last dose.

Exclusion criteria

• Contraindication to any study drug.
• Clinically significant liver disease, including viral or other hepatitis or cirrhosis (active HBV or active hepatitis C as defined).
• HIV infection.
• History of allergic disease, severe drug allergy, or known hypersensitivity to macromolecular protein preparations or any component of penpulimab.
• Prior anti-PD-1/PD-L1/PD-L2, anti-CTLA-4 antibody, CAR-T, or any other agent targeting T-cell co-stimulation or checkpoint pathways.
• Congestive heart failure (NYHA >2); acute myocardial infarction, unstable angina, stroke, or transient ischemic attack within 6 months.
• Congenital long QT syndrome or QTcF >480 ms.
• Other malignancy within the past 5 years (except adequately treated in situ cervical carcinoma, basal cell skin carcinoma, in situ breast carcinoma, or a second primary cancer cured and recurrence-free for 5 years).
• Pregnant or lactating women, or intending to become pregnant during the study.
• History of clinically significant neurological or psychiatric disorder, or substance/drug abuse.
• Clinically significant active infection.