This single-center, open, single-arm study aim to evaluate the efficacy and tolerability of a therapy introducing zanubrutinib on the basis of rituximab and methotrexate (MTX) [or temozolomide (TMZ), if intolerant to MTX] in treating patients newly diagnosed with primary CNS large B-cell lymphoma and intolerant to HSCT.

Participants will receive zanubrutinib in addition to first-line therapy consisting of rituximab and either MTX or TMZ. After treatment of 6 cycles with the new regimen, the patients achieving CR or PR would go on to receive zanubrutinib maintenance of 1 year (if tolerable).

Inclusion Criteria:

• 18 to 80 years old;
• Histopathologically confirmed CD20 positive primary large B-cell lymphoma of the central nervous system (CNS) or primary vitreoretinal lymphoma according to the 5th edition of the World Health Organization (WHO) Classification of Haematolymphoid Tumours [primary large B-cell lymphoma of the CNS previously named as primary diffuse large B-cell lymphoma (DLBCL) of the CNS in the revised 4th edition];
• Life expectancy of > 3 months (in the opinion of the investigator);
• Creatinine Clearance Rate (CCR) ≥ 50 mL/min or estimated Glomerular Filtration Rate (eGFR) ≥ 60 mL/(min·1.73 m^2);
• International Normalized Ratio (INR) ≤ 1.5 and activated Partial Thromboplastin Time (aPTT) ≤ 1.5 times the upper limit of normal;
• Left Ventricular Ejection Fraction (LVEF) ≥ 50%;
• Agreeing to provide written informed consent prior to any special examination or procedure for the research on their own or legal representative.

Exclusion Criteria:

• Pregnant or lactating women;
• Known Hepatitis B Virus (HBV) and/or Hepatitis C Virus (HCV) infection (HBV infection refers to HBV-DNA > detectable limit);
• With acquired or congenital immunodeficiency;
• With congestive heart failure in 6 months before enrollment, New York Heart Association (NYHA) heart function class III or IV, or LVEF < 50%;
• Known to be allergic to the test drug ingredients;
• Diagnosed with or being treated for malignancy other than lymphoma;
• With severe infection;
• Substance abuse, medical, psychological, or social conditions that may interfere with the subjects' participation in the study or evaluation of the study results;
• Deemed unsuitable for the group.