This is a prospective single-arm phase II study, with the purpose of evaluating the efficiency of ZR-MTX regimen (Rituximab, Zanubrutinib and methotrexate) combined with intravitreal methotrexate, then followed by minimal residual disease directed Zanubrutinib maintenance in newly-diagnosed primary intraocular lymphoma. The primary endpoint of this study is progression-free survival (PFS).

All the patients will be treated with ZR regimen (Rituximab 375mg/m2 IV d1, Zanubrutinib 160mg Bid, 21 days per cycle) as induction regimen. The response will be evaluated after 2 cycles of ZR regimen. Patients who achieved complete remission (CR) or partial remission (PR) or stable disease (SD) will receive 2 more cycles of ZR regimen. The patients with progressed disease (PD) will withdraw from the trial and receive salvage regimens. Then 2 more cycle of ZR regimen will be administrated. Patients will be evaluated again, those achieved CR or PR or SD will continue to receive 2 cycles of ZR-MTX regimen (Rituximab 375mg/m2 IV d1, Methotrexate 3.5g/m2 IV d1, Zanubrutinib 160mg Bid, 21 days per cycle), while those PD will drop out. In the meantime, intravitreal methotrexate will be given at a dose of 400ug for 16 doses. After total 6 induction cycles, the investigators evaluate the efficiency again, the patients with CR and MRD negativity (by CSF IL-10 and cfDNA) will stop treatment. Those with MRD positive CR or PR or SD will go to Zanubrutinib maintenance for 2 years or until progression of the disease (PD), unacceptable toxicity, or patient/investigator discretion. And the patients with PD will receive a salvage regimen. During following-up, surveillance ophthalmologic examination, and brain magnetic resonance imaging (MRI) scans can be performed every 3 months up to the first 2 years, followed by the doctor's visit every 6 months for up to 5 years or disease relapses.

Inclusion Criteria:

• • Newly-diagnosed primary vitreoretinal lymphoma

  • ECOG≤2
  • creatinine clearance rate (CCR) ≥ 60ml/h, according to Cockcroft-Gault
  • Total bilirubin # 2 upper limits of normal, alanine aminotransferase#ALT# < 3 upper limits of normal
  • Sign the Informed consent
  • Women of childbearing potential must understand that the study medication could have a potential teratogenic risk. They should undergo complete contraception during the study period.
  • Male subjects must agree to use condoms throughout study drug therapy.

Exclusion Criteria:

• • primary central nervous system lymphoma involved eyes and brain

  • systemic B cell lymphoma involved eyes
  • Pre-existing uncontrolled active infection
  • Clinical evidence of grade 3 or 4 heart failure as defined by the New York Heart Association criteria
  • Pregnancy or active lactation
  • Co-existing tumors
  • HIV or HBV or HCV infection

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