• Any of the following diseases histologically confirmed:

∙ Primary CNS lymphoma or isolated secondary CNS involvement by diffuse large B cell lymphoma with measurable disease

‣ Cytologic diagnosis of B cell non-Hodgkin's lymphoma with measurable disease

‣ Ocular lymphoma with histologic confirmation of ocular lymphoma and measurable intracranial tumor. Slit-lamp examination and vitreal or retinal biopsy will be done to confirm ocular lymphoma.

• Karnofsky performance status (KPS) ≥ 30% (≥ 50% for patients ≥ 60 years-old)

• Progressed during first-line chemotherapy and/or radiotherapy -OR- insufficient clinical response to previous therapy or relapsed after initial successful treatment OR unable to tolerate previous therapy defined as Grade 3+ acute kidney injury (AKI) and/or transaminase elevation according to CTCAE v 5.0 criteria preventing repeat treatment exposure OR prior glucarpidase use due to high dose methotrexate delayed clearance and/or toxicity OR those who would have been glucarpidase candidates due to delayed methotrexate clearance (plasma methotrexate concentrations greater than 2 standard deviations of the mean methotrexate excretion curve specific for the dose of methotrexate administered or toxic plasma methotrexate concentrations (\>1 micromole per liter) in patients with delayed methotrexate clearance) due to impaired renal function OR unable to receive high dose methotrexate induction on every 2 week +/- 3 days schedule due to deconditioning and/OR need for physical rehabilitation between the high dose methotrexate treatments

• No systemic lymphoma by positron emission tomography (PET) CT or CT scan of the chest, abdomen, and pelvis with contrast

• Adequate bone marrow and organ function demonstrated by:

∙ Absolute neutrophil count (ANC) ≥ 1.5 x 10\^9/L

‣ Platelets ≥ 75 x 10\^9/L and no platelet transfusion within the past 14 days prior to study enrollment

‣ Hemoglobin (Hgb) ≥ 8 g/dL and no red blood cell (RBC) transfusion within the past 14 days prior to study enrollment

‣ Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3 times the upper limit of normal

‣ Serum bilirubin ≤ 1.5 times the upper limit of normal; or total bilirubin ≤ 3 times the upper limit of normal with direct bilirubin within the normal range in patients with well documented Gilbert Syndrome

‣ Creatinine Clearance (CrCl)\> 45 mL/minute using Cockcroft-Gault formula

• Ability to understand and sign written informed consent prior to study entry unless the subject suffers from cognitive or physical impairment due to their CNS malignancy or due to a known underlying medical condition in which case consent could be signed by proxy

• Life expectancy of at least 2 months

• Females of childbearing potential must use highly effective method of contraception for the duration of the study and ≥ 30 days after the last dose of zanubrutinib. Female must also have a negative urine or serum pregnancy test ≤ 7 days before initial treatment.

‣ The investigator or a designated associate is requested to advise the patients how to achieve highly effective birth control (failure rate of less than 1%), e.g., intrauterine device (IUD), intrauterine hormone-releasing system (IUS), bilateral tubal occlusion, vasectomized partner and sexual abstinence. Females using hormonal contraception should use barrier methods in addition.

⁃ Male patients with a female partner of childbearing potential are eligible if abstinent, vasectomized, or if they agree to the use of barrier contraception with other methods described above during the study treatment period and for up to one week after the last dose of zanubrutinib.

• Agreement to use contraception during study participation

⁃ Female patients of childbearing potential must practice highly effective methods of contraception.

⁃ Male patients with female partners must be abstinent, vasectomized, or agree to the use of barrier contraception in combination with other methods. Acceptable contraception methods are included in the study protocol.

⁃ Patients using hormonal contraceptives (e.g., birth control pills or devices) must use a barrier method of contraception (e.g., condoms) as well.

• For patients with Infectious disease, must have:

∙ HIV positive with negative viral load and CD4 count \> 400

‣ Non-viremic Hepatitis C Virus (HCV)

‣ HBcAb (Hepatitis B core positive) and HBsAg negative