In view of the synergistic effects of rituximab, zanubrutinib, and lenalidomide and severe complications caused by current standard chemotherapy regimens in Patients for primary or secondary CNS lymphoma, we intend to conduct a prospective clinical study to evaluate the efficacy and toxicity of Rituximab, Zanubrutinib in combination with Lenalidomide. Besides, the efficacy of Zanubrutinib or Lenalidomide in maintenance was also compared.

Inclusion Criteria:

• voluntarily participate in clinical research, fully understand the study and sign the informed consent form (ICF), willing to follow and be able to complete all research steps
• histologically confirmed diffuse large B-cell lymphoma (DLBCL), all subjects must provide enough archived or fresh tumor tissue samples for immunhistochemistry (IHC) and gene expression profile (GEP) evaluation
• For untreated primary CNS lymphoma, patients should be with an age of 65 years or older, intolerable to first-line treatment
• Recurrent or refractory disease was defined as: 1) recurrence of disease after complete remission (CR), or 2) partial remission (PR), stable disease (SD), or progressive disease (PD) at the time of completion of treatment before inclusion
• Recurrent / refractory diffuse large B-cell lymphoma with CNS involvement confirmed by histopathology or imaging
• Age ≥ 18 years, ECoG score ≤ 2, expected survival time is more than 3 months
• Patients with solid lesions must obtain clear evidence of disease progression through imaging examination (head MRI or head CT) 21 days before enrollment. For patients with leptomeningeal involvement only, CSF cytology examination must confirm lymphoma cells and / or imaging findings consistent with CSF disease 21 days before enrollment (at the discretion of the investigator)
• With sufficient organ and bone marrow function , and no severe hematopoietic, heart, lung, liver, kidney, thyroid dysfunction and immune deficiency
• at least 100 days after transplantation for recurrent patients after ATST

Exclusion Criteria:

• Histologically transformed large cell lymphoma
• History of previous transplantation of allogeneic stem cells
• Received BTKi or Lenalidomide
• Received corticosteroid within 7 days for antitumor treatment
• Received chemotherapy, radiotherapy, monoclonal antibody, experimental treatment, or traditional Chinese Medicine within 4 weeks
• Received major surgery within 4 weeks
• Active malignant diseases within 2 years before entering the study
• Clinically significant cardiovascular diseases
• History of severe bleeding diseases
• history of stroke or intracranial hemorrhage within 6 months before the first administration
• Unable to swallow capsules or have diseases that significantly affect gastrointestinal function
• Uncontrolled systemic infection requiring parenteral anti infective therapy
• HIV infection or indicate active hepatitis B or C virus infection
• Drug allergies or metabolic disorders
• Pregnant or lactating women
• Any life-threatening diseases, medical conditions or organ system dysfunction that the researchers believe may affect the safety of the subjects or lead to research risks
• Required to continuously treated with potent and moderate CYP3A inhibitors or inducers
• History of deep venous thrombosis (DVT) or pulmonary embolism (PE) in the past 12 months