This is a prospective, single-arm, single-center clinical study. This clinical study aims to explore the efficacy and safety of the ZPR（Zanubrutinib, Polatuzumab vedotin and Rituximab）regimen in the treatment of patients with relapsed and refractory diffuse large B-cell lymphoma.

This is a prospective, single-arm, single-center clinical study. This clinical study aims to explore the efficacy and safety of the ZPR（Zanubrutinib, Polatuzumab vedotin and Rituximab）regimen in the treatment of patients with relapsed and refractory diffuse large B-cell lymphoma.

• Primary objective: use ORR to evaluate the effectiveness of ZPR in treating R/R DLBCL patients
• Secondary objective: Evaluate the safety of ZPR treatment for R/R DLBCL patients
• The subjects received 6 cycles of ZPR regimen, one cycle every 21 days. Then Zanubrutinib alone will continue to be used until Zanubrutinib has been used for 1 year or the disease progresses or the adverse effects, death, withdrawal of informed consent or study termination.

Zanubrutinib（Z）160 mg bid po Day 1-21; Polatuzumab vedotin（P）1.8 mg/kg ivgtt D1; Rituximab（R）375 mg/m2 ivgtt D1.

Inclusion Criteria:

Patients must meet all of the following inclusion criteria to be enrolled in this study:

• Patients with histopathologically confirmed DLBCL;

• Relapsed or refractory disease, defined as

  1. Disease relapse occurred after reaching disease remission (including complete response [CR] and partial response [PR]) at the end of the last treatment
  2. Maintain stable disease (SD) or progressive disease (PD) at the end of the last treatment

• The age of patients ≥ 18 years old and ≤ 80 years old;

• The ECOG score was 0-2;

• Good organ function;

• Measurable lesions detected by radiological imaging were defined as the longest diameter of at least 1 lymph node lesion > 1.5 cm, or the longest diameter of at least 1 extranodal lesion > 1.0 cm, and at least 2 vertical diameters that could be accurately measured;

• Previously received ≥ 1 systemic therapy for lymphoma;

• Participants who relapse after autologous stem cell transplantation may be included, provided that the transplantation treatment has been more than 6 months from the screening;

• Fresh tumor biopsies or recent tumor tissue samples must be provided (within 2 years after study entry [signed informed consent]);

• Fertile women must agree to use efficient contraceptive measures throughout the study and at least 90 days after the last dose of study drug. The effective forms of birth control are defined as abstinence, hysterectomy, bilateral oophorectomy without menstrual bleeding for up to 6 months, intrauterine contraception, hormonal methods such as contraceptive injection, oral contraceptives; Fertile men must undergo sterilization vasectomy or use condoms, while their female partners use the above efficient contraceptive measures;

• Life expectancy ≥ 6 months;

• Sign written informed consent.

Exclusion Criteria:

Patients with any of the following conditions cannot be enrolled in this study:

• Patients with primary central nervous system lymphoma;

• Patients with previous exposure to BTK inhibitors;

• Accompanied by uncontrolled cardiovascular and cerebrovascular diseases, coagulation disorders, connective tissue diseases, serious infectious diseases, etc;

• Currently clinically significant active cardiovascular disease, such as uncontrolled arrhythmia, congestive heart failure, any grade 3 or 4 heart disease defined by the New York Heart Association functional classification, or history of myocardial infarction within 6 months after screening. The left ventricular ejection fraction measured by echocardiography was < 50%;

• Abnormal laboratory indicators at screening (unless caused by lymphoma):

  1. ANC<1.5×10^9/l, PLT<80×10^9/l
  2. Coagulation function: INR greater than 1.5 times the upper limit of normal value; Pt and APTT were greater than 1.5 times the upper limit of normal
  3. Liver function: ALT or ast was 2 times higher than the upper limit of normal, AKP and bilirubin were 1.5 times higher than the upper limit of normal
  4. Renal function: creatinine was 1.5 times higher than the upper limit of normal, creatinine clearance rate was < 60 ml/min (estimated according to Cockcroft Gault formula)

• HIV-infected persons;

• HCV active infection;

• HBsAg positive patients need to be HBV DNA negative before enrollment; In addition, if the patient is HBsAg negative but HBcAb positive (regardless of HBsAb status), HBV DNA testing is still required. If the result is positive, antiviral treatment is required, and HBV DNA is required to be negative before enrollment;

• Other concurrent and uncontrolled medical conditions that the investigator believes will affect the patient's participation in the study, including psychiatric patients or other patients who are known or suspected to be unable to fully comply with the study protocol;

• Known allergy to test drug;

• Inability to swallow capsules or suffering from diseases that seriously affect gastrointestinal function, such as malabsorption syndrome, gastrectomy or small bowel resection, symptomatic inflammatory bowel disease, or partial or complete intestinal obstruction;

• Pregnant or lactating women;

• Corticosteroids (dose equivalent to prednisone > 20 mg/ day) were previously given for antitumor purposes within 7 days, and chemotherapy, targeted therapy, or radiotherapy were previously received within 3 weeks, or antibody-based therapy was received within 3 weeks, or traditional Chinese medicine anticancer therapy was performed within 4 weeks;

• Major surgery was performed within 4 weeks after screening;

• Sustained treatment with potent and moderate CYP3A inhibitors or CYP3A inducers is needed. Patients could not be enrolled if they had taken potent and moderate CYP3A inhibitors or CYP3A inducers within 7 days before the first administration of study drugs (or had taken these drugs for no more than 5 half-lives).

The data of all patients will be stored in the self-owned EDC system of Zhongshan Hospital Affiliated to Fudan University, and the research results will be published in the form of research papers.