This study aim to evaluate the efficacy and safety of zanubrutinib combined with R-CHOP in the treatment of DLBCL patients with p53 protein expression.

This is a prospective, single arm, single center study,it plans to recruit 41 newly diagnosed DLBCL patients with p53 protein expression(≥50%).According to Simon's two-stage optimal design criteria, 19 eligible patients were recruited in the first phase, and at least 12 patients were required to achieve complete response to enter the second phase. In phase 2, additional 22 patients were recruited. These patients will receive zanubrutinib plus RCHOP for 6 cycles. After 4 treatment cycles, an interim response assessment will be performed to evaluate disease progression for each participant. Participants with progressive or stable disease will be discontinued from treatment，Participants with complete/partial response will continue ZRCHOP until 6 cycles are completed.After completion of study drug, participants will undergo assessment of tumor response based on the Revised Response Criteria for Malignant Lymphoma.

Inclusion Criteria:

1. Age ≥18 years, ≤ 75 years, both sexes;
2. Diff use large B-cell lymphoma diagnosed by histopathology without previous systemic DLBCL treatment;
3. ECOG score: 0-2;
4. Predicted survival ≥3 months;
5. Patients with positive p53 expression detected by immunohistochemistry (≥50% );
6. The patients had certain conditions of organ function reserve, and the laboratory tests within 1 week before enrollment met the following conditions:

Blood routine: neutrophil count (NEUT) ≥1.5×10^9/L, platelet count (PLT)

≥75×10^9/L, hemoglobin (HGB) ≥80 g/L; G-CSF was not used in the past 7 days (the researchers judged that the lymphoma-induced cytopenia could be included).

Liver function: Total bilirubin (TBIL) ≤1.5× upper limit of the normal range (ULN); Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2.5×ULN; If liver metastases were present, TBIL≤3×ULN, ALT and AST≤5×ULN; Renal function: serum creatinine (Cr) ≤2.0×ULN or creatinine clearance (CCr) ≥60ml/min;

Cardiac function: LVEF≥50%, ECG did not indicate any acute myocardial infarction, arrhythmia, or atrioventricular conduction block above grade I;

Thyroid function: thyroid stimulating hormone (TSH) was within the normal range. If TSH is abnormal, free triiodothyronine (FT3) and free thyroxine (FT4) should be within the normal range or abnormal without clinical significance.

1. According to the Lugano2014 assessment criteria, patients must have measurable lesions, defined as the longest diameter of at least one nodule > 1.5cm, or the longest diameter of at least one nodule > 1cm, and at least two vertical diameters that can be accurately measured.
2. Patients volunteered to participate in the trial, understood the study procedure, and were able to sign in-person informed consent.

Exclusion Criteria:

1. Patients with definite lymphoma central nervous system (CNS) infiltration, including brain parenchyma, meningeal invasion, or spinal cord compression;
2. severe or uncontrolled infection;
3. with active autoimmune disease;
4. Other serious medical conditions, such as uncontrolled diabetes, gastric ulcers, other serious cardiopulmonary diseases, etc. (the decision was left to the investigator);
5. patients who received the live attenuated vaccine within 4 weeks before the first dose or planned to receive the live attenuated vaccine during the study;
6. The subject has previous or co -e xis ting other malignant tumors; Patients with basal cell carcinoma of the skin and uterine and neck carcinoma in situ who had been cured for more than 3 years, and patients with other malignant tumors who had been cured for more than 5 years were considered for inclusion.
7. HIV-positive patients with active hepatitis B ( HBV-DNA > 100 copies/m L), positive HCV antibody, or abnormal HCV-RNA
8. Women who were pregnant or lactating, women who planned to become pregnant between the study period and 6 months after the last dose, or men whose partners planned to become pregnant, who were unwilling to use a medically approve defective contraceptive method (e.g., intrauterine device or condom ) during the trial;
9. were allergic to any of the drugs in the study protocol;
10. ineligible for inclusion as judged by the investigator ;