This is a prospective, open-label, single-arm, single-center, Phase II clinical study designed to evaluate the efficacy and safety of Efficacy and Safety of Polatuzumab Vedotin in Combination With Zanubrutinib, Rituximab, Cyclophosphamide, Doxorubicin, and Prednisone in Patients With Previously Untreated Diffuse Large B-Cell Lymphoma of the MCD/BN2/N1 Subtypes.

After successful screening, enrolled patients will receive 6 treatment cycles (21 days per cycle). Disease response will be assessed by CT/PET-CT during treatment and after completion of induction. Patients who achieve CR/PR/SD will proceed to the maintenance phase; patients who do not achieve at least SD (i.e., fail to reach CR/PR/SD) during induction will discontinue the study. Patients with CR/PR/SD after induction will receive maintenance therapy with zanubrutinib plus tislelizumab until disease progression, unacceptable toxicity, or completion of 1 year of maintenance.

Efficacy and safety assessments will be performed per protocol. Tumor response will be assessed by site investigators according to the 2014 Lugano criteria, including determination of response status, date of response, and date of progression/relapse.

Inclusion Criteria:

• Age ≥18 years at the time of signing informed consent. Histologically confirmed Diffuse Large B-Cell Lymphoma (DLBCL) with MCD/BN2/N1 molecular subtypes defined by LymphGen classification.

Previously untreated (treatment-naïve). International Prognostic Index (IPI) score of 2-5. Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2. Life expectancy ≥6 months. At least one measurable lesion in two dimensions, defined as a maximum diameter >1.5 cm by CT or MRI.

Left Ventricular Ejection Fraction (LVEF) ≥50% as assessed by echocardiogram (ECHO).

Adequate hematologic function (unless due to underlying disease, e.g., extensive bone marrow involvement, or splenomegaly secondary to splenic involvement deemed by the investigator to be caused by DLBCL; blood product transfusions are allowed), defined as follows:

Hemoglobin ≥9.0 g/dL within 7 days prior to first treatment, without packed RBC transfusion.

Absolute Neutrophil Count (ANC) ≥1.0 × 10⁹/L. Platelet count ≥75 × 10⁹/L. Female participants of childbearing potential: Must agree to abstain from heterosexual intercourse or use contraception, and agree not to donate ova.

Male participants: Must agree to abstain from heterosexual intercourse or use contraception, and agree not to donate sperm.

Exclusion Criteria:

Contraindication to any component of the Pola-ZRCHP regimen. Known active bacterial, viral, fungal, mycobacterial, parasitic, or other infection (excluding onychomycosis) at screening, or any major infection occurring within 4 weeks prior to the first dose of study treatment (as judged by the investigator).

Suspected or latent tuberculosis (confirmed by positive IFNγ release assay). Currently pregnant or breastfeeding, or planning a pregnancy during the study period or within 12 months after the last dose.

History of confirmed Progressive Multifocal Leukoencephalopathy (PML). Current or history of Central Nervous System (CNS) lymphoma. Evidence of significant, uncontrolled concomitant disease that may affect compliance with the protocol or interpretation of results.

Severe or extensive cardiovascular disease, such as New York Heart Association (NYHA) Class III or IV, or objective assessment of Class C or D cardiac disease; myocardial infarction within the past 6 months; unstable arrhythmias; or unstable angina.

Clinically significant liver disease, including active viral hepatitis or other hepatitis, current alcohol abuse, or cirrhosis.

Any of the following abnormal laboratory values (unless these abnormalities are solely attributable to underlying lymphoma):

INR or PT >1.5 × Upper Limit of Normal (ULN) in the absence of therapeutic anticoagulation.

PTT or aPTT >1.5 × ULN in the absence of lupus anticoagulant. Serum AST and ALT ≥2.5 × ULN. Total bilirubin ≥1.5 × ULN. Estimated creatinine clearance <40 mL/min (using the Cockcroft-Gault formula). Positive HBV DNA test result. Positive Hepatitis C test result (Hepatitis C virus [HCV] antibody serology). Note:Patients with positive HCV antibody are eligible only if the PCR test for HCV RNA is negative.

Any other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding that gives reasonable suspicion of a disease or condition that contraindicates the use of the investigational drug(s).