This is a Phase I/II study. The Phase I part will evaluate the safety and tolerability of sonrotoclax in combination with polatuzumab vedotin plus rituximab, cyclophosphamide, doxorubicin, and prednisone (Pola-R-CHP), using a standard 3+3 dose-escalation design, to determine the maximum tolerated dose (MTD) and recommended Phase II dose (RP2D). The Phase II part will assess the efficacy of the combination regimen in patients with previously untreated LBCL with high BCL2 expression or MYC/BCL2 rearrangements.

Inclusion Criteria:

• Patients with newly diagnosed large B-cell lymphoma confirmed by histopathology, CD20-positive, excluding central nervous system lymphoma;
• Patients aged 18 to 75 years;
• International Prognostic Index score of 2 to 5;
• Patients with high BCL-2 expression or double-hit lymphoma characteristics;
• No prior anti-tumor treatment of any type;
• Estimated survival time ≥ 6 months;
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2;
• Measurable lesions confirmed by radiological examination, defined as: at least one lymph node lesion with the longest diameter > 1.5 cm, or at least one extranodal lesion with the longest diameter > 1.0 cm, and at least two accurately measurable perpendicular diameters;
• Patients or their legal representatives must provide written informed consent before conducting any study-specific examinations or procedures;
• No prior treatment for lymphoma (except glucocorticoids).

Exclusion Criteria:

• Prior solid organ transplantation or stem cell transplantation;
• Complicated with uncontrolled coagulation disorders, connective tissue diseases, severe infectious diseases, etc.;
• Suspected active or latent tuberculosis (confirmed by a positive interferon-gamma release assay);
• Any of the following abnormal laboratory test values (unless these abnormalities are all caused by the underlying lymphoma):
• Neutrophils < 1.0×10⁹/L;
• Platelets < 75×10⁹/L;
• Serum AST and ALT ≥ 2.5× upper limit of normal (ULN);
• Total bilirubin ≥ 1.5×ULN;
• Serum creatinine clearance < 30 mL/min (calculated using the Cockcroft-Gault formula);
• Uncontrolled or significant cardiovascular diseases, including but not limited to:
• Left ventricular ejection fraction (LVEF) < 50%;
• Primary cardiomyopathy, such as dilated cardiomyopathy, hypertrophic cardiomyopathy, restrictive cardiomyopathy, etc.;
• Clinically significant QTc prolongation, with QTc interval > 470 ms (females) or 480 ms (males), second-degree type II atrioventricular block, or third-degree atrioventricular block;
• Current or past history of central nervous system (CNS) diseases, such as stroke, epilepsy, CNS vasculitis, or neurodegenerative diseases. However, participants with a history of stroke who have not had a stroke or transient ischemic attack in the past 2 years and have no residual neurological deficits as judged by the investigator are allowed to participate in the study;
• Patients with mental illness or other patients known or suspected to be unable to fully comply with the study protocol;
• Patients infected with human immunodeficiency virus (HIV);
• History of other malignant tumors that may affect protocol compliance or interpretation of results:
• Participants with a history of cured basal or squamous cell carcinoma of the skin, melanoma, or carcinoma in situ of the cervix at any time before the study are eligible to participate;
• Participants with a history of untreated low-grade early-stage prostate cancer (Gleason score ≤ 6, Stage 1 or 2) at any time before the study are eligible to participate;
• Participants who received adjuvant endocrine therapy for non-metastatic, hormone receptor-positive breast cancer for ≥ 2 years before enrollment are eligible to participate;
• Participants with any other malignant tumor cured by appropriate radical treatment and in remission without treatment for ≥ 2 years before enrollment are eligible to participate;
• History of immune-related adverse events following prior immunotherapy drug-related treatment, as follows: known active bacterial, viral, fungal, mycobacterial, parasitic, or other infections (excluding onychomycosis) at study enrollment, or major infections within 4 weeks before the start of Cycle 1;
• Active hepatitis B virus (HBV) infection (positive result by PCR). For patients with positive HBsAg test results, HBV DNA test is required; if HBV DNA < 10³ IU/ml, they can be enrolled. If HBsAg test result is negative but HBcAb test is positive (regardless of HBsAb status), HBV DNA test is also required; if HBV DNA < 10³ IU/ml, they can be enrolled;
• Positive hepatitis C test result (serological test for hepatitis C virus [HCV] antibody):
• Eligibility to participate is only allowed if the PCR test result for HCV RNA is negative in patients with positive HCV antibody;
• Participants with a history of progressive multifocal leukoencephalopathy (PML);
• Currently pregnant or breastfeeding, or planning to become pregnant during the study or within 12 months after the last dose;
• Other concurrent and uncontrolled medical conditions that the investigator believes will affect the patient's participation in the study.