The purpose of this study is to compare the efficacy and safety of genotype-guided targeted agents in combination with polatuzumab vedotin plus rituximab, cyclophosphamide, doxorubicin, and prednisone (Pola RCHP-X) versus Pola RCHP in Chinese patients with previously untreated diffuse large B-cell lymphoma (DLBCL).

Inclusion Criteria:

• Signed Informed Consent Form

• Age 18-75 years at the time of signing Informed Consent Form and willingness to comply with study protocol procedures

• Previously untreated participants with CD20-positive DLBCL

• IPI score 2-5

• ECOG Performance Status of 0, 1, or 2

• After 1 cycle of Pola-R-CHP, ctDNA decreased by < 3.0 LFC

• Life expectancy ≥ 6 months

• Left ventricular ejection fraction (LVEF) ≥ 50% on cardiac multiple-gated acquisition (MUGA) scan or cardiac echocardiogram (ECHO)

• Adequate hematologic function (unless due to underlying disease, as established for example, by extensive bone marrow involvement or due to hypersplenism secondary to involvement of the spleen by DLBCL per the investigator for which blood product transfusions are permitted) defined as follows:

  • Hemoglobin ≥ 9.0 g/dL without packed RBC transfusion during 7 days before first treatment
  • ANC ≥ 1.0 x 10^9/L
  • PLT ≥ 75 x 10^9/L

Exclusion Criteria:

• Contraindication to any of the individual components of Pola-RCHP or Acalabrutinib/Lenalidomide/ Decitabine

• Prior solid organ transplantation or SCT

• Current diagnosis of the following: Follicular lymphoma grade 3B; mediastinal grey zone lymphoma; primary mediastinal (thymic) large B-cell lymphoma; Burkitt lymphoma; PCNSL

• History of other malignancy that could affect compliance with the protocol or interpretation of results

  • Participants with a history of curatively treated basal or squamous cell carcinoma or melanoma of the skin or in situ carcinoma of the cervix at any time prior to the study are eligible
  • Participants with low-grade, early-stage prostate cancer (Gleason score 6 or below, Stage 1 or 2) with no requirement for therapy at any time prior to study are eligible
  • Participants receiving adjuvant endocrine therapy for non-metastatic, hormone receptor-positive breast cancer for ≥ 2 years prior to enrollment are eligible
  • Participants with any other malignancy appropriately treated with curative intent and the malignancy has been in remission without treatment for ≥ 2 years prior to enrollment are eligible

• Significant or extensive history of cardiovascular disease such as New York Heart Association Class III or IV cardiac disease or Objective Assessment Class C or D, myocardial infarction within the last 6 months prior to the start of Cycle 1, unstable arrhythmias, or unstable angina

• Current or past history of CNS disease, such as stroke, epilepsy, CNS vasculitis, or neurodegenerative disease.

  - Participants with a history of stroke who have not experienced a stroke or transient ischemic attack in the past 2 years and have no residual neurological deficits, as judged by the investigator, are allowed

• History or presence of an abnormal ECG that is clinically significant in the investigator's opinion

• History of treatment-emergent immune-related adverse events associated with prior immunotherapeutic agents, as follows:

  - Known active bacterial, viral, fungal, mycobacterial, parasitic, or other infection (excluding fungal infections of nail beds) at study enrollment or significant infections within 4 weeks before the start of Cycle 1

• Active autoimmune disease which is not well controlled by therapy

  • Participants with a history of autoimmune-related hypothyroidism on a stable dose of thyroid-replacement hormone may be eligible
  • Participants with controlled Type 1 diabetes mellitus who are on an insulin regimen are eligible for the study
  • Participants with active autoimmune disease with dermatologic manifestations are eligible for the study
  • Participants with a history of autoimmune hepatitis, systemic lupus erythematosus, inflammatory bowel disease, vascular thrombosis associated with antiphospholipid syndrome, Wegener granulomatosis, Sjögren syndrome, multiple sclerosis, or glomerulonephritis will be excluded
  • Participants with a history of immune thrombocytopenic purpura, autoimmune hemolytic anemia, Guillain-Barré syndrome, myasthenia gravis, myositis, rheumatoid arthritis, vasculitis, or other autoimmune disease will be excluded unless they have not required systemic therapy in the last 12 months

• Any of the following abnormal laboratory values (unless any of these abnormalities are due to underlying lymphoma):

  • ANC < 1.0 x 10^9/L
  • PLT < 75 x 10^9/L
  • Serum AST and ALT ≥ 2.5 x ULN
  • Total bilirubin ≥ 1.5 x ULN
  • Serum creatinine clearance < 30 mL/min (using Cockcroft-Gault formula)

• Any active infection within 7 days prior to Cycle 1 Day 1 that would impact participant safety

• Suspected active or latent tuberculosis (as confirmed by a positive interferon-gamma release assay)

• Positive test results for chronic hepatitis B infection (defined as positive hepatitis B surface antigen [HBsAg] serology)

  - Participants with occult or prior hepatitis B infection (defined as positive total hepatitis B core antibody and negative HbsAg) may be included if hepatitis B virus (HBV) DNA is undetectable at the time of screening. Such participants must be willing to undergo HBV DNA testing every month and appropriate antiviral therapy as indicated

• Positive test results for hepatitis C (hepatitis C virus [HCV] antibody serology testing)

  - Participants positive for HCV antibody are eligible only if PCR is negative for HCV RNA

• Participants with a history of progressive multifocal leukoencephalopathy

• Pregnancy or breastfeeding, or intention of becoming pregnant during the study or within 12 months after final dose of Pola-RCHP-X

• Other concurrent and uncontrolled medical conditions that, in the opinion of the investigator, would affect the patient's participation in the study