Major Inclusion Criteria:  Previously untreated patients with local biopsy-proven, CD20-positive DLBCL, including one of the following diagnoses by 2016 World Health Organization (WHO) classification of lymphoid neoplasms are eligible:  DLBCL, NOS including GCB type, ABC type T-cell rich large BCL Epstein-Barr virus-positive DLBCL, NOS Anaplastic lymphoma kinase (ALK)-positive large BCL Human herpes virus-8 (HHV8)-positive DLBCL, NOS High-grade BCL with MYC and B-cell lymphoma 2 (BCL2) and/or B-cell lymphoma 6 (BCL6) rearrangements (double-hit or triple-hit lymphoma). Please note: Patients must be appropriate candidates for R-CHOP. If an investigator deems a patient with a known double- or triple-hit lymphoma (HGBL) should be treated more aggressively (e.g. dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin and rituximab [DA-EPOCH-R] or cyclophosphamide, vincristine, doxorubicin and dexamethasone (CVAD) followed by methotrexate and cytarabine [Hyper CVAD]), this patient would not be considered eligible for this study DLBCL coexistent with either follicular lymphoma (FL) of any grade, gastric MALT lymphoma or non-gastric MALT lymphoma FL grade 3b Availability of archival or freshly collected tumor tissue sent for retrospective central pathology review IPI status of 3 to 5 (for patients > 60 years of age) or aaIPI 2 to 3 (for patients ≤ 60 years of age) Diagnosis to treatment interval, defined as the time between the date of DLBCL diagnosis (date of the first biopsy specimen containing lymphoma according to the local pathology report) and the start of treatment (C1D1) ≤ 28 days ECOG performance status of 0, 1, or 2 Left ventricular ejection fraction equal to or greater than lower limit of institutional normal range, assessed by local echocardiography or cardiac multi-gated acquisition (MUGA) scan Adequate hematologic function Female participants: Agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive methods and refrain from breast feeding and donating eggs; agreement to ongoing pregnancy testing during the course of the study, and after study therapy has ended Male participants: agreement to remain abstinent (refrain from heterosexual intercourse) or use a condom and agreement to refrain from donating sperm  Major Exclusion Criteria:  Any other histological type of lymphoma according to WHO 2016 classification of lymphoid neoplasms, e.g., primary mediastinal (thymic) large B-cell lymphoma, Burkitt's lymphoma, BCL, unclassifiable, with features intermediate between DLBCL and classical Hodgkin lymphoma (grey-zone lymphoma); primary effusion lymphoma; primary cutaneous DLBCL, leg type; primary DLBCL of the CNS; DLBCL arising from CLL or indolent lymphoma  History of prior non-hematologic malignancy except for the following:  Malignancy treated with curative intent and with no evidence of active disease present for more than 2 years before screening Adequately treated lentigo maligna melanoma without current evidence of disease or adequately controlled non-melanomatous skin cancer Adequately treated carcinoma in situ without current evidence of disease Any systemic anti-lymphoma and/or investigational therapy prior to the start of C1D1, except for permitted pre-phase treatment Contraindication to any of the individual components of R-CHOP, including prior receipt of anthracyclines Known CNS lymphoma involvement Known active systemic bacterial, viral, fungal, or other infection at screening, including patients with suspected active or latent tuberculosis (as confirmed by a positive interferon-gamma release assay) History or evidence of clinically significant cardiovascular, CNS and/or other systemic disease that in the investigator's opinion would preclude participation in the study or compromise the patient's ability to give informed consent