Brief Summary: This study is investigating a new administration schedule of Rituximab, Cyclophosphamide, Doxorubicin, Vincristine, Prednisone (R-CHOP) chemotherapy for participants with Diffuse Large B-Cell Lymphoma (DLBCL), focusing on an underserved elderly population (aged 75 and up; certain participants 70-74 may be eligible) that is often excluded from clinical trials. Participants can expect to be on study for 2.5 years (treatment for 6 months and 2 years of post treatment follow-up).

Detailed Description: This study will test the efficacy of split-dose R-CHOP for the treatment of elderly patients with de novo diagnosis of DLBCL or transformed DLBCL. Split-dose R-CHOP involves giving Cyclophosphamide, Doxorubicin, Vincristine, Prednisone (CHOP) chemotherapy at 14 days' interval with Rituximab given once/month. The safety for every 14-day CHOP administration was studied in a large prospective randomized control trial of patients up to the age of 80 years. In this study, R-CHOP given every 14 days for up to 6 cycles was felt to be the best method of delivery of chemotherapy. Receiving greater than 6 cycles of R-CHOP chemotherapy was not found to be beneficial compared to participants receiving 6 cycles of R-CHOP. Additionally, an interim response adapted approach by combining imaging and MRD testing will be used to identify participants who will receive an abbreviated chemotherapy course if they are both Positron Emission Tomography/Computed Tomography (PET/CT) and Minimum Residual Dose (MRD) negative. In the proposed study, participants will receive a 50% dose reduction of CHOP chemotherapy on Day 1 and Day 15 of each cycle with full dose Rituximab on Day 1 for up to a total of 6 months of chemotherapy. Participants who are MRD and PET/CT negative after 2 months will be placed on an abbreviated regimen with R-CHOP x 4 additional doses with full dose Rituximab and a 50% dose reduction in CHOP chemotherapy. The hypothesis is that this method of administration of R-CHOP will be a safe and effective form of chemotherapy for older patients with DLBCL and will allow older patients to receive curative intent treatment.