Split-Dose R-CHOP for Older Adults With DLBCL

Inclusion Criteria: * Signed and dated informed consent document indicating that the participant (or legally acceptable representative) has been informed of all pertinent aspects of the trial * All patients age ≥75 years and participants aged 70-74 years who are determined to be unfit or frail by Cumulative Illness Rating Score-Geriatrics (CIRS-G) scale * For participants aged 70-74 years: CIRS-G score with 5-8 comorbid conditions scored 2 or ≥1 comorbidity scored 3-4. CIRS-G score is to be reviewed by the study PI prior to enrollment. * Newly diagnosed, untreated, biopsy proven CD20 positive DLBCL (including high grade B-cell lymphoma \& T-cell/histiocytic rich large B-cell lymphoma). Participants with discordant bone marrow (i.e. involved by low-grade/indolent NHL) are eligible. Participants with transformed DLBCL from underlying low-grade disease are eligible. Participants with composite DLBCL and concurrent low-grade lymphoma are eligible. * Copy of pathology report must be sent to coordinating site to confirm diagnosis for eligibility * Participants with prior treatment for low grade NHL with non-anthracycline based regimens are eligible * Measurable disease by PET/CT or Bone Marrow (BM) biopsy prior to enrollment * Left ventricular ejection fraction ≥50% by resting echocardiography or resting Multi-gated acquisition (MUGA) scan * Karnofsky Performance Score ≥50 * Ann Arbor Stage II bulky, III, or IV disease * Minimum life expectancy greater than 3 months * Negative HIV test * For participants with hepatitis B virus antigen (HbsAg) or core antibody (HbcAb) seropositivity, participants must have a negative Hep B viral load and an appropriate prophylaxis plan must be in place during chemotherapy therapy treatment. For all participants that have Hep B core antibody positive, they should take entecavir prophylaxis (0.5 mg PO daily) until 1 year from completion of chemotherapy. Hep B viral load should be checked on these participants prior to starting chemotherapy and every 3 months thereafter if initial Hep B viral load is negative (+/- 1 week if chemotherapy cycle is delayed). If Hep B viral load is positive, Hepatology or Identification (ID) referral is recommended, and hepatitis B virus (HBV) viral load should be checked monthly * For participants with hepatitis C Ab (HbcAb) positivity, a viral load must be checked and be negative for enrollment * Intrathecal chemotherapy for central nervous system prophylaxis only can be given at the discretion of the primary oncologist Exclusion Criteria: * History of previous anthracycline exposure * Central Nervous System (CNS) or meningeal involvement at diagnosis * Creatinine Clearance \<25 mL/min by body surface area (BSA)-adjusted Cockroft-Gault * Poor hepatic function, defined as total bilirubin concentration greater than 3.0 mg/dL or transaminases over 4 times the maximum normal concentration, unless these abnormalities are felt to be related to the lymphoma. * Pulmonary dysfunction defined as \>2 L of oxygen required by nasal cannula to maintain peripheral capillary oxygen saturation (SpO2) ≥90% unless felt to be related to underlying lymphoma. * Myocardial Infarction within 6 months of enrollment * Active, uncontrolled infectious disease * Known concurrent bone marrow malignancies (e.g. myelodysplastic syndrome) or poor bone-marrow reserve, defined as neutrophil count less than 1.5×10⁹/L or platelet count less than 100×10⁹/L, unless caused by bone-marrow infiltration with lymphoma * History of a second concurrent active malignancy or prior malignancy which required chemotherapy treatment within the preceding 2 years * Treatment with any investigational drug within 30 days before the planned first cycle of chemotherapy * Unable or unwilling to sign consent