ctDNA-guided Therapy Optimization in Newly Diagnosed DLBCL

Inclusion Criteria: 1. Patients with newly diagnosed, histologically confirmed CD20+ DLBCL * Stage II-IV disease * Planned for anthracycline-based therapy with standard dosed R-CHOP or R-pola- CHP without consolidative radiation * Measurable disease on cross sectional imaging ≥ 1.5 cm in longest diameter and measurable in two perpendicular dimensions, with at least one corresponding hypermetabolic lesion by Lugano classification on baseline FDG PET/CT or CT with intravenous contrast of the chest, abdomen, and pelvis if FDG PET/CT not available. 2. Age 18 years or older at time of screening 3. Subject/legal representative willing and able to provide written informed consent 4. Ability to comply with outpatient treatment, laboratory monitoring, and required clinic visits for duration of study participation 5. Organ function as assessed by laboratory and cardiac function testing and Eastern Cooperative Oncology Group (ECOG) performance status in appropriate range for receipt of R-CHOP or R-pola-CHP at standard dose as per treating physician Exclusion Criteria: 1. Previous treatment for diffuse large B-cell lymphoma, except as outlined below: * Up to 14 days of corticosteroids for the relief of lymphoma-related symptoms * A dose of pre-phase vincristine or rituximab * One cycle of R-chemotherapy (including but not limited to R-CHOP, R-pola-CHP, dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, rituximab \[DA-EPOCH-R) that has not started more than 28 days prior to consent * Intrathecal chemotherapy for central nervous system (CNS) prophylaxis * Radiation therapy for the treatment or prevention of spinal cord compression that has not started more than 28 days prior to enrollment 2. Simultaneous participation in other treatment clinical protocol 3. Planned anti-lymphoma therapies beyond R-CHOP or R-pola-CHP: * Consolidative radiation to any baseline sites of disease * Planned high-dose intravenous methotrexate for central nervous system (CNS) lymphoma prophylaxis (both mid-cycle and EOT excluded) * Any number of doses of intrathecal chemotherapy for CNS lymphoma prophylaxis are allowed 4. Transformed indolent lymphoma (including follicular lymphoma, marginal zone lymphoma, or lymphoplasmacytic lymphoma) or grade IIIB follicular lymphoma 5. Known CNS involvement by lymphoma. R-CHOP and R-pola- CHP are insufficient to treat CNS disease. 6. Any disease characteristics that would make R-CHOP or R-pola-CHP without radiation insufficient therapy at the discretion of the treating physician * High-grade B-cell lymphoma with rearrangement of MYC and BCL2, primary mediastinal B-cell lymphoma, and HIV-associated lymphomas are excluded 7. Richter transformation of chronic lymphocytic leukemia 8. Pregnancy and/or nursing period. R-CHOP and R-pola-CHP may cause fetal harm or birth defects, and effects of exposure in the breastfed infant are unknown. * A person who has had menses at any time in the preceding 12 consecutive months or who has semen likely to contain sperm is considered to be of "childbearing potential" * Women of childbearing potential are eligible if a negative serum or urine beta human chorionic gonadotropin pregnancy test is documented within 28 days of screening, and they must agree to us an effective contraception method during systemic treatment * Men who have partners of childbearing potential must agree to use an effective contraceptive method during systemic treatment * In addition to routine contraceptive methods, "acceptable contraception" also includes refraining from sexual activity that might result in pregnancy and surgery intended to prevent pregnancy (or with a side-effect of pregnancy prevention) including hysterectomy, bilateral oophorectomy, bilateral tubal ligation/occlusion, and vasectomy with testing showing no sperm in the semen. 9. Uncontrolled active systemic infection * Patients with a positive hepatitis B virus (HBV) core antibody and negative HBV surface antigen consistent with prior HBV exposure must be willing to take appropriate anti-viral prophylaxis. * Patients with evidence of chronic HBV infection must have undetectable HBV viral load on the most recent test results obtained within the last year and received suppressive therapy. * Participants with a history of hepatitis C virus (HCV) infection must have an undetectable viral load. Participants currently being treated for HCV infection must have undetectable HCV viral load test on the most recent test results obtained within 28 days prior to consent. 10. Active second malignancy unless in remission and with life expectancy \> 2 years with exception of patients diagnosed with basal cell or squamous cell carcinoma of the skin or carcinoma "in situ" of the cervix or breast who are eligible even if diagnosed within 2 years. If patients have another malignancy that was treated within the last 2 years, such patients may be enrolled, if the likelihood of requiring systemic therapy for this other malignancy within 2 years is less than 10%, as determined by an expert in that particular malignancy at CUIMC, and after consultation with the Principal Investigator. Hormone therapy for treated prostate and breast cancer is allowed. 11. Known hypersensitivity to any component of R-CHOP or R-pola-CHP