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 andmeasurable in two perpendicular dimensions, with at least one correspondinghypermetabolic lesion by Lugano classification on baseline FDG PET/CT or CTwith intravenous contrast of the chest, abdomen, and pelvis if FDG PET/CT notavailable.

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 requiredclinic visits for duration of study participation

5. Organ function as assessed by laboratory and cardiac function testing and EasternCooperative Oncology Group (ECOG) performance status in appropriate range forreceipt 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 daysprior to consent

• Intrathecal chemotherapy for central nervous system (CNS) prophylaxis

• Radiation therapy for the treatment or prevention of spinal cord compressionthat 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 lymphomaprophylaxis are allowed

4. Transformed indolent lymphoma (including follicular lymphoma, marginal zonelymphoma, or lymphoplasmacytic lymphoma) or grade IIIB follicular lymphoma

5. Known CNS involvement by lymphoma. R-CHOP and R-pola- CHP are insufficient to treatCNS disease.

6. Any disease characteristics that would make R-CHOP or R-pola-CHP without radiationinsufficient therapy at the discretion of the treating physician

• High-grade B-cell lymphoma with rearrangement of MYC and BCL2, primarymediastinal 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 birthdefects, and effects of exposure in the breastfed infant are unknown.

• A person who has had menses at any time in the preceding 12 consecutive monthsor who has semen likely to contain sperm is considered to be of "childbearingpotential"

• Women of childbearing potential are eligible if a negative serum or urine betahuman chorionic gonadotropin pregnancy test is documented within 28 days ofscreening, and they must agree to us an effective contraception method duringsystemic treatment

• Men who have partners of childbearing potential must agree to use an effectivecontraceptive method during systemic treatment

• In addition to routine contraceptive methods, "acceptable contraception" alsoincludes refraining from sexual activity that might result in pregnancy andsurgery intended to prevent pregnancy (or with a side-effect of pregnancyprevention) including hysterectomy, bilateral oophorectomy, bilateral tuballigation/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 HBVsurface antigen consistent with prior HBV exposure must be willing to takeappropriate anti-viral prophylaxis.

• Patients with evidence of chronic HBV infection must have undetectable HBVviral load on the most recent test results obtained within the last year andreceived suppressive therapy.

• Participants with a history of hepatitis C virus (HCV) infection must have anundetectable viral load. Participants currently being treated for HCV infectionmust have undetectable HCV viral load test on the most recent test resultsobtained within 28 days prior to consent.

10. Active second malignancy unless in remission and with life expectancy > 2 years withexception of patients diagnosed with basal cell or squamous cell carcinoma of theskin or carcinoma "in situ" of the cervix or breast who are eligible even ifdiagnosed within 2 years. If patients have another malignancy that was treatedwithin the last 2 years, such patients may be enrolled, if the likelihood ofrequiring 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 afterconsultation with the Principal Investigator. Hormone therapy for treated prostateand breast cancer is allowed.

11. Known hypersensitivity to any component of R-CHOP or R-pola-CHP