The purpose of this study is to find out if there is a benefit to giving rituximab with etoposide, prednisone, vincristine, cyclophosphamide and doxorubicin (R-EPOCH) in participants who have high-risk B-cell PTLD in their 2nd phase of treatment (consolidation) while those with low-risk disease will be spared of chemotherapy and treated with rituximab consolidation alone.

This study is also being done to find out about the usefulness of circulating tumor DNA (ctDNA), a novel blood test which, has been shown to help guide treatment decisions in other types of lymphoma. The goal is to answer the question if ctDNA is a viable and informative tool in treating PTLD with the hope that in the future it may be used to individualize study treatment for participants with PTLD in a way that limits study treatment toxicity without losing the effectiveness of the treatment plan.

This is a multi-center, phase 2, open-label clinical trial to evaluate the efficacy of dose modified R-EPOCH in high-risk, treatment naïve CD20+ posttransplant lymphoproliferative disorder (PTLD) patients. The purpose of this study is to define the benefit of rituximab with etoposide, prednisone, vincristine, cyclophosphamide and doxorubicin (R-EPOCH) in patients who have high-risk B cell PTLD while those with low-risk disease will be spared of chemotherapy and treated with rituximab alone. Concurrently this study also seeks to evaluate the usefulness of circulating tumor DNA (ctDNA), a novel blood test which has been shown to improve a physician's ability to prognosticate and guide treatment decisions in other types of lymphoma. The goal is to demonstrate that ctDNA is a viable and informative tool in treating PTLD with the hope that in the future it may be used to individualize treatment for patients with PTLD in a way that limits treatment toxicity without losing the effectiveness of the treatment plan.

Inclusion Criteria:

• Histologically confirmed CD20+ PTLD including the below subtypes:

  • Polymorphic
  • Monomorphic

• Age ≥ 15.

• Participants must have measurable disease, defined as lymph node ≥ 1.5 cm in greatest diameter per Lugano Classification

• Patients must have a PET-CT scan (preferred; alternatively CT chest, abdomen and pelvis with IV contrast) performed within 28 days prior to the start of the study.

• All participants must be screened for chronic hepatitis B virus (HBV) within 28 days prior to registration. Participants with known HBV infection (positive serology) must also have a HBV viral load performed within 28 days prior to registration, and participants must have an undetectable HBV viral load on suppressive therapy within 28 days prior to start of treatment. Participants found to be HBV carriers during screening are eligible and must receive standard of care prophylaxis. Participants with active Hepatitis B (HBV viral load > 500 IU/mL) within 28 days prior to registration are not eligible.

• Participants with a history of hepatitis C virus (HCV) infection must have been treated and cured. Participants with an active HCV infection who are currently on treatment must have an undetectable HCV viral load within 28 days prior to registration.

• Participants with known human immunodeficiency virus (HIV)-infection are eligible providing they are on effective anti-retroviral therapy and have undetectable viral load at their most recent viral load test (must be within 26 weeks prior to registration). Participants with known HIV must have a CD4 count checked within 28 days prior to registration, but may proceed with therapy regardless of CD4 count.

• Organ function as assessed by laboratory testing is in appropriate range for receipt of rituximab and R-EPOCH per individual treating physician discretion.

• Cardiac function testing is in appropriate range for receipt of rituximab and R-EPOCH per individual treating physician discretion.

• Eastern Cooperate Oncology Group (ECOG) performance status is in appropriate range for receipt of rituximab and R-EPOCH per individual treating physician discretion.

• Ability to understand and the willingness to sign a written informed consent document. In cases of partial impairment, impairment that fluctuates over time, or complete impairment due to dementia, stroke, traumatic brain injury, developmental disorders (including mentally disabled persons), serious mental illness, and delirium, a subject may be enrolled if the subject's legally authorized representative consents on the subject's behalf.

• Due to the potential teratogenic effects of chemotherapy, women of childbearing age must have a documented negative serum β-hCG measured within 2 weeks of starting treatment.

• Both women of childbearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence).

• Women must agree to not breastfeed during the entirety of the study period.

• Participants must not have had chemotherapy for other indications within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study and must have recovered from adverse events due to agents administered more than 4 weeks earlier.

• Participants must not have received more than a cumulative of dose 250 mg/m 2 of prior doxorubicin (or equivalent dose of another anthracycline, such as epirubicin) therapy (at any time prior to registration).

• Intrathecal chemotherapy administered for CNS prophylaxis is allowed in addition to protocol therapy per institution practice.

Exclusion Criteria:

• Patients who have received systemic chemotherapy for PTLD.
• Patients who have known lymphomatous involvement of the central nervous system (CNS).