People who have received a solid organ transplant can develop ongoing Epstein-Barr virus (EBV) infection in the blood, which increases the risk of a serious cancer called post-transplant lymphoproliferative disorder (PTLD). This study will test whether rituximab, a drug approved by the U.S. Food and Drug Administration (FDA) for several immune-related conditions, can safely clear EBV from the blood and help prevent PTLD when lowering immune-suppressing medications is not possible or effective. The study includes an initial smaller group focused on determining whether EBV can be cleared, followed by a larger group designed to determine whether treatment lowers the risk of developing PTLD. Researchers will also monitor side effects, transplant organ health, and immune system changes to better understand treatment safety and benefit.

Solid organ transplant recipients with persistent Epstein-Barr virus (EBV) DNAemia are at increased risk for post-transplant lymphoproliferative disorder (PTLD), and optimal preemptive management remains undefined. This Phase 1 study evaluates the efficacy and safety of rituximab in this population, with primary endpoints of EBV DNAemia clearance at 6 months. All participants will receive a single dose of intravenous rituximab (375 mg/m^2).

Inclusion Criteria:

1. Patients must have received a solid organ transplant.
2. Patients must not have a diagnosis of PTLD (confirmed with CT or PET imaging, and if there are concerning lesions present on imaging - a biopsy must be performed to rule out PTLD), or history of PTLD
3. Age ≥ 18
4. Patients must have EBV DNAemia ≥ 1000 IU/mL (plasma) on two consecutive measurements at least 1 week apart and within a 6-week period. The second measurement must be within 4 weeks of enrollment.
5. Patients must have had reduction in their immunosuppression according to institutional best practices prior to enrollment OR have documented clinical rationale for which immunosuppression may not be safely reduced (e.g. due to organ transplant rejection)
6. Patients with a positive hepatitis B virus (HBV) core antibody and negative HBV surface antigen consistent with prior HBV exposure must be 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.
7. 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.
8. 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 28 days 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.
9. Ability to understand and the willingness to sign a written informed consent document. If an individual lacks capacity, a legally acceptable surrogate/legally authorized representative should be able to understand and willing to sign a written informed consent document.
10. Must have a life expectancy > 6 months
11. Must not have an active 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.

Exclusion criteria:

- Under the age of 18 years