The Effect of Rituximab Treatment and Reducing Immunosuppression on the Development of Post-Transplant Lymphoproliferative Disorder in EBV-Positive Patients after Solid Organ Transplantation

CONTEXT: The association between EBV reactivation after solid organ transplantation (SOT) and the development of Post-Transplant Lymphoproliferative Disorder (PTLD) is well established. Reducing immunosuppression (IS) is a common intervention for EBV reactivation after SOT; however, there is currently no established pharmacologic agent routinely used as prevention for EBV positive patients at risk for development of PTLD.

OBJECTIVE: To determine whether administering rituximab in patients with EBV reactivation after SOT may have a clinical benefit in preventing or delaying development of PTLD.

DESIGN: This was a retrospective study including a subset of patients treated within the Lymphoma Department at CUIMC after SOT between 2004 and 2022. Data was collected on patients (>18 years of age) who were diagnosed with PTLD or referred for increasing EBV viremia without a diagnosis of PTLD.

SETTING: A single, large academic center.

PATIENTS: 101 patients met the inclusion criteria of having EBV reactivation after SOT. This included those with a diagnosis of PTLD (n=95) or who were treated with rituximab for increasing EBV viremia (n=6). Patients who developed PTLD and were EBV negative by serology were excluded from this analysis.

RESULTS: Median time from SOT to EBV reactivation was 1590 days (n=101; min 14, max 8766). Median time from EBV reactivation to PTLD diagnosis was 60 days (n=55; min 0, max 4483). Only 55 of the 101 patients had EBV PCRs sent prior to PTLD diagnosis; in many cases EBV was not routinely monitored by PCR testing until patients presented with a clinical change that aroused concern for development of PTLD, with EBV PCR subsequently sent as part of the diagnostic workup for PTLD. PTLD subtypes included monomorphic (40.6%), polymorphic (16.8%), plasmablastic/plasmacytic (10.9%), monomorphic T cell (6.9%), other [e.g., Burkitt type] (6.9%), and unknown morphology (1%), and the remaining 16.8% of patients (n=17) were EBV-positive but not yet diagnosed with PTLD. Of the 101 patients, 89 (88%) were treated with IS modification. Of these 89 patients, 78 had a diagnosis of PTLD, with 55 (70.5%) of these patients receiving IS modification before PTLD diagnosis, and 23 (29.5%) after PTLD diagnosis. Of the 89 patients treated with IS modification, 11 did not develop PTLD. The most common modification to IS was discontinuation of mycophenolate mofetil. Overall, 6 of the 101 patients received rituximab for increasing EBV viremia without a diagnosis of PTLD. Median EBV titer at peak was 6875 (n=6). Of the 6 patients who received rituximab, 2 to 8 doses were administered. None of these 6 patients have developed PTLD as of the time of last follow-up. Median time from EBV reactivation to last follow-up was 1657 days (n=6; min 616, max 6957) and median time from rituximab start date to last follow-up without PTLD diagnosis was 476 days (n=6; min 85, max 2048).

CONCLUSIONS: This retrospective analysis suggests that there may be a clinical benefit to treating EBV reactivation and increasing viremia with rituximab in addition to IS modification in terms of delaying PTLD diagnosis; however, the degree and clinical significance of this benefit is unclear given the small sample size and lack of randomization.

A limitation of this analysis is the lack of routine EBV PCR surveillance after SOT; for many patients in this analysis, the EBV conversion date is after the PTLD diagnosis date, most likely because the PTLD workup prompted the clinician to send the EBV PCR. Patients treated with rituximab for EBV under their transplant team without referral to the lymphoma service were not included. Larger prospective studies with standardized EBV surveillance after SOT are needed to assess the clinical benefit of administering rituximab to EBV-positive patients after SOT with regard to attenuation or prevention of the development of PTLD.

Lipsky:AbbVie: Consultancy; AstraZeneca: Consultancy; Synthekine: Consultancy. Sawas:Affimed: Research Funding; Seagen: Speakers Bureau; Acrotech Biopharma: Speakers Bureau; Daiichi Sankyo: Speakers Bureau; Seagen: Consultancy; Acrotech Biopharma: Consultancy; FlatIron Health: Current Employment; Roche: Current holder of stock options in a privately-held company. Pro:Seattle Genetics: Honoraria. Amengual:AstraZeneca: Consultancy; Daiichi Sankyo: Consultancy; Appia Pharmaceuticals: Research Funding.

Rituximab given to patients post solid organ transplant with increasing EBV viremia after transplant, but who did not yet develop post-transplant lymphoproliferative disorder