Prevalence and Characterization of EBV-Negative Post-Transplant Lymphoproliferative Disorder

Introduction: A common and potentially fatal post-solid organ transplant (SOT) complication is post-transplant lymphoproliferative disorder (PTLD). While the association of Epstein-Barr Virus (EBV) with the development of PTLD is well recognized, little is known about the etiology of EBV-negative PTLD. The aim of this study was to characterize the differences between EBV-positive and EBV-negative PTLD.

Methods: This was a retrospective study that reviewed patients at a single, large academic center who developed PTLD after SOT. Data was collected on PTLD patients (>18 years) from 2011 to 2021. A total of 99 patients met the inclusion criteria. Data included demographics, SOT type, time from SOT to PTLD development, tumor EBV status, PTLD site, histopathological morphology, tumor markers, and overall survival. EBV tumor status was compared using χ2, Fisher's Exact, and Wilcoxon Rank Sum tests.

Results: Of the total 99 patients, 45.5% (45/99 patients) were EBV-positive and 54.5% (54/99 patients) were EBV-negative. Tumor EBV status did not differ by race, but males were more likely to be EBV-negative (63% v. 44.4% of females, p=0.065). Tumor EBV status did not differ by SOT type. The interval between SOT and PTLD diagnosis was longer in EBV-negative patients (8.68 years) than EBV-positive patients (4.93 years) (p=0.001). There was a significant difference in EBV-negative PTLD site (p=0.046) and PTLD subtypes (p=0.002). Site of EBV-negative PTLD consisted of gastrointestinal (38.9% or 21/54 patients), head/neck (11.1% or 6/54 patients), liver/spleen (11.1% or 6/54 patients), CNS (3.7% or 2/54 patients), other nodal sites (24% or 13/54 patients), and other extra-nodal sites (11.1% or 6/54 patients). Monomorphic (65.5% or 38/58 patients) and T-cell (90% or 9/10 patients) subtypes were more common in EBV-negative patients, compared to the polymorphic (15.4% or 2/13 patients) and plasmablastic/plasmacytic (27.3% or 3/11 patients) subtypes. Expression of CD20 did not differ by tumor EBV status. Those who were CD30-negative and CD138-negative were more likely to be EBV-negative (90% v. 25%, p=<0.001 and 75% v. 26.7%, p=0.012, respectively). There was no difference in overall survival by tumor EBV status.

Conclusions: This single institution retrospective review shows that there are distinct differences between EBV-negative and EBV-positive PTLD. EBV-negative PTLD has a longer interval from SOT to PTLD development, is more likely to occur in the gastrointestinal tract, and is more likely to have a monomorphic morphology. Monomorphic morphologies are typically more aggressive, which is likely contributing to the difficulty associated with treating EBV-negative PTLD. It is important to note that EBV-negative PTLD was more likely to be CD30 and CD138 negative, which further limits targeted treatment options. It is surprising that there was no difference in overall survival in EBV-positive and EBV-negative PTLD. Overall, this study highlights the various differences seen with EBV-negative PTLD and demonstrates the need for more research on EBV-negative PTLD etiologies.

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.