Impact of EBV status on the characteristics and prognosis of post-transplant lymphoproliferative disorder in solid organ transplant recipients: Long-term experience from the GELTAMO group

Abstract Introduction Post-transplant lymphoproliferative disorders (PTLD) are a heterogeneous group of immunosuppression-related conditions that develop in transplant recipients. Most PTLDs are of B-cell origin, with diffuse large B-cell lymphoma (DLBCL) being the most common histological subtype. A significant proportion of cases are associated with Epstein-Barr virus (EBV) infection. It is well established that patients with typical EBV-associated PTLD—including those with monomorphic DLBCL—can often be cured with low-intensity therapeutic approaches, such as reduction of immunosuppression and rituximab monotherapy. However, for EBV-negative (EBV−) patients, some guidelines recommend more aggressive treatment. Nevertheless, whether EBV status serves as a prognostic marker for survival or treatment response remains controversial. The aim of this study is to describe the clinical characteristics, management, and outcomes of EBV− monomorphic PTLD patients compared to EBV-positive cases- Materials and Methods A retrospective study was conducted on patients diagnosed with PTLD after solid organ transplantation (SOT) between 2000 and 2024 across 20 hospitals within the GELTAMO group. Polymorphic PTLD were excluded. Histological categorization of PTLD was based on the 5th edition of the WHO classification. EBV status was defined as positive if Epstein-Barr virus–encoded RNA (EBER) in situ hybridization or immunohistochemistry (IHC) for latent membrane protein 1 (LMP1) was positive. Overall survival (OS) was calculated from the time of PTLD diagnosis to the time of death, regardless of the cause. Univariate survival analysis was performed using the log-rank test, and multivariate analysis was performed using a Cox regression model. PTLD treatment was determined by physician preference. Results A total of 427 cases of monomorphic PTLD were registered, including 305 diffuse large B-cell lymphoma (DLBCL), 23 Hodgkin lymphoma (HL), 20 primary central nervous system lymphoma (PCNSL), 19 T-cell lymphoma, 25 Burkitt lymphoma, and 14plasmablastic lymphoma. EBV status was available for 342 patients, of whom 174 (50.8%) were EBV-negative (EBV−) and 168 (49.2%) were EBV-positive (EBV+). Considering the different histological subtypes, the proportion of EBV+ cases varied significantly, with a higher frequency observed in Hodgkin lymphoma (88%) and PCNSL (86%). CD30 positivity by IHC was significantly more common in EBV+ cases (80.6% vs. 24.4%, p < 0.001). The most frequent type of transplantation was renal (42.1%), followed by liver (32.1%), heart (12.6%), and lung (7.9%). PTLD arising in lung transplant recipients was more likely to be EBV-positive, with a rate of 77.4%. EBV-negative patients were older (60 vs. 55 years; p = 0.001) and had less central nervous system involvement (2.1% vs. 9.4%, p = 0.008) and pulmonary involvement (2.8% vs. 16.1%, p < 0.001). Bulky disease was more frequently observed in EBV-negative patients (33.3% vs. 13.3%, p < 0.001). The remaining characteristics were similar between both groups. Notably, EBV− PTLD occurred significantly later than EBV+ PTLD; the median time from transplantation to diagnosis was 10.7 years for EBV− cases, compared to 7.4 years for EBV+ cases (p < 0.001). Additionally, 58% of EBV+ PTLD cases occurred within the first two years after transplantation, compared to only 17% of EBV− cases. Patients with monomorphic DLBCL were treated similarly regardless of EBV status with 58% and 52% of the patients treated with frontline rituximab monotherapy in the EBV+ and EBV- group, respectively. Overall response rate to initial treatment was slightly higher in EBV+ patients (86% vs. 78%, p = 0.054), with no difference in complete response rates (63.3% vs. 55.6%, p = 0.14), even when rituximab monotherapy was used. The estimated 5-year OS was 46% in EBV-negative patients and 50% in EBV-positive patients (Hazard Ratio 0.95 (95%CI 0.71-1.27), p = 0.74). However, death due to disease progression was more common in EBV-negative patients (46.7% vs. 34.1%, p = 0.01). Conclusion This is the largest real-life series of patients with PTLD after SOT showing that EBV status has no impact in OS. However, the high proportion of EBV-negative disease cases and the higher mortality due to progression in this group highlight the need for new strategies for the prevention and management of EBV-negative PTLD.