Development Of Post-transplant Lymphoproliferative Disorder Research Articles

Performance evaluation of the high-throughput quantitative Alinity m Epstein-Barr virus assay.

Epstein-Barr virus (EBV) infection and reactivation are associated with increased risk for post-transplant lymphoproliferative disorders (PTLD) in transplant recipients with the development of PTLD occurring predominantly within a year of transplant. Quantitative PCR for EBV is used to monitor the viral load of EBV with a negative result as a good negative predictor of PTLD. Nucleic acid amplification tests (NAATs) with high sensitivity and specificity are available on fully automated high-throughput instruments to provide accurate quantitation and improve test result turn-around time. This study evaluates the analytical and clinical performance of one such NAAT, the Alinity m EBV assay.

Rare Co-occurrence of Spinal Cord Hemorrhage from Radiation-induced Cavernous Hemangioma and Classical Hodgkin Lymphoma Post-transplant Lymphoproliferative Disorder.

Post-transplant lymphoproliferative disorders (PTLDs) are lymphoproliferative diseases that occur after solid organ transplantation or hematopoietic stem cell transplantation (HSCT). The development of PTLD is often associated with reactivation of Epstein-Barr virus (EBV). A 26-year-old woman with a history of HSCT and total-body irradiation developed spinal cord hemorrhage from a radiation-induced cavernous hemangioma (RICH) shortly after the development of classical Hodgkin lymphoma PTLD with EBV reactivation. Although little is known about the factors leading to hemorrhagic events from spinal cord RICH, we suspect that EBV reactivation may have been a factor contributing to the hemorrhage in the present case.

EBV Reactivation and Disease in Allogeneic Hematopoietic Stem Cell Transplant (HSCT) Recipients and Its Impact on HSCT Outcomes.

The acquisition or reactivation of Epstein-Barr virus (EBV) after allogeneic Hematopoietic Stem Cell Transplant (HSCT) can be associated with complications including the development of post-transplant lymphoproliferative disorder (PTLD), which is associated with significant morbidity and mortality. A number of risk factors for PTLD have been defined, including T-cell depletion, and approaches to monitoring EBV, especially in high-risk patients, with the use of preemptive therapy upon viral activation have been described. Newer therapies for the preemption or treatment of PTLD, such as EBV-specific cytotoxic T-cells, hold promise. Further studies to help define risks, diagnosis, and treatment of EBV-related complications are needed in this at-risk population.

Post-transplant lymphoproliferative disorder associated Epstein-Barr virus DNAemia after liver transplantation in children: Experience from single center.

The most prevalent malignancy that complicates both adult and pediatric solid organ transplantation is post-transplant lymphoproliferative disorder (PTLD). This study aimed to analyze the clinical and pathological characteristics, treatments, and outcomes of Epstein-Barr virus (EBV) DNAemia and PTLD in pediatric liver transplant recipients. A retrospective chart review was performed on 112 patients less than 18 years of age who underwent isolated orthotopic liver transplantation (OLT) between 2010 and 2022 at Ege University Children's Hospital. Data gathered for 1-year post-OLT included age at OLT, EBV, immunoglobulin (Ig)M/IgG status of the donor and recipient, indication for OLT, induction regimen, all immunosuppression levels, date and result of EBV polymerase chain reaction testing, rejection episodes documented by liver biopsy, and the development of PTLD. Forty-nine patients (43.75%) developed EBV DNAemia (median interval from surgery: 2 months, min-max: 2-36), of which 43 (87.8%) grafts came from living donors, and 6 (12.2%) came from deceased donors. Nine (18.4%) patients died during follow-up, and eight (16.3%) developed PTLD. Of these 8 patients; five patients developed EBV-related disease, one child developed hemophagocytic lymphohistiocytosis, one developed aplastic anemia, and one child developed B cell lymphoma. When PTLD patients and without-PTLD patients were compared, pediatric intensive care unit hospitalization, abnormal bone marrow biopsy findings, lymphadenopathy, age at diagnosis of EBV DNAemia, EBV viral load, tacrolimus (FK 506) pre-infection, were higher and tacrolimus 1-month levels were lower in patients with PTLD (p < 0.05). In logistic regression analysis, we showed that the age at diagnosis of EBV DNAemia was significantly higher in children with PTLD (p = 0.045; OR: 1.389; 95% CI: 1.007-1.914). PTLD is a rare but severe complication associated with EBV after OLT. This study demonstrated that PTLD is associated with older age, higher tacrolimus blood levels before EBV DNAemia, and higher peak EBV viral load at 1 month of EBV DNAemia.

#2992 Risk and prognostic factors for post-transplantation lymphoproliferative disease in solid organ transplant recipients—a multicenter analysis

Abstract Background and Aims Post-transplantation lymphoproliferative disorder (PTLD), a potentially fatal complication of transplantation, affects solid organ transplant recipients at different rates, depending on organ graft type: the risk greater in lung transplant recipients (LngTRs), lower for liver transplant recipients (LTRs) and lowest for kidney transplant recipients (KTR). In this study we aimed to investigate the factors affecting the development and treatment outcomes of PTLD and compare their effect on KTRs, LTRs and LngTRs. Method In this retrospective cohort study we have included all KTRs, LTRs and LngTRs diagnosed with PTLD at six transplantation centers in Poland. The data collected from medical records included: immunosuppression (IS), viral infections, PTLD type, treatment and outcomes. Chi-squared test was used to assess the differences in group composition. To determine the impact of variables upon PTLD time of onset and patient survival, univariate Cox regression was used. p-values below 0.05 were considered statistically significant. Results We enrolled 50 KTRs, 36 LTRs and 5 LngTRs from 6 transplantation centers in Poland. Based on the data from the most contributing centers in each group, the prevalence of PTLD was 0.82% of KTRs, 2.03% LTRs and 1.51% of LngTRs. Two thirds of the enrolled patients were male, the median age at first transplantation was 40 years for KTRs, 45 for LTRs and 25 for LngTRs (Table 1). The groups significantly differed in IS treatment: steroid (GCS) and cyclosporin (CsA) use was more frequent in KTRs (p&amp;lt;0.001 and p&amp;lt;0.001 and respectively), tacrolimus (TAC) and anti-CD25 induction in LTRs (p ≤ 0.001 and p&amp;lt;0.001 respectively), sirolimus (RAPA) in LngTRs (p&amp;lt;0.001). KTRs were the latest to develop PTLD (126 months after transplantation, p&amp;lt;0.001). In all groups Monomorphic B-cell PTLD was the most frequent. Initial IS treatment reduction was used in 80-86% of patients, R-CHOP chemotherapy was most common in LTRs (p=0.021), other chemotherapy regimens in KTRs (p=0.031). TAC had the opposite effect on PTLD time of onset in KTRs (HR=2.18, p=0.013) and LTRs (HR=0.18, p=0.036). The overall survival at the end of observation period was 26% for KTRs, 58% for LTRs and 80% for LngTRs. Loss to follow up was most frequent in KTRs at 26%. Patient survival was not affected by PTLD treatment. Conclusion KTRs develop PTLD later than LTRs and LngTRs, and time of disease onset is associated with TAC use. Lower survival in KTRs may result from the longer follow-up period compared to other solid organ transplant recipients.

Epstein-Barr virus-associated post-transplant lymphoproliferative disorders in pediatric transplantation: A prospective multicenter study in the United States.

Epstein-Barr virus (EBV)-associated post-transplant lymphoproliferative disorders (PTLD) is the most common malignancy in children after transplant; however, difficulties for early detection may worsen the prognosis. The prospective, multicenter, study enrolled 944 children (≤21 years of age). Of these, 872 received liver, heart, kidney, intestinal, or multivisceral transplants in seven US centers between 2014 and 2019 (NCT02182986). In total, 34 pediatric EBV+ PTLD (3.9%) were identified by biopsy. Variables included sex, age, race, ethnicity, transplanted organ, EBV viral load, pre-transplant EBV serology, immunosuppression, response to chemotherapy and rituximab, and histopathological diagnosis. The uni-/multivariable competing risk analyses revealed the combination of EBV-seropositive donor and EBV-naïve recipient (D+R-) was a significant risk factor for PTLD development (sub-hazard ratio: 2.79 [1.34-5.78], p = .006) and EBV DNAemia (2.65 [1.72-4.09], p < .001). Patients with D+R- were significantly more associated with monomorphic/polymorphic PTLD than those with the other combinations (p = .02). Patients with monomorphic/polymorphic PTLD (n = 21) had significantly more EBV DNAemia than non-PTLD patients (p < .001) and an earlier clinical presentation of PTLD than patients with hyperplasias (p < .001), within 6-month post-transplant. Among non-liver transplant recipients, monomorphic/polymorphic PTLD were significantly more frequent than hyperplasias in patients ≥5 years of age at transplant (p = .01). D+R- is a risk factor for PTLD and EBV DNAemia and associated with the incidence of monomorphic/polymorphic PTLD. Intensive follow-up of EBV viral load within 6-month post-transplant, especially for patients with D+R- and/or non-liver transplant recipients ≥5 years of age at transplant, may help detect monomorphic/polymorphic PTLD early in pediatric transplant.

The Effect of Preemptive Rituximab Treatment in Patients with EBV Viremia after Solid Organ Transplantation on the Development of Post-Transplant Lymphoproliferative Disorder

The association between Epstein-Barr Virus (EBV) reactivation after solid organ transplantation (SOT) and Post-Transplant Lymphoproliferative Disorder (PTLD) is well described. There are currently no guidelines regarding the use of rituximab preemptively in patients with EBV viremia after SOT to reduce the risk of PTLD. We sought to determine whether rituximab in SOT patients with EBV viremia has benefit in preventing PTLD. This retrospective analysis of electronic medical record data identified SOT recipients who experienced EBV viremia post-transplant between January 2010 and February 2023 at Columbia University Irving Medical Center (CUIMC). Data queries were clinically reviewed. Logistic regression analysis was performed to investigate the relationship between predictor variables including rituximab administration, log-transformed EBV peak titer, duration of EBV viremia, and time from SOT to EBV reactivation, with the binary primary outcome of PTLD diagnosis status. The analysis encompassed both univariate and multivariate logistic regression. There were 2,168 patients who met the inclusion criteria of having EBV reactivation after SOT, out of 6,395 total SOT performed at CUIMC during this timeframe. Patient characteristics are described in table 1. The median peak EBV titer was 154 (range: not quantifiable - 5,335,816), the median duration of EBV viremia was 78 days (range: 1 - 6,980), and the median time from SOT to EBV reactivation was 688 days (range: 0-11103). Of the 2,168 patients, 185/2168 (8.5%) received rituximab for indications other than PTLD including EBV viremia, treatment of rejection, antibody desensitization therapy/immunosuppression peri-transplant, and other non-transplant related indications (e.g. lupus nephritis). Of the patients who received rituximab, 182/185 (98.4%) did not develop PTLD. The 3/185 (1.6%) patients who did develop PTLD were all ≤ 20 years-old at time of diagnosis, and had EBER(+), monomorphic PTLD, diffuse large B-cell lymphoma type, with a non-germinal center phenotype, involving the gastrointestinal tract. Two were CD20 positive, all 3 had partial weak CD30 positivity, and all 3 had clonal immunoglobulin heavy chain rearrangements. Among the patients who did not receive preemptive rituximab post-SOT, 195/1983 (9.8%) developed PTLD, whereas 1788/1983 (90.2%) did not. Prior rituximab therapy for any indication in patients with EBV viremia post-SOT was associated with lower risk of subsequent PTLD by univariate analysis (0.14% vs 8.39%, OR 0.15, p = 0.0013, 95% CI 0.048-0.48). Receipt of rituximab (OR 0.12, p=0.0002), log-transformed peak EBV titer (OR 1.10, p&amp;lt;0.0001), and duration of EBV viremia in months (OR 1.01, p&amp;lt;0.0001) were all independently associated with risk for PTLD by multivariate analysis (figure 1). The relationship between time from SOT to EBV viremia was not significantly associated with development of PTLD. This retrospective analysis suggests that administering preemptive rituximab in SOT patients with EBV viremia may lower the risk of developing PTLD. The fact that peak EBV titer and duration of EBV viremia remain associated with PTLD in multivariate analyses suggests that the benefit of rituximab may be independent of the degree or duration of EBV viremia. A prospective analysis of factors such as area under the curve of EBV exposure, HLA status, T cell clonotype diversity, organ type, and immunosuppression type, is needed to better understand individual risks for improved selection of those who would benefit from preemptive rituximab.

Incidence, Management and Outcome of Post-Transplant Lymphoproliferative Disease after 5797 Solid-Organ Transplants over a 30-Year Period in a Single Hospital

Introduction: Post-transplant lymphoproliferative disorders (PTLD) are heterogenous lymphoproliferative disorders that develop because of immunosuppression in transplant recipients. Epstein-Barr Virus (EBV) infection is a major risk factor for the development of PTLD. Its management generally involves a reduction in immunosuppression and initial treatment with rituximab monotherapy (RM). Aim: To present the epidemiology, management, and outcomes of PTLD in a large unicentric Spanish cohort of solid organ transplant (SOT) recipient who were transplanted over a 30-year period. Methods: This is a retrospective study of 5797 SOT recipients who had their first transplant between 1992 and 2021 at Hospital Universitario 12 de Octubre. For each type of transplant, we calculated the incidence rate of PTLD. OS (Overall survival) was analyzed using the Kaplan-Meier model and the log-rank test Prognostic impact of the main clinical, analytical variables and prognostic indexes were analyzed. Results: With a median follow-up of 16.4 years, 105 of 5797 SOT developed a monomorphic or Hodking-like PTLD (1.8%). The incidence was: 10% multivisceral transplantation (MVT), 2.8% heart, 2.3% liver, 2.2% lung, 1.4% kidney and 1.3% simultaneous kidney-pancreas (SPK). Median age at transplant was 48.3 (1-89) years. 12 were pediatric recipients' (1 lung, 1 kidney, 10 liver). 72% were men. Histochemical stains for Epstein-Barr virus (EBV) were performed in 75 of 105 diagnoses. EBER-positive histology was observed in the majority of patients (n = 44/77, 57%). Median time from transplantation to PTLD was 6.7 (0-16.4) years (21% in the 1st year post-transplant). In EBER-positive the onset was earlier (3.2 vs 9.2 years; p: .004) with 36% arising the 1st year post-transplant. 5-years cumulative incidence was 10% in MTV compared to 0.18%-1.6% in the rest. With a median follow-up of 6.9 years; median OS was 79.5 months, with no difference between type of organ transplanted, era of transplant, EBER histology or time from transplant to PTLD. Using logistic regression, age, beta-2-microglobulin (B2M), as well as the IPI, modified R-IPI, NCCN-IPI and GELTAMO-IPI prognostic indices were found to be significant prognostic factors for OS ( Table 1). Interestingly, the highest OS stratification was observed with the modified R-IPI, showing a median OS not reached in the low-risk group, versus 38 months at high risk and 3.2 months at very high risk (p&amp;lt;0.001). Immunosuppression (IS) was switched as the 1st therapeutic aptitude in 57% of the patients. Median OS was not reached in patients with IS switch (n=41) (plateau at 10 years; estimated OS 56%) vs. 15.3m for patients without IS switch (n=39) (P: .004) ( Figure 1). IS was reduced in 80%. It also reached OS impact (P: .05). There were 89 monomorphic patients who were treated as follows: RM (n=22), R-Chemotherapy (n=37), chemotherapy (n=6), no treatment (n=7), unknown (n=16). Of the 22 RM patients, 9 (41%) achieved complete remission (CR) with RM and required no further treatment. In the R-Chemotherapy (n=37) group (70% R-CHOP), 26 (70%) reached CR. There was no significant difference in OS between the two groups. 8/22 (36%) died in the RM group (2/22 (9%) due progressive disease (PD), 2/22 (9%) died pre-remission of non-PTLD causes and 4/37 (18%) died in remission of unrelated causes). In the R-Chemo group 8/37 (48%) patients dead (4/37 (10%) patients died of PD, 6/37 (16%) died pre-remission of non-PTLD causes and 8/37 (22%) died in remission of unrelated causes). Conclusion: With this SOT cohort from a center with long experience we demonstrated an incidence of PTLD of 1.8%. EBV positive PTLD emerged sooner but OS was similar to those EBV negative. Stablished prognostic indices in DLBCL such as IPI, NCCN-IPI, and modified R-IPI were also applicable in PTLD. The modified R-IPI showed the best separation between the groups. Switch or reduction of the IS is an essential point to improve its prognosis. Our data suggest that first-line RM is an interesting option to consider. Strategies to tailor treatment with the least possible toxicity are necessary in these vulnerable patients. Additionally, our results suggest the utility of modified R-IPI in the clinical practice of PTLD and may serve as a basis for the development of specific prognostic models for this entity.

Herpes Virus Infection in Lung Transplantation: Diagnosis, Treatment and Prevention Strategies.

Lung transplantation is an ultimate treatment option for some end-stage lung diseases; due to the intense immunosuppression needed to reduce the risk of developing acute and chronic allograft failure, infectious complications are highly incident. Viral infections represent nearly 30% of all infectious complications, with herpes viruses playing an important role in the development of acute and chronic diseases. Among them, cytomegalovirus (CMV) is a major cause of morbidity and mortality, being associated with an increased risk of chronic lung allograft failure. Epstein-Barr virus (EBV) is associated with transformation of infected B cells with the development of post-transplantation lymphoproliferative disorders (PTLDs). Similarly, herpes simplex virus (HSV), varicella zoster virus and human herpesviruses 6 and 7 can also be responsible for acute manifestations in lung transplant patients. During these last years, new, highly sensitive and specific diagnostic tests have been developed, and preventive and prophylactic strategies have been studied aiming to reduce and prevent the incidence of these viral infections. In this narrative review, we explore epidemiology, diagnosis and treatment options for more frequent herpes virus infections in lung transplant patients.

Screening and Management of PTLD.

Posttransplant lymphoproliferative disorder (PTLD) represents a heterogeneous group of lymphoproliferative diseases occurring in the setting of immunosuppression following hematopoietic stem cells transplant and solid organ transplantation. Despite its overall low incidence, PTLD is a serious complication following transplantation, with a mortality rate as high as 50% in transplant recipients. Therefore, it is important to establish for each transplant recipient a personalized risk evaluation for the development of PTLD based on the determination of Epstein-Barr virus serostatus and viral load following the initiation of immunosuppression. Due to the dynamic progression of PTLD, reflected in the diverse pathological features, different therapeutic approaches have been used to treat this disorder. Moreover, new therapeutic strategies based on the administration of virus-specific cytotoxic T cells have been developed. In this review, we summarize the available data on screening and treatment to suggest a strategy to identify transplant recipients at a higher risk for PTLD development and to review the current therapeutic options for PTLD.

A pediatric case series of catastrophic gastrointestinal complications of posttransplant lymphoproliferative disease with increasing incidence, high association with coronavirus disease 2019, higher mortality, and a plea for early endoscopy to prevent late fatal outcome

BackgroundPosttransplant lymphoproliferative disorder is one of the most severe complications after transplantation, caused by uncontrolled proliferation of Epstein–Barr virus-positive B-cells in the setting of chronic immunosuppression. As one of the biggest transplant centers worldwide, we observed a potential increase in the number of patients with posttransplant lymphoproliferative disorder presenting with gastrointestinal symptoms in 1 year, during the coronavirus disease 2019 pandemic. There is limited information about dysregulation of the immune system following coronavirus disease 2019 infection, which may lead to Epstein–Barr virus reactivation in Epstein–Barr virus-positive B-cells and development of posttransplant lymphoproliferative disorder. Furthermore, there is no consensus in literature on a modality that can help in early diagnosis of posttransplant lymphoproliferative disorder with nonspecific gastrointestinal presentations before late and fatal complications occur.Case presentationOur case series includes five Iranian (Persian) patients, three female (2, 2.5, and 5 years old) and two male (2 and 2.5 years old), who developed gastrointestinal posttransplant lymphoproliferative disorder after liver transplantation. All of our patients were on a similar immunosuppressant regimen and had similar Epstein–Barr virus serologic status (seronegative at time of transplantation but seropositive at time of posttransplant lymphoproliferative disorder diagnosis). Four patients had either a positive coronavirus disease 2019 polymerase chain reaction test or exposure within the family. Although all of our patients presented with nonspecific gastrointestinal symptoms, four patients developed late posttransplant lymphoproliferative disorder complications such as bowel perforation and obstruction. All five patients with gastrointestinal posttransplant lymphoproliferative disorder received chemotherapy, but only two survived and currently are continuing the therapy. In one of the surviving patients, prompt endoscopic investigation resulted in early diagnosis of posttransplant lymphoproliferative disorder and a better outcome.ConclusionSince 80% of our patients had exposure to coronavirus, a potential relationship might be suggested between the two. Furthermore, as we witnessed in one case, urgent endoscopic investigation in immunocompromised patients presenting with gastrointestinal symptoms can improve the clinical outcomes and therefore should be considered for early diagnosis of posttransplant lymphoproliferative disorder.

Growth Transformation of B Cells by Epstein-Barr Virus Requires IMPDH2 Induction and Nucleolar Hypertrophy.

The in vitro growth transformation of primary B cells by Epstein-Barr virus (EBV) is the initial step in the development of posttransplant lymphoproliferative disorder (PTLD). We performed electron microscopic analysis and immunostaining of primary B cells infected with wild-type EBV. Interestingly, the nucleolar size was increased by two days after infection. A recent study found that nucleolar hypertrophy, which is caused by the induction of the IMPDH2 gene, is required for the efficient promotion of growth in cancers. In the present study, RNA-seq revealed that the IMPDH2 gene was significantly induced by EBV and that its level peaked at day 2. Even without EBV infection, the activation of primary B cells by the CD40 ligand and interleukin-4 increased IMPDH2 expression and nucleolar hypertrophy. Using EBNA2 or LMP1 knockout viruses, we found that EBNA2 and MYC, but not LMP1, induced the IMPDH2 gene during primary infections. IMPDH2 inhibition by mycophenolic acid (MPA) blocked the growth transformation of primary B cells by EBV, leading to smaller nucleoli, nuclei, and cells. Mycophenolate mofetil (MMF), which is a prodrug of MPA that is approved for use as an immunosuppressant, was tested in a mouse xenograft model. Oral MMF significantly improved the survival of mice and reduced splenomegaly. Taken together, these results indicate that EBV induces IMPDH2 expression through EBNA2-dependent and MYC-dependent mechanisms, leading to the hypertrophy of the nucleoli, nuclei, and cells as well as efficient cell proliferation. Our results provide basic evidence that IMPDH2 induction and nucleolar enlargement are crucial for B cell transformation by EBV. In addition, the use of MMF suppresses PTLD. IMPORTANCE EBV infections cause nucleolar enlargement via the induction of IMPDH2, which are essential for B cell growth transformation by EBV. Although the significance of IMPDH2 induction and nuclear hypertrophy in the tumorigenesis of glioblastoma has been reported, EBV infection brings about the change quickly by using its transcriptional cofactor, EBNA2, and MYC. Moreover, we present here, for the novel, basic evidence that an IMPDH2 inhibitor, namely, MPA or MMF, can be used for EBV-positive posttransplant lymphoproliferative disorder (PTLD).

1588. Epidemiology of Chronic High Level (CHL) Epstein-Barr virus (EBV) DNAemia in Pediatric Solid Organ Transplant Recipients (SOTR) at Texas Children’s Hospital (TCH)

Abstract Background EBV infections cause significant morbidity and mortality in pediatric SOTR and can be complicated by post-transplant lymphoproliferative disorder (PTLD). Contemporary data on CHL EBV DNAemia and the development of PTLD are limited. Methods A retrospective cohort study of patients ≤ 21 years of age who received heart, lung, liver, kidney, or multi-organ transplants at TCH between 2011–2018 was conducted. Primary outcome was CHL EBV DNAemia, defined as peripheral blood lymphocyte EBV values ≥ 500 copies/ug or whole blood EBV values ≥ 10,000 IU/mL for ≥ 6 months. Associations with CHL EBV DNAemia were measured using chi-squared or Fisher exact test and multivariate logistic regression. Time to CHL EBV DNAemia was assessed using Kaplan-Meier method. Results Among 687 SOTR (152 heart, 87 lung, 259 liver, 175 kidney, 14 multi-organ), 87 (13%) developed CHL EBV DNAemia; this included 15 (9%) heart, 9 (10%) lung, 59 (22%) liver, 2 (1%) kidney, and 2 (14%) multi-organ recipients. Receiving a heart [OR 2.1, 95% CI (2.1 – 62.4)], lung [7.7, 95% CI (1.5 – 39.3)], liver [OR 31.8, 95% CI (4.9 – 208.7)], or multi-organ [OR 18.3, 95% CI (2.0 – 170)] transplant and being 1–5 years of age [OR 4.0, 95% CI (1.6 – 9.8)] were associated with CHL EBV DNAemia. SOTR transplanted from 2015–2018 were less likely to develop CHL EBV DNAemia than those transplanted from 2011–2014 [OR 0.5, 95% CI (0.3 – 0.8)]. EBV risk status, CMV risk status, gender, and induction therapy were not associated with developing CHL EBV DNAemia. The median maximum peripheral blood lymphocyte and whole blood EBV values for those with CHL EBV DNAemia were 9475 (993 – 258151) copies/ug and 22093 (564 – 550000) IU/mL, respectively. Organ transplanted (p&amp;lt; 0.01), age (p&amp;lt; 0.01), and EBV risk status (p&amp;lt; 0.01) were associated with time to CHL EBV DNAemia (Figure 1). PTLD occurred in 28 (4%) of SOTR; 14 (50%) had preceding CHL EBV DNAemia (p&amp;lt; 0.01). Figure 1 Time to CHL EBV DNAemia. Conclusion This cohort of pediatric SOTR demonstrates a low prevalence of CHL EBV DNAemia and PTLD. Receiving a heart, lung, liver, or multi-organ transplant and being 1–5 years of age were associated with developing CHL EBV DNAemia. SOTR who developed CHL EBV DNAemia were more likely to develop PTLD, suggesting that further interventions targeting this group may be warranted. Disclosures Flor M. Munoz, MD, MSc, Gilead: Grant/Research Support Elizabeth A. Moulton, MD, PhD, Pfizer: Co-investigator for SARS-CoV-2 pediatric vaccine trials.

209. Epstein-Barr Virus Surveillance in Lung Transplantation: Post-transplant Lymphoproliferative Disorder and Impact on Survival

Abstract Background Epstein-Barr virus (EBV) donor seropositive/recipient seronegative (D+/R-) status is a risk factor for post-transplant lymphoproliferative disorder (PTLD) which is associated with increased mortality post-lung transplant. The optimal surveillance strategy for PTLD post-lung transplant stratified by EBV serostatus for early diagnosis is unknown. We assessed serial EBV viral loads (VL) for early diagnosis of PTLD and compared outcomes in EBV D+/R- and R+ lung transplant recipients at our center. Methods A single-center retrospective study of lung transplants between January 2017 and September 2021 was performed, with a 6-month minimum follow-up. Recipient characteristics, outcomes, and serial EBV VL (biweekly months 1-3, monthly 4-12; using the cobas quantitative PCR assay on serum) were assessed. Results Of the 242 lung transplant recipients, 14 (6%) were EBV D+/R- and 228 (94%) were EBV R+ [Figure 1]. Median age and lung allocation score were similar between the two cohorts [Table 1]. 7 (50%) EBV D+/R- recipients had 2 consecutive, detectable EBV VL in the first-year post-transplant compared to 30 (13%) R+ recipients (p=0.002). 5 (71%) EBV D+/R- recipients with 2 consecutive, detectable EBV VL developed PTLD compared with 2 (7%) R+ recipients (p=0.001). Median weeks post-transplant for two consecutive, detectable EBV VL were 14 (IQR 7, 15) and 10 (IQR 6, 24); and median weeks post-transplant for diagnosis of PTLD were 22 (IQR 17, 31) and 17 (IQR 16, 17) for EBV D+/R- and R+, respectively. Only recipients with at least 2 consecutive, detectable VL in the first-year post-transplant developed PTLD. EBV VL level was not associated with development of PTLD. 6-month outcomes were similar between EBV D+/R- and R+. Though there were no differences in mortality at 1 and 2-years stratified by EBV serostatus, all 5 EBV D+/R- recipients with PTLD were alive 2 years post-transplant, whereas both EBV R+ PTLD recipients died &amp;lt; 2 years post-transplant (p=0.048). Figure 1:Study cohort characteristics and PTLD outcomes based on serial EBV viral loads within the first-year post-lung transplant*7 recipients were excluded per study criteria due to having died less than 1-month post-transplant and therefore not having sufficient EBV VL testing post-transplant for this analysis.Table 1:Baseline characteristics, index hospitalization, and clinical outcomes of lung transplant recipients stratified by EBV serostatus*P-values are based on Fisher’s two-sided exact test (for categorial variables) or the Wilcoxon rank-sum test (for continuous variables).**Time to ≥2 consecutive, detectable EBV VL was calculated based on the date of the second consecutive, detectable result. Conclusion Two consecutive, detectable EBV VL within the first-year post-lung transplant should prompt additional work-up for the early diagnosis of PTLD in all recipients regardless of the EBV VL level or serostatus. Though the attack rate of PTLD was greater in EBV D+/R- recipients, survival outcomes were similar irrespective of serostatus. Disclosures Nicolas C. Issa, MD, AiCuris: Grant/Research Support|Merck: Grant/Research Support.

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

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

Epstein-Barr Virus DNAemia and post-transplant lymphoproliferative disorder in pediatric solid organ transplant recipients.

Pediatric solid organ transplant (SOT) recipients commonly have Epstein-Barr virus (EBV) DNAemia and are at risk of developing post-transplant lymphoproliferative disorder (PTLD). EBV DNAemia has not been analyzed on a continuous scale in this population. All children ≤ 18 years of age who underwent SOT at a single center between January 1, 2007 and July 31, 2018 were included in this retrospective study. Transplant episodes in which PTLD occurred were compared to transplant episodes without PTLD. Multivariable logistic regression was used to identify factors associated with the development of EBV DNAemia and maximum height of EBV DNAemia. A Cox proportional hazards model was used to calculate hazard ratios for time to PTLD. Of 275 total transplant recipients and 294 transplant episodes, there were 14 episodes of PTLD. Intestinal and multivisceral transplant were strongly associated with PTLD (p = 0.002). Risk factors for the development of EBV DNAemia include donor and recipient positive EBV serologies (p = 0.001) and older age (p = 0.001). Maximum level of EBV DNAemia was significantly associated with development of PTLD (p<0.0001). Every one log (log10) increase in the maximum level of EBV DNAemia was associated with a more than doubling of the hazard on developing PTLD (HR: 2.18, 95% CI 1.19-3.99). Transplant type was strongly associated with development of PTLD in pediatric SOT recipients. EBV serologies and age were associated with the development of EBV DNAemia and height of DNAemia. High levels of EBV DNAemia were strongly associated with an increased hazard for PTLD.

ABCL-542 Prevalence and Characterization of EBV-Negative Post-Transplant Lymphoproliferative Disorder

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. To characterize the differences between EBV-positive and EBV-negative PTLD to better understand the pathogenesis of EBV-negative PTLD. This was a retrospective study that reviewed patients who developed PTLD after SOT. Data was collected on PTLD patients (>18 years) from 2011 to 2021. 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. A single, large academic center. A total of 99 patients met the inclusion criteria. Of those, 45.5% were EBV-positive and 54.5% 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). EBV tumor 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%), head/neck (11.1%), liver/spleen (11.1%), CNS (3.7%), other lymph (24%), and other non-lymph (11.1%). Monomorphic (65.5%) and T-cell (90%) subtypes were more common in EBV-negative patients, compared to the polymorphic (15.4%) and plasmablastic/plasmacytic (27.3%) subtypes. Expression of CD20 did not differ by tumor EBV status. Those who were CD30-negative were more likely to be EBV-negative (90% v. 25%, p=<0.001). Those who were CD138-negative were more likely to be EBV-negative (75% v. 26.7%, p=0.012). There was no difference in overall survival by tumor EBV status. 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.

Early- and late-onset posttransplant lymphoproliferative disorders among adult kidney and liver transplant recipients.

ObjectivesPosttransplant lymphoproliferative disorder (PTLD) in solid organ transplant recipients has a high mortality and may present early (<2 years) or late (≥2 years) posttransplantation. We investigated the clinical characteristics of early and late PTLD among kidney and liver transplant recipients.MethodsRecipients, transplanted at Rigshospitalet, with PTLD development as adults from January 2010 to August 2020, were included. Clinical characteristics, laboratory parameters, and pathology of early and late PTLD were compared.ResultsThirty‐one PTLD cases were detected where 10 (32%) were early and 21 (68%) were late PTLD. EBV DNA in plasma was detected in 78% versus 28% in early and late PTLD (p = .037). None of the recipients with early PTLD and nine recipients with late PTLD (47%) had Ann Arbor stage IV at the time of their diagnosis (p = .006). Cyclophosphamid–Hydroxyrubicin–Oncovin–Prednisolon was used for treatment in 10 (48%) recipients with late PTLD (p = 0.032) only. There was no difference in mortality between the two groups.ConclusionsRecipients with late PTLD had a lower prevalence of detectable EBV DNA in plasma, were diagnosed with more advanced disease, and were more frequently treated with chemotherapy compared to recipients with early PTLD.

Characterization of primary cutaneous T-cell lymphoma following solid organ transplantation.

Immunosuppression following solid organ transplantation is a known risk factor for the development of posttransplant lymphoproliferative disorders (PTLD). Primary cutaneous T-cell lymphoma (CTCL) occurring in the posttransplant setting is rare, which has made comprehensive understanding of this disease challenging. This study aims to further characterize the spectrum of clinicopathologic features of CTCL in solid organ transplant recipients (SOTR). A retrospective chart review was performed for SOTR who were diagnosed with CTCL at a multi-site academic medical center from January 1, 1998, to December 31, 2013. Eight patients fulfilled the inclusion criteria and were included in this study. Data collected included patient demographics, transplanted organ, the time between transplant and CTCL diagnosis, clinical presentation and rash morphology, a histological subtype of CTCL, immunosuppression regimens, and patient status. Twelve diagnostic skin biopsies for five patients were examined and reviewed by a board-certified dermatopathologist. Six (75%) out of the eight patients were men, two (25%) were women, and the median age was 53 years. The median time from the date of transplant to the diagnosis of CTCL was 8.2 years. Transplanted organs included the liver (4), kidney (3), and heart (1). Clinical presentation varied from papulonodules, comedone-like lesions, intense pruritis, and scaly erythematous eruptions. The most common histologic presentation was folliculotropic mycosis fungoides (FMF) (7/12). Epstein-Barr virus-in situ hybridization (EBV-ISH) was negative in all specimens. We emphasize the rarity of CTCL among SOTR. Although rare in the general population, the FMF subtype appears to be disproportionately seen in SOTR compared with other CTCL.

Spleen-Restricted Posttransplant Lymphoproliferative Disorder in the First Year After Kidney Transplant – A Case Report

Posttransplant lymphoproliferative disorders (PTLDs) are a feared complication after transplant. They are mostly of B cell origin and are frequently Epstein-Barr virus (EBV)-positive, particularly in early onset PTLD. Later on, non-B and EBV-negative PTLD are increasingly reported. EBV seronegative receptors (particularly when paired with an EBV seropositive donor) together with the net degree of immunosuppression-a concept often difficult to quantify-are the most consistently described risk factors for the development of PTLD. Conversely, its association with a particular immunosuppressive agent or other virus, namely cytomegalovirus (CMV) infection or disease, has been inconsistently reported. We present a challenging case where an EBV negative monomorphic peripheric T-cell lymphoma was diagnosed in the first year after kidney transplant in a patient with a recent history of CMV disease from a resistant strain.