PTLD Diagnosis Research Articles

Risk Factors Associated with PTLD Related Mortality in Adult Multivisceral Transplant Recipients - A Single Centre Cohort Study.

Background: PTLD is a heterogeneous group of lymphoproliferative diseases which can add significant mortality following multivisceral transplantation (MVTx). Our study aimed to identify potential risk factors of mortality in adult MVTx recipients who developed PTLD. Methods: All adult recipients of intestinal-containing grafts transplanted in our institution between 2013 and 2022, and who developed PTLD, were included in the study. Results: PTLD-associated mortality was 28.6% (6/21). Increased relative risk of mortality was associated with Stage 3 ECOG performance score (p=0.005; HR 34.77; 95%CI 2.94-410.91), if the recipients had a splenectomy (p=0.036; HR 14.36; 95%CI 1.19-172.89), or required retransplantation (p=0.039; HR 11.23; 95% CI 1.13-112.12). There was a significant trend for increased risk of PTLD mortality with higher peak EBV load (p=0.008), longer time from MVTx to PTLD diagnosis (p=0.008), and higher donor age (p 0.001). Peak LDH before treatment commencement was significantly higher in the mortality group vs the survival group (520.3 +- 422.8 IU/L vs 321.8 +- 154.4 IU/L; HR 1.00, 95%CI 1.00 to 1.01, p=0.019). Peak viral load prior to treatment initiation (Cycle Threshold (CT) cutoff = 32) correlated with the relative risk of death in MVTx patients who developed PTLD [29.4 (3.5) CTs in survivors compared to 23.0 (4.0) CTs in the mortality group]. Conclusions: This is the first study to identify risk factors for PTLD-associated mortality in an adult MVTx recipient cohort. Validation in larger multicentre studies and subsequent risk stratification according to these risk factors may contribute to better survival in this group of patients.

#4585 POST-TRANSPLANTATION LYMPHOPROLIFERATIVE DISORDER: COMPARISON OF RISK AND PROGNOSTIC FACTORS BETWEEN KIDNEY AND OTHER ORGAN TRANSPLANT RECIPIENTS

Abstract Background and Aims Post-transplantation lymphoproliferative disorder (PTLD) is a potentially fatal complication of transplantation, pathogenesis of which remains to be fully understood. In solid organ transplant recipients, the risk of disease development is associated with graft type and is lowest for kidney (KTR), intermediate for liver (LTR) and high for lung (LngTR) transplant recipients. The aim of this study was to investigate the factors contributing to the development and treatment outcomes of PTLD and compare their impact on the populations of KTRs, LTRs and LngTRs. Method In this retrospective cohort study we have included all KTRs, LTRs and LngTRs diagnosed with PTLD at four transplantation centers in Poland between 2002 and 2022. The following data were collected from the patients’ medical records: immunosuppression (IS), viral infections, PTLD type, treatment and outcomes. Mann-Whitney U-test was used to assess the differences in group composition, and univariate Cox regression was used to determine the impact of variables upon PTLD time of onset and patient survival. p-values below 0.05 were considered statistically significant. Results We identified 31 KTRs, 31 LTRs and 5 LngTRs who fulfilled the inclusion criteria. Among the patients of the transplantation center leading this study, PTLD was diagnosed in 22 (0.82%) out of 2699 KTRs and 29 (2.03%) out of 1386 LTRs. Two thirds of the patients were male, the median age at first transplantation was 39 years and the median age at PTLD diagnosis was 48 years. KTRs and LTRs significantly differed in IS treatment: more KTRs used steroids (GCS, p = 0.042) and cyclosporin (CsA, p = 0.001), more LTRs used tacrolimus (TAC, p<0.001) and anti-CD25 induction (p = 0.003). KTRs developed PTLD later than LTRs (141 months after transplantation vs 53 months, p = 0.004) and LngTRs (5 months after transplantation, p = 0.001). Monomorphic PTLD was the most frequent in KTRs (80.6%, p = 0.032). Initial IS treatment reduction was used in 91% of all patients. The groups did not significantly differ in the type of PTLD treatment. TAC had the opposite effect on PTLD time of onset in KTRs (HR = 2.92, 95%CI 1.35-6.34, p = 0.007) and LTRs (HR = 0.18, 95%CI 0.04-0.89, p = 0.036). At the end of the observation period 16.7% of KTRs, 51.6% of LTRs and 80% of LngTRs were alive. Complete remission was achieved in 48.4% of KTRs, 61.3% of LTRs and 80% of LngTRs. KTRs had the highest rate of loss to follow up at 41.4%. Patient survival was longer in patients who were treated with anti-CD20 monotherapy (HR = 0.28, 95%CI 0.08-0.96, p = 0.042) and surgery (HR = 0.33, 95%CI 0.12-0.91, p = 0.031). Conclusion KTRs develop PTLD significantly later than LTRs and LngTRs, and disease onset is associated with TAC use. Low KTR survival rate is related to the high rate of loss to follow up (e.g. loss of graft function and return to hemodialysis). Surgical treatment, used mainly in focal PTLD improves patients’ survival. The positive effect of anti-CD20 monotherapy on patients’ survival reflects the efficacy of current stratified treatment regimens for PTLD.

The IPTA Nashville Consensus Conference on Post-Transplant lymphoproliferative disorders after solid organ transplantation in children: III - Consensus guidelines for Epstein-Barr virus load and other biomarker monitoring.

The International Pediatric Transplant Association convened an expert consensus conference to assess current evidence and develop recommendations for various aspects of care relating to post-transplant lymphoproliferative disorders after solid organ transplantation in children. In this report from the Viral Load and Biomarker Monitoring Working Group, we reviewed the existing literature regarding the role of Epstein-Barr viral load and other biomarkers in peripheral blood for predicting the development of PTLD, for PTLD diagnosis, and for monitoring of response to treatment. Key recommendations from the group highlighted the strong recommendation for use of the term EBV DNAemia instead of "viremia" to describe EBV DNA levels in peripheral blood as well as concerns with comparison of EBV DNAemia measurement results performed at different institutions even when tests are calibrated using the WHO international standard. The working group concluded that either whole blood or plasma could be used as matrices for EBV DNA measurement; optimal specimen type may be clinical context dependent. Whole blood testing has some advantages for surveillance to inform pre-emptive interventions while plasma testing may be preferred in the setting of clinical symptoms and treatment monitoring. However, EBV DNAemia testing alone was not recommended for PTLD diagnosis. Quantitative EBV DNAemia surveillance to identify patients at risk for PTLD and to inform pre-emptive interventions in patients who are EBV seronegative pre-transplant was recommended. In contrast, with the exception of intestinal transplant recipients or those with recent primary EBV infection prior to SOT, surveillance was not recommended in pediatric SOT recipients EBV seropositive pre-transplant. Implications of viral load kinetic parameters including peak load and viral set point on pre-emptive PTLD prevention monitoring algorithms were discussed. Use of additional markers, including measurements of EBV specific cell mediated immunity was discussed but not recommended though the importance of obtaining additional data from prospective multicenter studies was highlighted as a key research priority.

Incidence of Lymphoproliferative Disorders After Renal Transplantation is Down, but the Poor Prognosis Remains. Multicenter 32-Year Cohort Study.

Post-transplant lymphoproliferative disorders represent rare but serious complications of kidney transplantation. We assessed incidence, risk factors, and outcomes in 21,546 patients receiving grafts between 1990 and 2009. Data were compared by decade of transplant (1990-1999 vs 2000-2009). Patients were followed for at least 12 years over a 32-year study period. In total, 331 patients (1.5%) developed PTLD: 189 of 9740 transplanted in the first decade, and 142 of 11,806 in the second. Incidence decreased significantly (19.40 vs12.02 cases/1000 patients; P < .001). Mean age at diagnosis was 50.2 years (standard deviation 14.7), and the median time from transplant to PTLD diagnosis was 48 months (interquartile range, 14.7-77.5), with no difference between cohorts. The origin of PTLD was mostly (86%) B-cell proliferation. No classical risk factors were reported in 31.7% of affected patients. Compared with 2000 to 2009, in 1990 to 1999 there was a higher frequency of induction therapy (P=.023) and detection of the Epstein-Barr virus in lymphoproliferative tissue (71.3% vs 52.7% P=.019). After diagnosis, 1- and 5-year patient survival was 51% and 38%. Graft survival was 48% and 33%. Survival was stable throughout the study period. Post-transplant lymphoproliferative disorders have a low and decreasing incidence, but the poor prognosis has not changed.

Single-center “Argentine” analysis of post-transplant lymphoproliferative disorders: incidence, histopathological characteristics and EBV status

IntroductionPost-transplant lymphoproliferative disorders (PTLDs) are a heterogeneous group of lymphoid proliferations occurring after solid organ or bone marrow transplantation. The primary aims of our study were to characterize cumulative incidence of PTLDs, clinical and pathological features according to the Epstein-Barr virus (EBV) status and survival. MethodsThis was a retrospective cohort study on adult and pediatric patients, from January 2001 to December 2017. The cumulative incidence of PTLD was calculated by analyzing all the patients transplanted at our hospital, based on the database of the Organ Donation and Ablation Authority of Argentina (INCUCAI). The Kaplan-Meier method was used to plot the survival. ResultsFifty-eight cases of biopsy-confirmed PTLD were identified and 12 cases of clinical data were incomplete and these patients were excluded. The median age at the time of the PTLD diagnosis was 17.5 years (interquartile range [IQR] 9 - 57). The median interval between transplant and PTLD diagnosis was 39 months (IQR 9 - 113). The most commonly transplanted organ was the liver (24 cases, 52.2%), followed by kidney (20 cases, 43.5%). The Epstein-Barr encoding region in situ hybridization (EBER ISH) was positive in 29 (69.8%) of the 43 evaluable biopsies. The PTLD cumulative incidence was 1.84% (95%CI 1.77 - 1.91) for solid organ and 0.84% (95%CI 0.48 - 1.2) for bone marrow transplant patients. The overall survival rate at 5 years was 0.77 (95%CI 0.61 - 0.87). Subgroups by the EBV EBER status, transplant type, PTLD subtype and age group (adult vs. pediatric) showed no statistically significant association with the overall survival. ConclusionThe PTLD incidence was similar to that of previous series and the EBER did not appear as a relevant factor in our patient survival.

Prognostic superiority of International Prognostic Index over [18F]FDG PET/CT volumetric parameters in post-transplant lymphoproliferative disorder

BackgroundPost-transplant lymphoproliferative disorders (PTLDs) are a spectrum of hematological malignancies occurring after solid organ and hematopoietic stem cell transplantation. [18F]FDG PET/CT is routinely performed at PTLD diagnosis, allowing for both staging of the disease and quantification of volumetric parameters, such as whole-body metabolic tumor volume (MTV) and total lesion glycolysis (TLG). In this retrospective study, we aimed to determine the prognostic value of MTV and TLG in PTLD patients, together with other variables of interest, such as the International Prognostic Index (IPI), organ transplant type, EBV tumor status, time after transplant, albumin levels and PTLD morphology.ResultsA total of 88 patients were included. The 1-, 3-, 5- year overall survival rates were 67%, 58% and 43% respectively. Multivariable analysis indicated that a high IPI (HR: 1.56, 95% CI: 1.13–2.16) and an EBV-negative tumor (HR: 2.71, 95% CI: 1.38–5.32) were associated with poor overall survival. Patients with a kidney transplant had a longer overall survival than any other organ recipients (HR: 0.38 95% CI: 0.16–0.89). IPI was found to be the best predicting parameter of overall survival in our cohort. Whole-body MTV, TLG, time after transplant, hypoalbuminemia and PTLD morphology were not associated with overall survival.Conclusion[18F]FDG PET/CT whole-body volumetric quantitative parameters were not predictive of overall survival in PTLD. In our cohort, high IPI and an EBV-negative tumor were found to predictors of worse overall survival while kidney transplant patients had a longer overall survival compared to other organ transplant recipients

Management and Outcomes of Diffuse Large B Cell Lymphoma Post-Transplant Lymphoproliferative Disorder in the PET/CT Era: A Multicentre Study from the Australasian Lymphoma Alliance

Management and Outcomes of Diffuse Large B Cell Lymphoma Post-Transplant Lymphoproliferative Disorder in the PET/CT Era: A Multicentre Study from the Australasian Lymphoma Alliance

P1704POST-TRANSPLANTATION LYPMHOPROLIFERATIVE DISORDER (PTLD) RISK AND PROGNOSTIC FACTORS IN KIDNEY AND LIVER TRANSPLANT RECIPIENTS

Abstract Background and Aims Post-transplantation lymphoprolipherative disorder [PTLD] is a serious, potentially fatal complication of transplantation [Tx], pathogenesis of which remains to be fully understood. Due to the intrinsic difficulty of assembling a large cohort of rare disease patients, most research papers have investigated PTLD in the general graft recipient population. They report however, that the relative risk of disease development significantly varies in relation to the type of transplanted organ, with multiorgan and intestinal graft recipients possessing the highest risk (RR=239.5), liver (RR=29.9) and the lowest for kidney transplant recipients (RR=12.6). The aim of this study was to investigate the factors contributing to the development, course, treatment and outcomes of PTLD and compare their impact on the populations of liver [LTR] and kidney [KTR] transplant recipients. Method In this retrospective cohort study we have included all KTRs and LTRs diagnosed with PTLD at our centres between 2002 and 2017. The following data were collected from the patients’ medical records: immunosuppression (IS), viral infections, PTLD type, treatment and outcomes. Mann-Whitney U-test was used to assess the differences in group composition, and the Log-rank test was used to compare Kaplan-Meier curves. Statistical analysis was performed in R version 3.2.3., p-values below .05 were considered statistically significant. Results We have identified 23 LTR and 16 KTR who matched our inclusion criteria. The mean age was 40.69 years. 61.5% of the patients were male, 38.5% female. Analysis of Kaplan-Meier curves revealed that PTLD occurred earlier in: LTRs (p&amp;lt;.001); patients above the median age of 45 years at Tx (p=.002); patients whose IS regimens at the time of PTLD diagnosis contained tacrolimus [TAC] (p&amp;lt;.001) or did not contain cyclosporin [CsA]. Among KTRs PTLD was diagnosed earlier in males (p&amp;lt;0.05), patients over 45 years at Tx (p&amp;lt;0.05), and those receiving TAC-containing IS regimens at PTLD diagnosis (p&amp;lt;0.05). These factors were not statistically significant for LTRs, among whom PTLD development was affected by the presence of MMF in IS regimens at diagnosis (p&amp;lt;0.05). Survival time was longer for patients receiving MMF-containing IS regimens (p&amp;lt;0.05). LTRs were more likely than KTRs to achieve complete remission in response to treatment (p&amp;lt;0.05). Conclusion Our results indicate, that in comparable KTR and LTR populations, the course of PLTD and response to treatment vary significantly. Factors such as patients’ age at transplantation, sex, type of maintenance IS have a different impact depending on graft type. In our opinion these findings, when applied to further research, could enhance our ability to identify patients at risk and potentially lead to the formation of more personalised guidelines to the diagnosis and treatment of PTLD.

P1685POST-TRANSPLANT LYMPHOPROLIFERATIVE DISORDER (PTLD): SINGLE INSTITUTIONAL EXPERIENCE OF TWO DECADES

Abstract Background and Aims Post-transplant lymphoproliferative disorders (PTLD) are a group of heterogeneous lymphoid proliferations in chronic immunosuppressed recipients of solid organ and hematopoietic stem cell transplantation. Due to rarity of this disease, retrospective studies from transplant centers have been the main source to provide knowledge and treatment guidelines, which are still in evolution. This study examined the clinical outcomes and identified the predictors of mortality in adult renal transplant recipients who developed PTLD. Method We have studied the incidence of PTLD in adult renal transplant recipients who were transplanted in our hospital from 1996 to 2019. Data was collected for demographics, transplant and immunosuppression history, EBV and CMV serostatus, diagnosis, treatment and outcomes of PTLD. We performed univariate and multivariate analysis to identify prognostic factors. PTLD was classified according to 2018 WHO lymphoma classification. Results Twenty-four patients (12 males and 12 females) were eligible for the analysis. Mean age at time of the transplant was 43.1 ± 16.9 years, with a time between grafting and PTLD of 66 months (IQR 36-98 months). Mean follow-up time was 87 months (IQR 61-117 months). 25% of patients received a living donor renal transplant. 12,5% of patients received induction therapy with thymoglobulin. Mean age at time of PTLD diagnosis was 48,8 ± 17,9 years. Five cases were from Epstein-Barr virus (EBV) mismatched (D+/R-) transplants and there was seroconversion at time of PTLD diagnosis. 25% of patients had central nervous system involvement. 19 patients have monomorphic PTLD and the most common histological diagnosis was diffuse large B cell lymphoma. We identified that age &amp;gt;30 years at time of the transplant was predictor of mortality (HR 33.01; 95% CI: 3.24-336.14; p=0.003). Surprisingly, presence of B symptoms at time of PTLD diagnosis confer a better prognosis (HR 0,143; 95% CI: 0,035-0,579; p=0.006). All cases were managed with reduction in immunosuppression and converted to everolimus. 8 patients were treated with rituximab and there was no significant difference in the survival of these patients. By the end of follow-up, 7 patients went into remission, 1 returned to chronic dialysis, and 16 patients died (15 of them due to the disease). Mean time between PTLD and death was 3 months (IQR 1-6 months). Conclusion PTLD is an infrequent disease with a poor prognosis in renal transplant patients. Some cases have a close relationship with EBV, but it can also develop in the absence of the classical risk factors. The factor affecting mortality in our population was age &amp;gt;30 years at time of the transplant. Presence of B symptoms at time of PTLD diagnosis seems to confer a better prognosis probably due to early investigation and diagnosis of the disease.

Frequency, characteristics, and outcome of PTLD after allo-SCT: A multicenter study from the Spanish group of blood and marrow transplantation (GETH).

To estimate the frequency and management of PTLD in Spain and to identify prognostic factors influencing outcomes. Multicenter, retrospective analysis of allo-SCT performed in 14 transplant units over a 15-year period. 102 PTLD were diagnosed among 12641 allo-SCT, leading to an estimated frequency of 0.8%. PTLD was diagnosed at a median of 106days after SCT. Eighty-seven cases (85%) were diagnosed between 2007 and 2013. At diagnosis, 22% and 17% of the patients had gastrointestinal tract and CNS involvement. Eighty-seven (85%) received rituximab treatment, alone or in combination with immunosuppression reduction, with an ORR of 50.6%. With a median follow-up for survivors of 58months, the 2-year overall survival (OS) was 33% and the PTLD-related mortality 45%. Age≥40years, malignant underlying disease, non-response to rituximab, and severe thrombocytopenia or lymphocytopenia at PTLD diagnosis were associated with worse overall survival. Only a small proportion of allografted patients were diagnosed a PTLD. Its clinical course was highly aggressive, and prognosis poor, especially in those failing rituximab. The prognostic impact found of the platelet, and lymphocyte count at diagnosis requires further confirmation.

Epstein-Barr Virus Status in Diffuse Large B Cell Lymphoma Post-Transplant Lymphoproliferative Disorder

BackgroundDiffuse large B cell lymphoma post-transplant lymphoproliferative disorder (DLBCL-PTLD) represents a fatal complication after a solid organ transplant (SOT). Approximately 50% of DLBCL-PTLD can be related to Epstein Barr Virus (EBV) infection. However, the EBV status is not taken into account in the DLBCL-PTLD categorization, although increasing evidence suggests its critical role in biological, clinical and prognostic aspects of the disease. In this single center retrospective study, we compared clinical and histological features, as well as outcomes of DLBCL-PTLDs by EBV status.MethodsThis study focused on patients with SOT who were diagnosed with DLBCL-PTLD at Mayo Clinic (Rochester, MN). Patients were identified through the Mayo Clinic Lymphoma Data base and the University of Iowa/Mayo Clinic SPORE Molecular Epidemiology Resource (MER), between 1989 and 2017. The histology was re-reviewed (RLK) and classified according to the WHO Classification or Tumours of Haematopoietic and Lymphoid Tissues 2017. Cell of origin (COO) was performed by Hans algorithm. EBV RNA in situ hybridization (EBER) was performed. Cox proportional hazards models were used to assess the association of clinical factors in overall survival (OS).Results148 DLBCL-PTLD were identified. The median age at SOT and at the time of PTLD diagnosis were 50 years (range: 15-71) and 56 years (range: 18-82), respectively. The median time to PTLD diagnosis from SOT was 38 months (range: 1-499). The types of SOT included renal (44%), liver (36%), cardiac (9%), renal/pancreas (5%), pancreas (8%), lung (7%) and multiorgan (4%). 62% were stage III-IV, 30% had elevated LDH and 67% had an IPI >1. 88% of patients presented with extranodal disease, and 16% had involvement of the grafted organ. Eighty-three (56%) cases were EBV positive. The COO information was available on 35 cases. The non-GCB subtype was identified in 24 cases and GCB subtype in 11 cases. The initial treatment was as follows: reduction in immunosuppression (12%), immunosuppression reduction with rituximab (26%), rituximab alone (5%), chemotherapy with or without rituximab (35%). Patients with EBV positive PTLD were more likely to have grafted organ involvement (20% vs. 8%, p=0.047) and late PTLD (occurring after 12 months from SOT - 60% vs. 8%, p<0.001) than patients with EBV negative PTLD. There was no association between EBV status and age, sex, stage, LDH, and extranodal site involvement. At a median follow-up of 80 months (range 9-269), 83 patients (56%) had died. The 5-year survival rate from PTLD diagnosis was 56% (95% CI: 48-65%). The median OS was 85 months (95% CI: 37-148). There was no difference in OS in patients with EBV positive PTLD (median OS=84.7 months, HR=1.21, 95% CI: 0.77-1.92) versus patients with EBV negative DLBCL-PTLD (median OS=85.4 months, p=0.41).ConclusionOur study assessed the impact of EBV status on the presentation and clinical outcome of DLBCL-PTLD in a 148-patient single-institution cohort. 56% of cases were EBV positive. EBV positivity was associated with grafted organ involvement and late PTLD diagnosis. Patients with EBV-negative and EBV-positive disease had similar survival from PTLD diagnosis. DisclosuresMaurer:Celgene: Research Funding; Morphosys: Research Funding; Nanostring: Research Funding. Cerhan:Nanostring: Research Funding; Jannsen: Other: Scientific Advisory Board; Celgene: Research Funding.

Different causes of early and late-onset post transplant lymphoproliferative disorder in kidney transplantation patients after 2000

The purpose of this study was to analyze the link between PTLD incidence and its occurrence time in patients at a single center in comparable medical environments after 2000. Retrospectively, total 3305 kidney transplantation patients medical data were analyzed. Patients were divided into two groups based on the period from the day of kidney transplantation to the day of PTLD diagnosis. Early-onset was defined as PTLD development within two years after transplantation, whereas all other cases were categorized as late-onset PTLD. In the early-onset group, young age (0-19 years) was confirmed as a risk factor for PTLD incidence (HR 1.49, p=0.038). In the late-onset group, history of anti-rejection therapy was confirmed as a risk factor (HR 1.32, p=0.031). Overall survival rates were not significantly different between the two groups (p=0.556). Graft survival rates were also not different between the two groups (p=0.549). When patients with PTLD were classified into early-onset group and late-onset group at two years, overall survival and graft survival were comparable. And patients with early-onset PTLD are more likely to be associated with EBV, the late-onset patients are more likely to be immunosuppressed.

Clinical Utility of Epstein-Barr Virus Viral Load Monitoring and Risk Factors for Posttransplant Lymphoproliferative Disorders After Kidney Transplantation: A Single-Center, 10-Year Observational Cohort Study.

BackgroundPosttransplant lymphoproliferative disease (PTLD) is an important cause of morbidity and mortality in solid organ transplants. Epstein Barr virus (EBV) plays a major role in PTLD development. Guidelines recommend EBV viral load (VL) monitoring in high-risk populations in the first year.MethodsRetrospective observational study in all adult patients who had at least 1 EBV-VL performed in the postkidney transplant (KT) period from January 2005 to December 2014 at the Policlinico Modena Hospital. We compared patients with negative EBV-DNA to patients with positive EBV-DNA and we described PTLD developed in the study period.ResultsOne hundred ninety (36.3%) KT patients of 523 were screened for EBV-DNA with 796 samples. One hundred twenty-eight (67.4%) of 190 tested patients presented at least 1 positive sample for EBV. Older age, the use of sirolimus, everolimus, and steroids were associated with EBV-DNA positivity in the univariate analysis. Nine (1.7%) of 523 patients had PTLD. Incidence rate of PTLD in the KT cohort was 0.19/100 person year follow-up (95% confidence interval, 0.09-0.37). One of 9 patients developed early PTLD and was a high-risk patient. Only this PTLD case was positive for EBV. No PTLD case had an EBV-VL superior to 4000 copies/mL.ConclusionsOur results suggest that the keystone of PTLD diagnosis is the clinical suspicion. Our study suggests that, in line with guidelines, EBV-VL assays may be avoided in low-risk patients in the absence of a strong clinical PTLD suspicion without increasing patients' risk of developing PTLD. This represents a safe and cost-saving clinical strategy for our center.

Pancreas.

Even though pancreas transplant numbers have steadily declined over the past decade, new listings increased in 2014 compared with the previous year, notably for pancreas transplant alone (PTA) and simultaneous pancreas-kidney transplant. The number of new PTAs also increased over the past two years. Whether this is a sustainable trend remains to be seen. Significant events in 2014 included implementation of a new pancreas allocation system and development of a proposed uniform definition of pancreas graft failure. Meanwhile, overall pancreas transplant rates and outcomes continued to improve. Substantial decline in pancreas after kidney transplants remains a serious concern. SRTR has not published pancreas graft failure data in the program-specific reports for the past two years. While this will not change in the near future, the acceptance of a uniform definition of graft failure is a crucial first step toward resuming graft failure reporting. Continued improvements and innovation, both surgical and immunological, will be critical to keep pancreas transplant as a viable option for treatment of insulin-dependent diabetes. As alternative therapies for diabetes such as islet transplant and artificial pancreas are evolving, improved outcomes with minimizations of complications are more important than ever.

Prognosis of Patients with Primary Central Nervous System Post-Transplant Lymphoproliferative Disorder (PTLD-CNS) Treated with Immunossupression Reduction, Intrathecal Chemotherapy and Whole-Brain Radiotherapy: An Analysis of 23 Patients in a Brazilian Cohort

Introduction: Post-transplant lymphoproliferative disorders are a rare heterogenous group of diseases occurring in the setting of post-transplant immunossupression (IS). Clinically, extranodal involvement is common, and it occurs in the central nervous system (CNS) in approximately 7-15% of cases. Most data on PTLD-CNS are based on case series/reports and due to paucity of data no treatment algorithms have been established. In our series, we retrospectively analyzed 23 consecutively cases of PTLD-CNS in Hospital do Rim, Sao Paulo, Brazil.Methods: We retrospectively reviewed all cases of PTLD-CNS diagnosed between 2001 and 2014 at Hospital do Rim (HRim), a school hospital from the Federal University of São Paulo, Brazil. HRim is considered the leading renal transplant hospital in the world for the past 15 years. For this study, only PTLD patients with tumors whose histology could be confirmed by hemopathologist review, EBV-association established and whose clinical, epidemiological and laboratorial parameters could be retrieved were included in this study. Response was defined as complete (CR) or less than CR (partial response or refractory disease). Event was defined as treatment related mortality, progression (defined as time for initiation of second-line therapy) or relapse.Results: From 2001 to 2014, from a total of 98 PTLD patients, 23 patients (23%) were diagnosed with PTLD-CNS. Median age at time of diagnosis was 36, with a male:female ratio of 0.9:1. Fifteen (65%) patients received anti-thymocyte globulin (ATG) at the time of transplant and 17 (74%) had at least one episode of acute rejection. The most common immunossupressive regimen (IR) consisted of cyclosporine or tacrolimus associated with prednisone and azathioprine (15, 65%). Median time from transplant to PTLD diagnosis was 31 months (ranging from 8.4 to 153). EBV was positive in tumor lymphocytes by in situ hybridization in 21 cases (91%). Monomorphic cases were diagnosed in 21 (91%) patients. All patients had their IR reduced, usually with suspension of azathioprine and calcineurin inhibitors and change from prednisone to dexamethasone, 19 (82%) patients underwent WBRt (from 25 to 40 Gy) together with intra-thecal (IT) chemotherapy with methotrexate (MTX) 12mg and dexamethasone 2mg. Only 1 patient received high dose MTX and died due to treatment-related toxicities 1 month after diagnosis and 2 patients died before starting WBRt due to disease progression and poor performance status (PS). For those patients who received WBRt together with IT chemotherapy, fourteen patients (74%) had CR, 2 patients (10%) had refractory disease and 3 patients (16%) had relapsed disease within 2 years. Overall Survival (OS) for the group treated with WBRt and IT chemotherapy was 62% in 5 years (CI95% 69-82%). In our series, induction therapy with ATG and acute rejection were associated with increased risk of PTLD-CNS. Age and PS at diagnosis were the only 2 factors predictive of survival. No serious cognitive impairment was identified among the survivors.Conclusions: The current study demonstrated that PTLD-CNS is a serious late EBV-induced B-cell lymphoma, mostly monomorphic with an incidence of 23%, higher than previously described in the post renal transplant setting. Treatment with immunossupression reduction, intrathecal chemotherapy and whole-brain radiotherapy showed a high CR rate with favorable survival in many cases. DisclosuresNo relevant conflicts of interest to declare.

Outcome Of Rapamycin Therapy For Post Transplant- Lymphoproliferative Disorder After Kidney Transplantation: Case Series

BackgroundPost transplant lymphoproliferative disorders (PTLD), are a complication of chronic immunosuppressive therapy in solid organ transplantation with a high mortality rate. Alternative treatments such as rapamycin have been explored. MethodsA detailed retrospective analysis was performed according to data collected from thirteen patients with PTLD. At the time of PTLD diagnosis, immunosuppressive therapy was decreased and rapamycin administered. Overall survival and disease free survival of patients and graft survival were determined. ResultsAmong 590 kidney transplant recipients, thirteen adult patients with PTLD were included in this study. The mean age of the patients was 42.15 (range: 25-58) years at the time of PTLD diagnosis, and 9 patients were male. Histology was distributed in 9 diffuse large B cell, 1 Malt lymphoma, 1 Burkitt lymphoma, 2 Hodgkin-like PTLD. The response rate to rapamycin alone was 30.8%. The mean overall survival period is 27.4 months with 9 patients still living. In total, 10 patients (76.9%) achieved a complete remission, with functioning graft in 11 (84.6%) patients. ConclusionsDespite to retrospective and limited number of patients, this study provides promising results regarding the effectiveness of stopping calcineurin inhibitors and switching to rapamycin for patients with PTLD. Disclosures:No relevant conflicts of interest to declare.

Clinicopathologic features of post‐transplant lymphoproliferative disorders arising after pediatric small bowel transplant

Few studies examined the clinicopathologic features of PTLD arising in pediatric SBT patients. Particularly, the association between ATG and PTLD in this population has not been described. Retrospective review of 81 pediatric patient charts with SBT--isolated or in combination with other organs--showed a PTLD incidence of 11%, occurring more frequently in females (median age of four yr) and with clinically advanced disease. Monomorphic PTLD was the most common histological subtype. There was a significant difference in the use of ATG between patients who developed PTLD and those who did not (p < 0.01); a similar difference was seen with the use of sirolimus (p < 0.001). These results suggested a link between the combination of ATG and sirolimus and development of more clinically and histologically advanced PTLD; however, the risk of ATG by itself was not clear. EBV viral loads were higher in patients with PTLD, and median time between detection of EBV to PTLD diagnosis was three months. However, viral loads at the time of PTLD diagnosis were most often lower than at EBV detection, thereby raising questions on the correlation between decreasing viral genomes and risk of PTLD.

Long Term Follow-Up in Small Bowel Transplant Recipients: Ebv Infections and Post Transplant Lymphopfoliferative Disease Surveillance

Background: Control of complications is still one of the most important clinical challenge in small bowel transplantation. Early diagnosis and fast treatment can avoid negative outcomes, so obviously reliable monitoring protocols are capital: the aim of this study was to evaluate endoscopic and histological diagnostic value on a long term follow-up in case of EBV infection and PTLD occurrence. Patients and methods: We evaluated endoscopies performed during last six years on 18 recipients submitted to small bowel transplant between the year 2000 and 2006: follow-up endoscopies and biopsies after 5 years from transplant were routinely scheduled once every 6 months, otherwise more often in case of clinical indications. At transplant, recipients underwent preemptive antiviral therapy and subsequently serial monitoring of Epstein-Barr-Viral load was performed. In case of intestinal EBV infection with negative blood viral load the patients were treated only with low immunosuppression regimen. Patients with EBV infection found both on intestinal specimen and on blood samples, were treated reducing immunosuppression regimen and with i.v. Gancyclovir administration (5mg/Kg 2 times/day) for 2 weeks; patients with PTLD diagnosis were treated with low immunosuppression regimen and with Rituximab administration (375 mg/m2, once/week for 4 weeks). Results: In our series we were able to diagnose EBV infections (both in blood and intestinal mucosa), and consequently to make an early diagnose of PTLD when occurring thanks to close follow-up: endoscopy with biopsies and EBV monitoring on specimen and blood every month, PET scan every 6 month in case of positive blood EBV infection. During the considered follow-up period, with at least 5 years from transplant, we diagnosed 12 cases of EBV intestinal infections, 5 of them with positive blood viral load. Among these five cases, even if they were all treated with Gancyclovir administration, 3 patients developed PTLD occurrence and they were all treated with four weeks Rituximab schedule: we registered negative outcome in one case (the patient died due to post-operative complications after intestinal resection of obstructive intestinal PTLD); other two patients appear now free from disease, with complete PET healing on latest follow-up, even if one of them still has EBV positive intestinal biopsies and blood samples and he is under antiviral therapy up to now. Conclusion: EBV infection is one of the most common complication after intestinal transplantation, with an incidence of 67% in our series. After a median follow-up of 36 months (12-60 months) the overall survival is 88,8 %. Therefore, concerning EBV infections and PTLD surveillance during long term follow-up, endoscopy and histological analysis are good tools to provide faster diagnostic orientation, to plan appropriate treatment earlier, and to achieve positive outcomes.

Graft rejection in pediatric liver transplant patients with Epstein‐Barr viremia and post‐transplant lymphoproliferative disease

Treatment of primary EV and PTLD in pediatric LT recipients (pLT) involves IS reduction/cessation. Retrospective review of pLT at our institution from 2001-2009 was conducted to characterize risk factors for GR after EV/ PTLD. Of 184 pLT, EV occurred in 61 (33%) at mean 16.5 m (0-82) and PTLD in 18 (9.8%) at mean 17.7 m (3-78) post-LT. Median age at pLT was 11 m (1-245 m) and follow-up six yr. For EV, 86% underwent IS reduction and 51% received antivirals. GR occurred in 12 (27.9%) with EV and 15 (83.3%) after PTLD diagnosis (relative risk of GR for PTLD 2.98). GR treated with methylprednisolone bolus in half and/or oral IS in half. Following GR therapy, four had PTLD relapses, no graft loss and one EV patient required re-transplantation. GR history before EV was a risk factor for GR after EV (p = 0.024). GR at any point after pLT was a risk factor for PTLD (p = 0.001). Children with EV and GR prior to EV should be monitored closely for GR after IS reduction and GR is a significant risk factor for PTLD. Most children with PTLD eventually developed GR.

Posttransplant Lymphoproliferative Disorder in Kidney Transplant Patients: A Report of 68 Cases

Abstract 2662Posttransplant Lymphoproliferative Disorder (PTLD) is a rare complication of kidney transplantation that often arises due to reactivation of the Epstein-Bar Virus (EBV). Given the rarity of this disease, a full understanding of its presentation and optimal therapies has yet to be determined. Out of the 3160 patients who received a kidney transplant at the Hospital of the University of Pennsylvania between October 1987 and December 2010, we provide a retrospective analysis of 68 patients who developed PTLD. These patients were 82% Caucasian, 62% male, and 9% combined kidney and pancreas transplant patients. The most common underlying diseases leading to transplantation were glomerulonephritis (26%) and diabetes mellitus (17%). Most patients received a kidney from an unrelated donor (74%) and experienced one or more rejection episodes prior to PTLD diagnosis (59%). The median age at PTLD diagnosis was 48 yrs (range 17–76 yrs), and the median time from transplantation to diagnosis was 3 yrs (range 6 days– 25 yrs). PTLD histology consisted of 48% monomorphic, 37% polymorphic, 7% plasmacytoma, 4% T cell, and 3% Hodgkin lymphoma. At diagnosis, patients were taking steroids (96%), cyclosporine (53%), tacrolimus (35%), azathioprine (52%), and/or mycophenolate mofetil (28%). Common initial PTLD symptoms include fever (48%), pain (42%), weight loss (33%), fatigue (33%), and mass (24%). The disease commonly presented in lymph nodes (38%), kidney allograft (29%), and/or GI tract (18%). Most PTLD cases were diagnosed at stage 1 (43%) or stage 4 (31%). Laboratory analyses reveal that 62% of patient tumors tested positive for EBV and 61% of patients had elevated LDH levels. Common PTLD therapies included reduction of immunosuppression (88%), treatment with rituximab (31%), surgery (29%), and/or radiation therapy (9%). Reduction of immunosuppression alone led to CR (50%), PR (8%), SD (4%), and PD (38%). Of the 68 patients, 21 (31%) ultimately died a PTLD related death.Interestingly, PTLD patients under age 40 were more likely to have allograft involvement (p=0.007) and a polymorphic histology (p=0.007). Furthermore, allograft involvement tended to occur sooner after transplant (p=0.0001) and those with allograft involvement were more likely to present with allograft failure (p= 0.0001). Compared to monomorphic PTLD, polymorphic PTLD was more likely to be EBV positive (82% vs 51%, p=0.03) and have a lower chance of PTLD-related death (15% vs 40%, p=0.03). Finally, patients with allograft PTLD were more likely to have a polymorphic histology (80%, p<0.001). In summary, PTLD occurs in about 2% of kidney recipients and is typically EBV-associated. EBV positive PTLD is more common in younger recipients, frequently presenting with polymorphic histology in the allograft and appears to have a better prognosis. Disclosures:No relevant conflicts of interest to declare.