Development Of Post-transplant Lymphoproliferative Disease Research Articles

Single-Center Outcomes of Epstein-Barr Virus DNAemia in Adult Solid Organ Transplant Recipients.

Immunosuppression in solid organ transplantation (SOT) increases the risk of Epstein-Barr virus (EBV) DNAemia, which may herald development of posttransplant lymphoproliferative disease (PTLD). Few studies have characterized the incidence, risk factors, and clinical impact of EBV DNAemia in adult SOT recipients (SOTR). A single-center, retrospective review of adult (≥18 years) SOTR between 01 January 2015 and 31 December 2019 was conducted. Patients were stratified by the primary study endpoint of development of EBV DNAemia (whole blood EBV DNA PCR > 200 copies/mL). Secondary endpoints included development of PTLD, reduction in immunosuppression (RIS), use of pre-emptive therapy, and all-cause mortality. Among 442 adult SOTR, the predominant transplant organs were the kidney (258, 58%) and liver (141, 31.9%). EBV serostatus in most subjects (430, 97%) was classified as intermediate risk (R+). Eight subjects (2%) were high risk (donor (D+/R-), and 4 (1%) were low risk (D-/R-). The overall incidence of EBV DNAemia was 4.1% (18/442) with a median time to detection of 14 months (range 3-60). The highest proportion of DNAemia was observed in D+/R- subjects (37.5%; p < 0.001). Development of PTLD was significantly associated with EBV DNAemia and occurred in 3/18 patients with DNAemia (16.7%) vs. 3/424 (0.7%) without DNAemia (p < 0.001). All patients with PTLD were managed with RIS and rituximab. We observed that EBV D+/R- serostatus and development of sustained EBV DNAemia were high risk features associated with subsequent development of PTLD in our cohort of adult SOTR.

Post-transplant lymphoproliferative disease after pediatric kidney transplant.

Post-transplant lymphoproliferative disease (PTLD) is the most common malignancy complicating solid organ transplantation (SOT) in adults and children. PTLD encompasses a spectrum of histopathologic features and organ involvement, ranging from benign lymphoproliferation and infectious-mononucleosis like presentation to invasive neoplastic processes such as classical Hodgkin lymphoma. The predominant risk factors for PTLD are Epstein-Barr virus (EBV) serostatus at the time of transplant and the intensity of immunosuppression following transplantation; with EBV-negative recipients of EBV-positive donor organs at the highest risk. In children, PTLD commonly presents in the first two years after transplant, with 80% of cases in the first year, and over 90% of cases associated with EBV-positive B-cell proliferation. Though pediatric kidney transplant recipients are at lower risk (1-3%) for PTLD compared to their other SOT counterparts, there is still a significant risk of morbidity, allograft failure, and an estimated 5-year mortality rate of up to 50%. In spite of this, there is no consensus for monitoring of at-risk patients or optimal management strategies for pediatric patients with PTLD. Here we review pathogenesis and risk factors for the development of PTLD, with current practices for prevention, diagnosis, and management of PTLD in pediatric kidney transplant recipients. We also highlight emerging concepts, current research gaps and potential future developments to improve clinical outcomes and longevity in these patients.

MO993: Incidence of Ptld and Its Relationship with Cmv-Serostatus Positivity Among Childhood and Adulthood Population: A Registry Data Study

Abstract BACKGROUND AND AIMS It is unknown how the epidemiology of post-transplant lymphoproliferative disease (PTLD) and its relationship with CMV infection differ between adult and pediatric kidney transplant recipients. In addition, with current advancements in immunosuppressive therapy, the incidence of PTLD has changed dramatically. The aim of our study is to elucidate the relationship between PTLD and CMV infection. Moerover, to assess the incidence of PTLD among Adult and pediatric renal transplant patients in the current era. METHOD All renal transplant patients registered in the Organ Procurement and Transplantation Network between 2005 and 2019 were retrospectively reviewed. Patient were followed up till December 2020. Patients who had multiple organ transplant or those with previous renal transplants were excluded from the study. Data about recipient factors (age, sex ethnicity, diabetes, CMV serostatus, and EBV serostatus), donor factors (living or deceased), transplant factors (PRA, Cold ischemia time, HLA mismatches, induction and immunosuppressive therapy) were reviewed. Incidence rate of PTLD at one year and five years post-transplant were calculated among the Adult and Pediatric population. Univariate and Multivariate cox-hazard regression models were performed to assess the relationship between CMV serostatus and occurrence of PTLD. RESULTS About 10 947 pediatric renal transplant patients were included. About 315 pediatric patients developed PTLD during the follow-up time (2.88%). About 50.55% of PTLD occurred within the first-year post-transplant. 60% occurred within two-year post-transplant, while 80.63% of them occurred within five years post-transplant. CMV recipient infection was not associated with PTLD occurrence in the pediatric population (HR = 0.88, Pvalue = 0.81, 95% confidence interval ranged between 0.66 and 1.18). Proportional hazard assumption was not violated with P = 0.55. Among the adult population, 1990/277 955 developed PTLD (0.77%). About 25.77% of PTLD among the adult population occurred within the first-year post-transplant. About 39.39% of PTLD in the adult occurred within two-year post-transplant. About 66.55% of PTLD in the adult occurred within five-years post-transplant. CMV recipient positive serostatus was associated with a protective effect against occurrence of PTLD (HR = 0.82, Pvalue &amp;lt;0.01, 95% confidence interval ranged between 0.73 and 0.94). The most common type of PTLD among the pediatric and adult population was monomorphic PTLD ( 40% and 34%, respectively). CONCLUSION PTLD is a rare complication of renal transplantation in the current era. The risk of development of PTLD is highest during the first-year post-transplant. CMV recipient positive serostatus has a protective effect against development of PTLD.

934. Epidemiology and Outcomes of Epstein-Barr Virus DNAemia in Adult Solid Organ Transplant Recipients

BackgroundImmunosuppression in solid organ transplantation (SOT) increases the risk of Epstein-Barr virus (EBV) DNAemia, which may herald development of post-transplant lymphoproliferative disease (PTLD). The objective of this study was to characterize the epidemiology and risk factors for EBV DNAemia and to describe the impact of these factors on development of PTLD in a cohort of SOT recipients.MethodsWe retrospectively examined adult (≥18 years) SOT recipients between 1/1/2015 to 12/31/2019. Demographics, immunosuppression, and clinical outcomes were examined. Subjects were stratified as having a positive (EBV viral load > 200 copies/mL) or negative viral load. Sustained EBV DNAemia was defined as EBV DNA detection ( > 200 copies/mL) on at least 3 consecutive samples. Categorical variables were analyzed using chi-square or Fishers exact test. Mann-U Whitney test was used for continuous variables. Results442 SOT recipients (258 kidney, 141 liver, 22 kidney-pancreas (KP), 15 kidney-liver, 6 pancreas) were examined. Most subjects (430, 97%) were EBV intermediate risk (recipient (R)+). 8 subjects (2%) were EBV high risk (donor (D)+, R-) and 4 (1%) were EBV low risk (D-/R-). EBV viral loads were obtained in 177/442 (40.0%) recipients. DNAemia was detected in 18/442 subjects (4.1%). It was most common in pancreas recipients(1/6; 16.7%) compared with kidney (10/258; 3.9%), liver (5/141; 3.5%), and KP recipients (1/22; 4.5%). DNAemia was most frequently observed in the D+/R- (3/8; 37.5%) group compared to intermediate risk (R+) (15/430; 3.5%) and D-/R- (0%) groups. Median time to EBV viral load detection was 14 months (range 3-60). In univariate analysis, EBV high-risk serostatus was the factor most strongly associated with development of EBV DNAemia (p< 0.001). Sustained DNAemia (median viral load 1829 copies/mL; peak viral load 1.9 million copies/mL) was observed in 8 subjects (1.8%). PTLD developed in 6 subjects (1.4%); 50% had sustained DNAemia prior to diagnosis.ConclusionWhile uncommon, development of sustained EBV DNAemia was associated with subsequent development of PTLD in our cohort of adult SOT recipients. These data provide guidance for identifying subjects at risk for PTLD above and beyond baseline EBV high-risk serostatus. Disclosures All Authors: No reported disclosures

Demographics of PTLD Patients Who Died during 2010-2017 Period: A NCDB Based Study

Background:Post-transplant lymphoproliferative disease (PTLD) is a rare, but well-known complication of solid organ transplants and hematopoietic stem cell transplantation. . In most affected patients, PTLD is an Epstein-Barr virus (EBV)-positive B cell proliferation occurring in the setting of immunosuppression and decreased T cell immune surveillance. PTLDs are among the most serious complications of transplantation. The principal risk factors underlying the development of PTLD are the degree of T cell immunosuppression and the Epstein-Barr virus (EBV) serologic status of the recipient. Early lesions of PTLD are treated with reduction in immunosuppression alone and those who do not have a complete response to this intervention have been treated with chemotherapy, immunotherapy, and occasionally surgical resection. Utilizing the NCDB, we aim to study the clinical and demographic characteristics of PTLD patients who were declared dead during period of 2010-2017.MethodsA total of 425 patients diagnosed with PTLD above the age of 18 years between 2010 and 2017 were identified utilizing the National Cancer Database (NCDB). Patients were identified with ICD-O-3 morphologic code 9971/3 and data extracted from PUF using SPSS. Demographic factors (Race, gender, facility location, annual household income, facility type, Charlson-Deyo score, treatment received, age at diagnosis) were studied in relation to patient's vital status (alive or dead). We have separated data for patients declared dead during this period and formulated a table stating the demographic characteristics. We have excluded people whose vital status was unknown or missing (60 patients).ResultsOf the 365 patients diagnosed with PTLD between 2010-2017, 215 patients were alive during the entire period and 150 (41%) were declared dead in this time frame. Of these, 62.7% were in the age group less than 60 years and 37.3% above 60 years. 9.3% (14/150) received no treatment at all and 88% received some form of treatment, of which 39.3% (59/150) received immunotherapy (34 received immunotherapy alone and 23 received Immuno+chemo). Amongst these, 80% were Caucasians and 13.4% were African Americans. 41.6% (57/137) belonged to median income quartile >=$63,333, whereas 16% (22/137) belonged to median quartile income <$40,227 (Median Quartiles 2012-2016). 83.2% received care at an academic/research program and 8.8% in a Comprehensive community cancer program. 64.7% (97/150) of patient's had Charlson-Deyo score of 0 whereas 14% (21/150) had a score of 3.ConclusionThis study contains largest cohort of patients diagnosed with PTLD, identifying clinical and demographic factors of patients with PTLD who were declared dead during the period of 2010-2017. The data shows significant variations in the populations stratified based on age, income quartiles, treatment received and race. These data may provide insight into identifying the factors influencing mortality of patients diagnosed with PTLD. The major limitations of our study include no data on specific therapy received, reasons for choosing the treatment modality used, no data on the cause of mortality and age at death. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Use of induction therapy in pediatric heart transplant recipients in Switzerland – Analysis of the Swiss national database

BackgroundData on individualized immunosuppressive protocols for the pediatric heart recipients are missing in Europe. To contribute to this very small but specialized field, we describe the use of induction therapy (IT) in pediatric heart transplant patients in Switzerland and the retrospective outcomes. MethodThis is a retrospective national database analysis of children <19 years of age at time of heart transplantation (HT) from 05/2008–01/2018. Use of IT or no IT, use of steroids, calculated panel reactive antibodies (cPRA) and outcomes (Mortality, post-transplant lymphoproliferative disease (PTLD), rejection rates) were studied within a mean follow-up period of 2.9 years (0.2–8.1 years). ResultsAll 32 patients (12♂, 20♀), median age at HT of 6.4 years (24 days - 18 years) received IT using either polyclonal antibodies (ATG; 72%) or interleukin-2 receptor antagonist (anti-IL-2R mAb; 28%). Length of treatment was median of 4 (1–63) days. At time of HT all patients received steroids, while at discharge 32% and one year after HT 19%. Kaplan-Meier analysis of survival revealed a one-year survival of 86%. Three out of 7 patients with elevated cPRA (43%) died. Median time to first treated rejection was 19.4 months (±60.5 SD) without significant difference if treated with anti-IL-2R mAb or ATG (p:0.5). No development of PTLD, chronic renal failure needing ongoing renal replacement therapy or diabetes mellitus were recorded. DiscussionThis is the first report of the national practice use of IT within Switzerland. It reveals a high use of IT, no development of PTLD and a low use of steroids at one-year post HT.

Post-Transplant Lymphoproliferative Disorder after Liver Transplant: A Systematic Review

Background: Post-transplant lymphoproliferative disease (PTLD), a group of lymphoid disorders ranging from indolent polyclonal proliferation to aggressive lymphomas is a known complication following solid organ transplantation. The aim is to study the incidence, characteristics, predictive factors, management, and outcomes of PTLD after liver transplantation in particular. Methods: Following the PRISMA guideline, we performed a comprehensive literature search on PubMed, Cochrane Library, Embase, and clinicaltrials.gov from the past ten years on May 04, 2020. We used the MeSH terms of organ transplantation and lymphoproliferative disorders. The initial search revealed 1741 articles. We excluded all case reports, case series, pre-clinical trials, review articles, and meta-analysis. We found fifteen studies including retrospective observational and cohort studies. We extracted the data for baseline characteristics, the reason for transplantation, recipient &amp; donor EBV status, immunosuppression used, type &amp; stage of PTLD, organ system involved, duration between transplant and PTLD diagnosis, treatment, response to therapy, adverse effects of therapy and mortality. Results: We included 15 studies with a total (n) of 10706 post-liver transplant patients. 294 (2.74%) patients developed PTLD as a complication, out of which 104 (35.3%) were males, 106 (36%) females, and 84 unknowns. Table 1. The incidence of PTLD in the pediatric group was 135/3116 (4.3%) whereas in the adult population it was 115/7545 (1.5%). Data from eleven studies show that out of 202 participants, 67 recipients were positive, 39 negative, and 18 donors positive for EBV infection at the time of transplant. Data on the EBV serostatus for the remaining 106 recipients was not known at the time of transplant. Data from two studies showed that 25/29 patients who later developed PTLD were seronegative for EBV prior to the transplant and 26/29 were reported to undergo seroconversion partly due to transplantation with EBV positive donors (7/13). Post-transplant immunosuppression was achieved with cyclosporine, tacrolimus, azathioprine, mycophenolate mofetil, sirolimus, prednisone, OKT3 for acute cellular rejection and induction with monoclonal antibodies. Data from four studies conclude the median age at the time of PTLD diagnosis is 47.6 months in the pediatric population while 54 years in adults, overall ranging from 1 year to 73 years. Ten studies show the overall median duration from organ transplant to the diagnosis of PTLD is 23.5 months. The median duration for the pediatric population was 11.6 months from the data collected from 55 patients whereas five studies with 166 adult liver transplant recipients showed a median duration of 35.5 months. Histopathological types were diagnosed via biopsy samples, with monomorphic in 76 (25.8%), early lesions in 22 (7.4%), polymorphic in 19 (6.4%), and classic Hodgkin lymphoma like PTLD in 8 (2.7%) of the samples. Among the monomorphic type, Diffuse Large B-Cell Lymphoma (DLBCL) was the most commonly reported i.e. 10/50 (20%) of patients with monomorphic type in two studies. Treatment of PTLD consisted of reduction or cessation of the post-transplant immunosuppressive drugs, anti-CD20 antibody (rituximab), antiviral treatment with ganciclovir, and lymphoma treated with chemotherapy, radiotherapy, and surgical resection. Data from eight studies show a mortality rate of 61/214 (28.5%) with Huang, et al. reporting ¾(75%) of total deaths due to PTLD progression. Two studies report an overall survival rate of 26/32 (81.3%) and five-year survival of 15/41 (36.6%). Conclusions: Our analysis shows the incidence of PTLD after liver transplant is low with no significant gender predominance but a difference in the incidence was observed with significantly higher rates in the pediatric group as compared to the adult population. The most common biopsy proved histopathological type was monomorphic, with the least common type being Hodgkin lymphoma like PTLD. Among the monomorphic, DLBCL was the most common subtype. After liver transplantation, the development of PTLD is observed earlier in pediatric patients in comparison to adult recipients. EBV naive patients prior to liver transplantation are at higher risk for seroconversion post-transplant if transplanted with EBV positive donors and hence at increased risk of PTLD development. Disclosures Anwer: Incyte, Seattle Genetics, Acetylon Pharmaceuticals, AbbVie Pharma, Astellas Pharma, Celegene, Millennium Pharmaceuticals.: Honoraria, Research Funding, Speakers Bureau.

Post-Transplant Lymphoproliferative Disorder after Solid Organ Transplant in the Pediatric Population: A Systematic Review

Background: Post-transplant lymphoproliferative disease (PTLD), is one of the major complications after organ transplantation. The aim of this study is to study the incidence, risk factors especially EBV status, histopathological types, management, and outcomes of PTLD in the pediatric groups. Methods: Following the PRISMA guideline, we performed a comprehensive literature search on PubMed, Cochrane Library, Embase, and clinicaltrials.gov from the past ten years on May 04, 2020. We used the MeSH terms of organ transplantation and lymphoproliferative disorders. The initial search revealed 1741 articles. We excluded all case reports, case series, pre-clinical trials, review articles, and meta-analysis. We found twenty-eight studies. We extracted the data for baseline characteristics, recipient &amp; donor EBV status, immunosuppression used, type &amp; stage of PTLD, organ system involved, duration between transplant and PTLD diagnosis, treatment, and mortality. Results: We included 32 studies with a total (n) of 15597 pediatric patients after a solid organ transplant. 1210 (7.75%) patients developed PTLD, out of which 609 (50.33%) were male participants, 453 (37.4%) female, and 148 (12.23%) the gender was unknown. (Table 1) Data from 19 studies showed that among PTLD patients, 115 recipients &amp; 76 donors tested positive for Epstein-Barr Virus (EBV), 187 recipients were seronegative and the rest were unknown at the time of transplant. Immunosuppressive drugs used after organ transplantation included; cyclosporine, tacrolimus, sirolimus, azathioprine, mycophenolate, prednisone, mTOR inhibitors, induction therapy with OKT3, IL-2 inhibitors (basiliximab, daclizumab) and anti-thymocyte/anti-lymphocyte globulin. In two studies, antiviral prophylaxis with ganciclovir/valganciclovir was achieved. Data from nine studies showed the median age at PTLD diagnosis was 6.8 years. L'Huillier et al. stated that the median duration for EBV positive recipients to develop PTLD was 1.92 years (0.35-3.09 years), compared to EBV negative recipients, which was 0.95 years (2.48-2.92 years). Overall, the median duration from organ transplant to the diagnosis of PTLD among 15 studies was 29.1 months, ranging from 0.9 months to 186 months. The histopathology of PTLD was confirmed via biopsy specimen showing predominance in monomorphic type, i.e; 265/1210 (21.9%), followed by polymorphic type with 140/1210 (11.5%), an early lesion with 46/1210 (3.80%), Non-Hodgkin lymphoma 28/1210 (2.3%), Hodgkin lymphoma 33/1210 (2.72%) and mixed type (polymorphic &amp; monomorphic) 4/1210 (0.33%). Histopathological data for 694 patients were not available. Treatment of PTLD was achieved with reduction or complete cessation of immunosuppressive therapy, anti-CD20 antibody (rituximab), antiviral treatment with ganciclovir/valganciclovir, lymphoma treatment with chemotherapeutic agents, radiotherapy, and surgical resection. Gajarski et al. concluded that patients who received induction therapy [OKT3, IL-2 antagonists (basiliximab, daclizumab) and anti-thymocyte globulin] had significantly less PTLD development as compared to those who did not receive induction therapy, i.e., (2.9% vs. 4.9%) among 2374 total patients. According to Hayes Jr. et al., recipient EBV seronegativity continued to be associated with lower mortality hazard (HR 0.715; 95 % CI 0.547, 0.935; p = 0.014). Data from 19 studies showed the mortality rate among 494 PTLD diagnosed patients was 22.7% (112) with an overall survival of 84.2% respectively from three studies. Data from five studies showed that direct PTLD related mortality accounted for 63% (17/27) of deaths in PTLD diagnosed patients. Conclusion: Our analysis shows that post-transplant EBV positive recipients who undergo multiorgan transplants are more likely to develop PTLD compared to EBV positive recipients with single organ transplantation. The median duration from organ transplants to the diagnosis of PTLD ranged from months to years, however, this duration was reported to be less in EBV negative recipients compared to EBV positive recipients with organ transplants. The most common histological type of PTLD among pediatric groups was monomorphic and the least common was Classic Hodgkin lymphoma. Rituximab use in the treatment of PTLD was associated with a decreased use of alkylating agents and as a result, the side effects associated with these agents were reduced. Disclosures Anwer: Incyte, Seattle Genetics, Acetylon Pharmaceuticals, AbbVie Pharma, Astellas Pharma, Celegene, Millennium Pharmaceuticals.: Honoraria, Research Funding, Speakers Bureau.

Post-Transplant Lymphoproliferative Disorder after Renal Transplant in the Pediatric Population: A Systematic Review

Background: Post-transplant lymphoproliferative disease (PTLD), is one of the major complications after organ transplantation. The aim of this study is to study the incidence, various risk factors especially EBV status, histopathological types, management, and outcomes of PTLD following kidney transplantation in the pediatric groups. Methods: Following the PRISMA guideline, we performed a comprehensive literature search on PubMed, Cochrane Library, Embase, and clinicaltrials.gov from the past ten years on May 04, 2020. We used the MeSH terms of organ transplantation and lymphoproliferative disorders. The initial search revealed 1741 articles. We excluded all case reports, case series, pre-clinical trials, review articles, and meta-analysis. We found five retrospectives observational, one retrospective questionnaire survey, one prospective observational, and one prospective trial study. We extracted the data for baseline characteristics, the reason for transplantation, recipient &amp; donor EBV status, immunosuppression used, type &amp; stage of PTLD, organ system involved, duration between transplant and PTLD diagnosis, treatment, response to therapy, adverse effects of therapy and mortality. Results: We included eight studies with a total (n) number of 1713 post-kidney transplant pediatric patients, out of which 148 (8.63%) patients who developed PTLD as a complication of transplantation were studied(table 1). Among the 148 patients diagnosed with PTLD, 96 (64.86%) were males, 49 (33.1%) female participants and 3 (2.2%) were unknown. 34/148 (22.97%) PTLD recipients were EBV (+), 86 (58.1%) EBV (-) and 28 (18.9%) unknown at the time of transplant. EBV status for donors was known in only 2 studies, showing 7/99 (7.1%) to be EBV (+) at the time of transplant. Höcker et al. have shown that antiviral prophylaxis with ganciclovir/valganciclovir in the first year post-renal transplant reduces the risk of EBV viremia. Post-transplant immunosuppressive drugs included tacrolimus, mycophenolate mofetil, azathioprine, sirolimus, cyclosporine, IL-2R antagonist, methylprednisolone, basiliximab, daclizumab, anti-thymocyte globulin/anti-lymphocyte globulin, OKT3. In some cohorts, rituximab and antiviral prophylaxis with ganciclovir or valganciclovir were also used in some patients. The median time from transplant to the diagnosis of PTLD from five studies with 125 patients was 16 months (0.9m-186m). Longmore et al. reported a bimodal distribution curve, with 50% presenting with early PTLD, i.e. after a median duration of 313 days and 50% presenting late after a median duration of 8 years. The histopathological types of PTLD were diagnosed via biopsy samples, showing predominance with polymorphic type 48 (32.4%), followed by monomorphic type 45 (30.4%), early lesion 4 (2.7%), Kaposi like PTLD 1 (0.67%) and Hodgkin lymphoma 1 (0.67%). The histological testing results from two of the studies also showed that 18/19 (94.7%) of diagnosed PTLD samples were EBV positive. PTLD was managed with reduction or cessation of the immunosuppressive drugs, anti-CD20 antibodies, chemotherapy for lymphoma, and in some cases mTOR inhibitors, intravenous immunoglobulins, and surgical resection. Data from 5 studies show the mortality rate of 12/51 (23.5%) among PTLD groups. The survival rate from 2 studies was 100% among 17 PTLD patients and 1 study showed a 5-year survival rate of 85% among 92 PTLD patients. Cleper et al. in their study concluded that the type of PTLD might have a significant effect on the outcome, as ¾ (75%) deaths in the PTLD group were attributed to anaplastic T-cell type. Conclusions: Our analysis shows the EBV infection is closely associated with a higher risk of PTLD development. Recipients' EBV seronegativity and positive EBV status of the donor have been shown to increase post-transplant EBV infection risk which is associated with a higher risk of PTLD development. Furthermore, our study shows that PTLD may occur in less than a month to more than 15 years of renal transplant. The polymorphic type was the most common and Hodgkin lymphoma-type, the least commonly reported PTLD type. The main therapeutic approach is the reduction or cessation of immunosuppression. Disclosures Anwer: Incyte, Seattle Genetics, Acetylon Pharmaceuticals, AbbVie Pharma, Astellas Pharma, Celegene, Millennium Pharmaceuticals.: Honoraria, Research Funding, Speakers Bureau.

Relationship between rabbit anti-thymocyte globulin and development of PTLD and its aggressive form in renal transplant population

ABSTRACT: Introduction The aim of our study is to explore the relationship of rabbit anti-thymocyte globulin (R-ATG) on development of post-transplant lymphoproliferative disease (PTLD) and its aggressive forms (monomorphic PTLD and Hodgkin lymphoma) in renal transplant recipients. Methodology All patients diagnosed with PTLD post-renal transplant in the United States’ Organ Procurement and Transplantation Network from 2003 till 2013 and followed up till 2017 were retrospectively reviewed. Multi-variable logistic regression analysis assessed association of R-ATG to development of PTLD and its aggressive form. Results Risk of developing PTLD post renal transplant is 1.35%. In comparison to interleukin-2 blocker induction therapy, R-ATG is associated with increased risk of development of PTLD (Odds Ratio = 1.48, confidence interval ranges from 1.04 to 2.11, p = .02) and is associated with higher risk of development of aggressive PTLD (Odds Ratio = 1.83, confidence interval ranges from 1.001 to 3.34, p = .04). Conclusion We conclude that R-ATG induction is associated with a higher risk of PTLD and its aggressive form (monomorphic PTLD and Hodgkin lymphoma). Careful monitoring for development of PTLD in renal transplant recipients receiving R-ATG induction therapy is advised.

1564. Lower Rates of Epstein–Barr Virus (EBV) Viremia in Pediatric Solid Organ Transplant (SOT) Recipients Who Received Valganciclovir Prophylaxis

BackgroundAntiviral prophylaxis to prevent PTLD remains controversial, but some data suggest that valganciclovir or ganciclovir ([val]ganciclovir) use in EBV high-risk pediatric renal transplants reduces EBV viremia. We evaluated the impact of [val]ganciclovir on EBV viremia and post-transplant lymphoproliferative disease (PTLD) in pediatric nonrenal SOT recipients.MethodsRetrospective study of 100 patients who underwent a first heart, liver, lung, intestine, or multivisceral SOT between November 2013 and November 2016 at Boston Children’s Hospital who survived without re-transplantation for at least 30 days. Data collected included EBV donor/recipient serostatus, donor’s age >2 years-old (to avoid misclassification of EBV risk due to maternal antibody), antiviral use ([val]ganciclovir or acyclovir), time to EBV viremia (>1,000 copies/mL by whole blood PCR), and time to development of PTLD. EBV high-risk patients were those with donor EBV positive [D+]/recipient EBV negative [R–] serologies; intermediate-risk were EBV R+; low risk were EBV D–/R–. Time-to-event analysis using the Kaplan–Meier method was performed and significance (P = 0.05) was evaluated using the log-rank test.ResultsHigh (n = 45) or intermediate (n = 27) EBV risk was associated with increased EBV viremia (P = 0.007, table). EBV viremia was significantly decreased in the subgroup of high-risk patients with donors >2 years old who received [val]ganciclovir vs. those who received no antiviral (n = 23, n = 4, P = 0.03, Figure 1). Most PTLD cases (8/9) occurred in the high-risk group (P = 0.03, Figure 2). Overall, patients who received [val]ganciclovir had less PTLD than those who did not (P = 0.03), but this was not significant in the high-risk subgroup (P = 0.14, Figure 3).ConclusionLower rates of EBV viremia occurred in high EBV risk transplant recipients who received [val]ganciclovir, possibly by preventing primary EBV infection. Recipients with high EBV risk have the highest rate of PTLD.cases=100EBV RiskOutcomeOrganUnknownLowIntermediateHighViremiaPTLDHeart581320185Liver11101862Lung114462Intestine10Multivisceral11Dual organ31Total7212745439AntiviralNo Antiviral6652Acyclovir213873[Val]ganciclovir5132431314OutcomeViremia2214259PTLD189 Disclosures F. M. Marty, Merck: Consultant and Investigator, Consulting fee, Research support and Speaker honorarium; Astellas: Consultant and Investigator, Consulting fee and Research support; Chimerix: Consultant and Investigator, Consulting fee and Research support; Fate Therapeutics: Consultant, Consulting fee; GlaxoSmithKline: Consultant, Consulting fee; LFB: Consultant, Consulting fee; Roche Molecular Diagnostics: Consultant, Consulting fee; Shire: Consultant and Investigator, Consulting fee and Research support.

Subsequent malignancies after allogeneic hematopoietic stem cell transplantation.

We evaluated 979 patients for the development of post-transplant lymphoproliferative disease (PTLD) and solid malignancies after allogeneic hematopoietic stem cell transplantations (allo-HSCT) as a late complication. We found 15 (1.5%) subsequent malignancies; three of these malignancies were PTLD, and twelve were solid tumors. The median time from allo-HSCT to the development of PTLD was 9 (3-20) months and that from allo-HSCT to the development of solid tumors was 93 (6-316) months. The cumulative incidence of evolving subsequent malignancy in patients was 1.3% (±0.5SE) at 5years and 3.9% (±1.2SE) at 10years. The cumulative incidence of developing subsequent malignancy in patients with benign hematological diseases as the transplant indication was 7.4%±4.2SE at 5years. More subsequent malignancy developed in patients having ≥1year chronic graft-vs-host disease (GVHD; 3.7% in ≥1year chronic GVHD and 0.7% in <1year chronic GVHD patient groups, P=.002). Subsequent epithelial tumor risk was higher in ≥1year chronic GVHD patients than <1year (3.7% vs 0.1%, P<.001). In multivariate analysis, benign hematological diseases as transplant indication (RR: 5.6, CI 95%: 1.4-22.3, P=.015) and ≥1year chronic GVHD (RR: 7.1, 95% CI: 2.3-22.5, P=.001) were associated with the development of subsequent malignancy.

Sa1466 - A National Study of Cancer Diagnoses in Irish Liver Transplant Recipients with Primary Sclerosing Cholangitis

Background Primary sclerosing cholangitis (PSC) is associated with an increased risk of cholangiocarcinoma, colorectal and gallbladder cancers. Orthotopic liver transplantation (OLT) patients are at risk of developing de novo malignancies, however limited/conflicting data exists regarding cancer risk post OLT for PSC. Aim To examine all recorded malignancies over 2 decades in OLT-PSC patients; to compare these to non-transplanted PSC cohort; to analyse for any associated factors. Method We studied PSC patients attending SVUH (1/1/1994–30/9/2016). We integrated this database with National Cancer Registry Ireland, to enable accurate determination of number of malignancies. Results 173 PSC pts (75.7% male) have attended SVUH since 1994. 107 (61.8%) have undergone 124 OLT. 27/107 were transplanted for cholangiocarcinoma. 12 de novo cancers (excluding non-melananomatous skin) were found during 737.8 person years of follow-up. Median time to cancer diagnosis post OLT was 5 years. As expected, cholangiocarcinoma as OLT indication (p=0.005) and older age at transplant (p=0.05) were associated with higher mortality. Post-transplant lymphoproliferative disease (PTLD) remains a major complication. 5 pts developed lymphoma post OLT (4.7% of cohort). Two patients developed CRC post OLT; 4 developed colonic dysplasia. 3/4 underwent colectomy. All who developed colonic dysplasia/CRC post OLT had IBD. All 5 colectomies for dysplasia/CRC showed significant co-existing inflammation. Conclusions This represents national cancer figures for PSC-OLT. The rates of PTLD are slightly higher than previously reported. We could not find any association between the development of PTLD and immunosuppressive regimes for IBD post OLT. This study highlights that IBD/PSC patients remain at significant risk of colonic neoplasia after OLT and require intensive surveillance.

Outcomes of Rituximab for EBV Viremia/Post-Transplant Lymphoproliferative Disease in CD34+ Selected Allogeneic Hematopoietic Stem Cell Transplantation

Recipients of T-cell depleted allogeneic hematopoietic stem cell transplants (SCT) are at high risk forEpstein Barr Virus (EBV) reactivation and post-transplant lymphoproliferative disease (PTLD). Early treatment strategies, including chemotherapy and de-escalation of immunosuppression, proved unsuccessful. Unselected donor leukocyte infusions (DLIs) can be effective, but increase the risk of graft-versus-host disease (GVHD). Rituximab is increasingly used as preemptive therapy for EBV viremia to prevent PTLD development, leading to improved outcomes.However, there are limited data on rituximab-related toxicities in this population. The purpose of this study is to retrospectively describe these outcomes and toxicities in CD34+ selected SCT.Patients who received a CD34+ selected SCT between January 2008 and February 2015 at Memorial Sloan Kettering Cancer Center were evaluated for inclusion. All patients with EBV reactivation post-transplant were included. Proven PTLD was defined as biopsy-confirmed, with corresponding clinical manifestations. Probable PTLD was defined as significant lymphadenopathy or end-organ disease with EBV viremia in the absence of another cause. All patients with EBV reactivation received rituximab per institutional guidelines.Response to rituximab was assessed by viral clearance and the criteria for PTLD, described by Cheson, et al. Patients without repeat imaging were assessed for clinical response (resolution of PTLD signs and symptoms without need for additional therapy). Toxicities assessed 1 year post-rituximab include new-onset hypogammaglobulinemia (IgG <500 mg/dL), new-onset neutropenia, (absolute neutrophil count ≤1000/mm3), and infections (e.g. viral, bacterial, and fungal).The cumulative incidence of each outcome was determined using the cumulative incidence method for competing risks, with death as the competing event. A landmark analysis investigated possible differences in outcomes related to the number of rituximab doses received by 4 weeks (>3 or ≤3 doses). Differences in outcomes due to EBV diagnosis, prior GVHD or immunosuppressant use, or number of rituximab doses by 4 weeks were evaluated using Gray’s test. For all analyses, pvalues <0.05 were considered statistically significant.Eighty-eight patients had EBV reactivation (16.6% of CD34+ selected SCT recipients). EBV viremia was most common (n=42), followed by probable PTLD (n=28), and proven PTLD (n=18). Baseline demographics are summarized in Table 1.Patients with EBV viremia received fewer doses of rituximab (median 2, range 1 - 5) compared to patients with probable (median 4, range 2 - 5) or proven PTLD (median 4, range 3 - 11). Viral clearance occurred in >95% of patients with EBV viremia and probable PTLD versus 77.7% of patients with proven PTLD. For EBV viremia, viral clearance occurred after a median of 1 dose of rituximab (range 1 - 4).Figure 1 depicts treatment responses to rituximab. The complete response (CR) rate was higher in patients with probable versus proven PTLD (39.3% vs. 22.2%). Patients with probable PTLD also had a higher clinical response rate (50.0% vs. 27.8%). Only patients with proven PTLD received subsequent therapy after rituximab (45.5%).The cumulative incidence of infection of any type was 71.8% (95% confidence interval [CI], 60.9 to 80.1) at 1 year post-rituximab. By univariate analysis, infectious outcomes were not impacted by number of rituximab doses by 4 weeks, EBV diagnosis, prior GVHD or immunosuppressant use. New-onset neutropenia occurred in 39/71 patients, with a cumulative incidence of 55.2% (95% CI, 42.7 to 66.0) at 1 year. New-onset hypogammaglobulinemia occurred in 18/64 patients, with a cumulative incidence of 28.4% (95% CI, 17.8 to 39.8) at 1 year. The cumulative incidence of hypogammaglobulinemia was significantly higher in the proven PTLD cohort (53.8% [95% CI, 22.3 to 77.5]) than in the probable PTLD (24.5% [95% CI, 9.6 to 42.9]) and viremia (19.4% [95% CI, 6.9 to 36.8]) cohorts (p=0.03).This study shows that rituximab is effective and clears EBV viremia in >95% of CD34+ selected SCT recipients with EBV viremia or probable PTLD. However, only 22.2% of patients with proven PTLD achieved a CR. Hypogammaglobulinemia and neutropenia are important toxicities of rituximab. Infectious complications were common, but difficult to attribute solely to rituximab. Further research and prolonged follow-up are needed. [Display omitted] [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Posttransplant lymphoproliferative disease and survival in adult heart transplant recipients

BackgroundThe influence of posttransplant lymphoproliferative disease (PTLD) on long-term survival after heart transplantation (HTx) in adult recipients needs better characterization. MethodsThe United Network for Organ Sharing database was queried from 2006 to 2015 to compare survival between adult HTx recipients with and without PTLD. Cox proportional hazards models were used to analyze the primary outcome of survival, and competing-risks regression was used to analyze the outcome of PTLD development. ResultsA total of 14,487 HTx recipients who had data on PTLD were included in univariate Cox analysis and Kaplan–Meier survival function, while 10,422 were included in multivariable Cox analysis and 162 selected for a matched-pairs sample after matching on the propensity of developing PTLD. The cohort included 120 patients who were diagnosed with PTLD. Onset of PTLD, treated as a time-varying covariate, was adversely associated with survival in univariate (HR=4.953; 95% CI: 3.768, 6.511; p<0.001) and multivariable (HR=3.849; 95% CI: 2.669, 5.552; p<0.001) Cox proportional hazards models. Cox regression stratified on matched pairs of PTLD cases and non-PTLD controls confirmed the risk for death associated with PTLD onset (HR=2.667; 95% CI: 1.043, 6.815; p=0.040). ConclusionsPTLD onset negatively influenced survival in adult HTx recipients, whereas no characteristics predisposing patients to PTLD development were identified in multivariate analysis.

Abstract IA22: Immunotherapy with virus-specific T cells

Abstract Epstein-Barr virus (EBV) reactivation post allogeneic hematopoietic stem cell transplantation (HSCT) can lead to the outgrowth of EBV-infected B cells and the development of post-transplant lymphoproliferative disease (EBV-PTLD). Since 1993 our group has used adoptive transfer of in vitro expanded EBV-specific T cells as a means to prevent or treat these EBV-driven lymphomas. In a series of Phase I and II clinical trials we have assessed the safety and clinical benefit associated with these transferred cells in allogeneic HSCT recipients. The T cell products infused were generated using 3 different manufacturing methodologies - [(i) EBV-transformed lymphoblastoid cell lines (EBV-LCLs) (~12 weeks manufacturing time), (ii) plasmid-nucloefected dendritic cells (DCs) (17 day manufacturing) and (iii) direct stimulation of PBMCs using overlapping peptide libraries (10 day manufacturing)] and were administered to either prevent (n=162) or treat (n=47) EBV reactivation/disease in a total of 209 allogeneic HSCT recipients ranging in age from 6 months to 63 years. Of 162 patients infused prophylactically only 1 (0.6%) developed EBV-PTLD, which occurred following the administration of steroids 3 weeks-post VST infusion. However, this patient responded to a second VST infusion after the steroids. 31 of 36 (86%) patients with elevated viral load (n=21) or biopsy-proven/probable LPD (n=15) achieved durable complete remissions and the infused cells persisted long term as demonstrated in 26 patients who received gene-marked VSTs that were detectable for up to 9 years post-infusion. To extend the approach to additional viruses we initially developed methodology for using genetically modified antigen presenting cells approach to generate VSTs from donor peripheral blood that target CMV, EBV and adenovirus and showed that adoptively transferred donor-derived VSTs can reconstitute antiviral immunity to all three viruses and effectively treat established infections. However, the time taken to prepare patient-specific products and the lack of virus-specific memory T cells in cord blood and seronegative donors restricts application. More recently we have evaluated whether T-cell lines manufactured using overlapping peptide pools and extended the specificity to include HHV6 and BK. When administered to 11 recipients of allogeneic transplants, 8 of whom had up to four active infections with the targeted viruses, these VSTs proved safe in all subjects and produced an overall 94% virological and clinical response rate that was sustained long-term. Another means of avoiding growing CTLs for individual patients is to bank lines that are then available as an off the shelf product of most closely HLA-matched allogeneic cytotoxic T lymphocyte lines. We evaluated this strategy in a multicenter study through the NHLBI Specialized Centers for Cell-Based Therapy (SCCT) program in HSCT recipients who had viral reactivation or infection refractory to standard therapy. The overall cumulative incidence of first CR/PR in 50 patients based on viral load by day 42 was 74.0% (73.9% for CMV, 66.7% for EBV and 77.8% for adenovirus). In a follow up study using the peptide induced VSTs that recognize 5 viruses, based on viral load measurements by quantitative PCR a single VST infusion successfully controlled active infections in 19/21 evaluable patients. These results demonstrate the feasibility and safety of 3rd party multivirus-directed VSTs, generated by direct stimulation of PBMCs with synthetic peptides and administered as an off the shelf product. Citation Format: Helen E. Heslop, Ifigenia Tzannou, Bilal Omer, Malcolm K. Brenner, Ann M. Leen, Cliona M. Rooney. Immunotherapy with virus-specific T cells. [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr IA22.

Epstein-Barr Virus-Positive Posttransplant Lymphoproliferative Disease After Solid Organ Transplantation: Pathogenesis, Clinical Manifestations, Diagnosis, and Management.

Posttransplant lymphoproliferative disease (PTLD) is a potentially fatal complication after (solid organ) transplantation, which is highly associated with Epstein-Barr virus (EBV). The EBV-specific cytotoxic T cell response that is essential in controlling the virus in healthy individuals is suppressed in transplant recipients using immunosuppressive drugs. A primary EBV infection in EBV-seronegative patients receiving an EBV-seropositive donor organ or a reactivation in those who are already latently infected pretransplantation can lead to uninhibited growth of EBV-infected B cells and subsequently to PTLD. Effective preventive strategies, such as vaccines and antiviral agents, are lacking. Because not every transplant recipient with increasing EBV viral load develops PTLD, it is hard to decide how intensively these patients should be monitored and how and when a preemptive intervention should take place. There is a need for other tools to help predict the development of PTLD in patients at risk to make timing and strategy of preemptive intervention easier and more reliable.The cornerstone of the treatment of patients with PTLD is restoring the host's immunity by reduction of immunosuppressive drug therapy. American and British guidelines recommend to add rituximab monotherapy or rituximab in combination with cyclophosphamide, doxorubicin, vincristine, and prednisolone, depending on histology and clinical characteristics. Although response to these therapies is good, toxicity is a problem, and PTLD still has a relatively high mortality rate. An evolving therapy, especially in PTLD occurring in allogeneic stem cell transplantation, is restoring the host's immune response with infusion of EBV-specific cytotoxic T cells. This may also play a role in the future in both prevention and treatment of PTLD in SOT.

Adoptively-Transferred EBV-Specific T Cells to Prevent or Treat EBV-Related Lymphoproliferative Disease in Allogeneic HSCT Recipients - a Single Center Experience Spanning 22 Years

▪Epstein-Barr virus (EBV) reactivation post allogeneic hematopoietic stem cell transplantation (HSCT) can lead to the outgrowth of EBV-infected B cells and the development of post-transplant lymphoproliferative disease (EBV-PTLD). Since 1993 our group has used adoptive transfer of in vitro expanded EBV-specific T cells as a means to prevent or treat these EBV-driven lymphomas. In a series of Phase I and II clinical trials we have assessed the safety and clinical benefit associated with these transferred cells in allogeneic HSCT recipients. The T cell products infused were generated using 3 different manufacturing methodologies - [(i) EBV-transformed lymphoblastoid cell lines (EBV-LCLs) (~12 weeks manufacturing time), (ii) plasmid-nucloefected dendritic cells (DCs) (17 day manufacturing) and (iii) direct stimulation of PBMCs using overlapping peptide libraries (10 day manufacturing)] and were administered to either prevent (n=162) or treat (n=47) EBV reactivation/disease in a total of 209 allogeneic HSCT recipients ranging in age from 6 months to 63 years.198/209 patients were infused with donor-derived virus-specific T cells (VSTs) and administered at doses ranging from 5x106 to 1.2x108 cells/m2. Infusions were well tolerated, with acute graft versus host disease (aGvHD) grade I-II documented in just 10 patients, of which 2 cases were de novo. Chronic GvHD occurred in 13 patients and was extensive in 2. Other toxicities were seen only in patients with active disease and included localized swelling at the tumor site due to EBV-specific T cell infiltration (n=4), which was severe in 2 causing transient airway obstruction. An additional patient with bulky, Rituximab-resistant EBV-PTLD developed fever and sepsis-like signs post-infusion, coincident with a decrease in viral load, an increase in the frequency of circulating EBV-specific T cells and an elevation in plasma cytokines consistent with a cytokine release syndrome. However, the symptoms resolved within hours of administering steroids and an anti-TNF antibody and did not recur. Of 162 patients infused prophylactically only 1 (0.6%) developed EBV-PTLD, which occurred following the administration of steroids 3 weeks-post VST infusion. However, this patient responded to a second VST infusion after the steroids. 31 of 36 (86%) patients with elevated viral load (n=21) or biopsy-proven/probable LPD (n=15) achieved durable complete remissions and the infused cells persisted long term as demonstrated in 26 patients who received gene-marked VSTs that were detectable for up to 9 years post-infusion.Based on the safety and efficacy profile of donor-derived EBV-specific VSTs we extended our approach to provide an "off the shelf" product to third party recipients, generating and banking T cell lines from 88 consenting normal donors. To date we have treated 11 patients, all of whom had drug-refractory EBV infections. Two patients were treated for elevated viral loads while 9 had established PTLD. Patients received 1-5 doses (fixed dose - 2x107 cells/m2) with 3rd party VSTs matching at one to three of six HLA alleles. Despite the HLA disparity the cells have proven safe with a single case of grade I GvHD reported. Of the 11 patients infused, 8 responded to therapy with 5 complete and 3 partial responses for an overall response rate of 73%.Overall our experience with adoptively-transferred EBV-specific T cells over a 22-year period demonstrates the safety and efficacy of this approach for the prevention and treatment of post-transplant EBV disease. DisclosuresOff Label Use: Adoptively transfered T cells administered under an IND. Rooney:Celgene: Other: Collaborative research agreement; Cell Medica: Other: Licensing Agreement. Heslop:Cell Medica: Other: Licensing Agreement; Celgene: Other: Collaborative research agreement.

Primary CNS lymphoproliferative disease, mycophenolate and calcineurin inhibitor usage.

Immunosuppression for solid organ transplantation increases lymphoproliferative disease risk. While central nervous system (CNS) involvement is more rare, we noticed an increase in primary CNS (PCNS) disease. To investigate a potential association with the immunosuppressive regimen we identified all post-transplant lymphoproliferative disease (PTLD) cases diagnosed over a 28-year period at our institution (174 total, 29 PCNS) and all similar cases recorded in a United Network for Organ Sharing-Organ Procurement and Transplant Network (UNOS-OPTN) datafile. While no PCNS cases were diagnosed at our institution between 1986 and 1997, they comprised 37% of PTLD cases diagnosed from 2011-2014. PCNS disease was more often associated with renal vs. other organ transplant, Epstein-Barr virus, large B-cell morphology and mycophenolate mofetil (MMF) as compared to PTLD that did not involve the CNS. Calcineurin inhibitors were protective against PCNS disease when given alone or in combination with MMF. A multivariate analysis of a larger UNOS-OPTN dataset confirmed these findings, where both MMF and lack of calcineurin inhibitor usage were independently associated with risk for development of PCNS PTLD. These findings have significant implications for the transplant community, particularly given the introduction of new regimens lacking calcineurin inhibitors. Further investigation into these associations is warranted.

Effect of Irradiation on Incidence of Post-Transplant Lymphoproliferative Disorder after Hematopoietic Cell Transplantation in Miniature Swine

Post-transplant lymphoproliferative disease (PTLD) is a major complication of clinical organ and cell transplantation. Conditioning and immunosuppressive regimens that significantly impair T cell immunity, including depleting antibodies and calcineurin inhibitors, increase the risk of PTLD after transplantation. Swine PTLD has been shown to closely resemble human PTLD in morphology, histology, and viral-driven reactivation of B cells. Previously, we reported high incidences of PTLD after hematopoietic cell transplantation (HCT) in miniature swine recipients conditioned with thymic irradiation (TI) in addition to T cell depletion and cyclosporine A monotherapy after transplantation. Replacement of TI with 100 cGy of total body irradiation resulted in similar numbers of B cells early post-transplantation, greater numbers of T cells at day 0, and markedly decreased incidence of PTLD, suggesting that a threshold number of T cells may be necessary to prevent subsequent B cell proliferation and development of overt PTLD. Results from this large cohort of animals provide insight into the important effect of irradiation and T cell immunity on the incidence of PTLD after HCT and reinforce the pig model as a valuable tool for the study of PTLD and HCT.