Late-onset Post-transplant Lymphoproliferative Disorder Research Articles

Incidence and mortality of post-transplant lymphoproliferative disorders after kidney transplantation: A real-world retrospective analysis in Japan.

Post-transplant lymphoproliferative disorder is a potentially life-threatening complication that has a greater risk of occurrence in the setting of immunosuppression and oncogenic viral infections after transplant surgery. Few studies have reported the cumulative incidence, histological subtypes and clinical outcomes of this disorder in kidney transplant recipients. We retrospectively investigated 34 post-transplant lymphoproliferative disorder patients diagnosed out of the 1210 kidney transplant recipients who had undergone the surgery at the two largest centers in Japan between January 1983 and December 2017. A total of 32 patients (94.1%) developed late-onset post-transplant lymphoproliferative disorder (diagnosed 1year after transplantation). The cumulative incidence rates were 0.76% and 1.59% at 5 and 10years post-transplantation, respectively. The central nervous system was the most common site (35.3%, 12/34). Overall survival was similar between patients with and without central nervous system lesions (P=0.676). Of all of the cases, 23.5% (8/34) were detected through cancer screening. Importantly, patients with screening-detected post-transplant lymphoproliferative disorder had better overall survival than those with the disorder who had been symptom detected (P=0.0215). Overall survival was significantly reduced in patients who developed the disorder compared with those who did not (P=0.0001). Post-transplant lymphoproliferative disorder was more likely to occur in the late post-transplantation period, which showed that long-term medical examination for transplant recipients is required. Based on our findings, we propose vigilant, long-term, cancer screening in kidney transplant recipients.

A systematic review of post-transplant lymphoproliferative disorder after lung transplant.

e19046 Background: Post-transplant lymphoproliferative disorder (PTLD) is a serious complication after solid organ transplantation. This study aims to explore the association of PTLD diagnosed after lung transplant with infectious agents and immunosuppression regimen, explore types of PTLD, and their outcome. Methods: Following the PRISMA guideline, we searched the literature on PubMed, Cochrane, Embase, and clinicaltrials.gov. 1741 articles were screened and included five studies. Results: We analyzed data from five studies, n=13,643 transplant recipients with n=287 (2.10%) developed PTLD. Four studies showed that 32/63 (51%) PTLD patients were male and 31 (49%) were female. Three studies reported 53/55 (96.4%) patients were EBV positive at PTLD diagnosis. Courtwright. et al, reported that 217/224 (97%) PTLD was associated with either EBV positive donor or recipient. Four studies showed that the monomorphic B cell type 48/63 (76%) was the most common histological type of PTLD diagnosed with DLBCL the most common subtype 31/48 (64.6%). Data from 3 studies showed that the onset of PTLD following lung transplant varies with a median duration of 18.3 months (45 days to 20.2 years). Three studies showed that 26/55 (47.3%) patients had early-onset (≤ 1 yr of Tx) and 29/55 (52.7%) patients had late-onset PTLD (> 1 yr of Tx). Management of PTLD included a reduction in immunosuppression including corticosteroids, CNI, purine synthesis inhibitors, Rituximab, and chemotherapeutic agents. Three studies showed a mortality rate of 30/45 (66.7%) and 13/30 (43.3%) deaths were PTLD related. Conclusions: Our review concludes that PTLD is a serious complication, only 2% of lung transplant recipients developed PTLD. EBV seropositivity is the most factor associated with PTLD diagnosis. Monomorphic PTLD was reported as the most common type in the adult population and no association between gender and PTLD was found. The analysis shows that there is a slightly lower incidence of early (≤ 1 yr of Tx) than late-onset (> 1 yr of Tx) PTLD. Table 1 PTLD after a Lung transplant in adults - a review. [Table: see text]

Evidence of Epstein-Barr virus heterogeneous gene expression in adult lung transplant recipients with posttransplant lymphoproliferative disorder.

Epstein-Barr virus (EBV)-driven posttransplant lymphoproliferative disorder (PTLD) is a serious complication following lung transplant. The extent to which the presence of EBV in PTLD tissue is associated with survival is uncertain. Moreover, whether the heterogeneity in expression of EBV latency programs is related to the timing of PTLD onset remains unexplored. We retrospectively performed a comprehensive histological evaluation of EBV markers at the tissue level in 34 adult lung transplant recipients with early- and late-onset PTLD. Early-onset PTLD, occurring within the first 12 months posttransplant, had higher odds to express EBV markers. The presence of EBV in PTLD was not associated with a difference in survival relative to EBV-negative tumors. However, we found evidence of heterogeneous expression of EBV latency programs, including type III, IIb, IIa, and 0/I. Our study suggests that the heterogeneous expression of EBV latency programs may represent a mechanism for immune evasion in patients with PLTD after lung transplants. The recognition of multiple EBV latency programs can be used in personalized medicine in patients who are nonresponsive to traditional types of chemotherapy and can be potentially evaluated in other types of solid organ transplants.

Risk of Lymphoproliferative Disorders After Bone Marrow Transplantation: A Multi-Institutional Study

We evaluated 18,014 patients who underwent allogeneic bone marrow transplantation (BMT) at 235 centers worldwide to examine the incidence of and risk factors for posttransplant lymphoproliferative disorders (PTLD). PTLD developed in 78 recipients, with 64 cases occurring less than 1 year after transplantation. The cumulative incidence of PTLD was 1.0% +/- 0.3% at 10 years. Incidence was highest 1 to 5 months posttransplant (120 cases/10,000 patients/yr) followed by a steep decline to less than 5/10,000/yr among >/=1-year survivors. In multivariate analyses, risk of early-onset PTLD (<1 year) was strongly associated (P <.0001) with unrelated or human leukocyte antigen (HLA) mismatched related donor (relative risk [RR] = 4.1), T-cell depletion of donor marrow (RR = 12.7), and use of antithymocyte globulin (RR = 6.4) or anti-CD3 monoclonal antibody (RR = 43.2) for prophylaxis or treatment of acute graft-versus-host disease (GVHD). There was a weaker association with the occurrence of acute GVHD grades II to IV (RR = 1.9, P =.02) and with conditioning regimens that included radiation (RR = 2.9, P =.02). Methods of T-cell depletion that selectively targeted T cells or T plus natural killer (NK) cells were associated with markedly higher risks of PTLD than methods that removed both T and B cells, such as the CAMPATH-1 monoclonal antibody or elutriation (P =.009). The only risk factor identified for late-onset PTLD was extensive chronic GVHD (RR = 4.0, P =.01). Rates of PTLD among patients with 2 or >/=3 major risk factors were 8.0% +/- 2.9% and 22% +/- 17.9%, respectively. We conclude that factors associated with altered immunity and T-cell regulatory mechanisms are predictors of both early- and late-onset PTLD.

Single-institution Retrospective Analysis of Prognostic Factors Influencing Very Late-onset Post-transplant Lymphoproliferative Disorder.

BackgroundPost-transplant lymphoproliferative disorder (PTLD) is a rare complication following transplant (solid organ or allogeneic) due to the proliferation of lymphoid cells in the immunosuppressed state. The incidence of PTLD follows a bimodal distribution, with high incidence immediately after transplant (early-onset PTLD), followed by a decline and then a high-incidence again five years after transplantation (late-onset PTLD). This study exclusively aims to identify prognostic factors for the subgroup of PTLD, described as very late-onset PTLD, occurring after 10 years of transplant.MethodsThis study was conducted at the University of Florida, with the requisite study population identified through the cancer registry. Data were collected by individual chart review and analyzed. Survival estimates and univariate and multivariate analyses were performed to measure the effects of each variable on overall survival.ResultsA total of 33 patients were identified, with a median age at transplant of 42.3 years, while the median age at PTLD diagnosis was 54.7 years. Median time from transplant to PTLD diagnosis was 13.3 years. Kidney (30.3%), liver (27.3%), and heart (24.2%) transplants were the most common allografts associated with very late PTLD development. The most common pathology was diffuse large B-cell lymphoma (DLBCL) in 45.5% of patients. CHOP+/-R (cyclophosphamide, doxorubicin hydrochloride (hydroxydaunorubicin), vincristine sulfate (Oncovin), prednisone, rituximab) was the most common chemo regimen used as the initial choice in 36.4% of patients.Median survival was 5.4 years. Univariate analysis showed that age at diagnosis over 65, male gender, bone marrow involvement, past medical history (PMH) of malignancy, immunosuppression regimen at PTLD diagnosis, and initial and final best response to treatment were statistically significant (p <0.05) factors associated with survival. On multivariate analysis, bone marrow involvement was significantly associated with poor survival (p=0.008). Surprisingly, performance status, Epstein-Barr virus (EBV) status, pathology type, Ann-Arbor stage, and chemotherapy regimen were not significantly associated with survival. At the end of the study, 48.5% of patients achieved complete remission and the allograft survived in 84.8%.ConclusionsIn this retrospective study of very-late onset PTLD, we identified factors associated with survival different from early and late PTLD. These factors should be considered during the treatment of this subgroup of PTLD patients.

1598 Late-Onset Post-Transplant Lymphoproliferative Disorder Presenting as Diffuse Large B-Cell Lymphoma in the Ascending and Transverse Colon

INTRODUCTION: A serious complication of solid organ transplantation is post-transplant lymphoproliferative disorder (PTLD). The vast majority of PTLD was previously found to present within the first year after transplant, when immunosuppression is highest. However, newer studies suggest a bimodal peak in incidence. 1 This case describes PTLD occurring in the colon as a late complication of multi-organ transplant. CASE DESCRIPTION/METHODS: A 54-year-old male with a complicated transplant history, on tacrolimus for immunosuppression, presented with worsening abdominal pain, nausea, diarrhea, and weight loss. His transplant history includes cardiac transplants in 1980 and 1993 for idiopathic cardiomyopathy, and renal transplant in 2003 due to tacrolimus toxicity. He denied fever, night sweats, or recent sick contacts, and was hemodynamically stable. On exam, he had diffuse abdominal pain with mild guarding but no rebound. Laboratory findings revealed a tacrolimus level of 11.1. Abdominal computed tomography scan was significant for fluid-filled loops of small bowel with focal thickening of the transverse colon, concerning for colonic malignancy (Figure 1). Gastroenterology was consulted for urgent colonoscopy, which showed mucosal ulceration and inflammation throughout the colon, with sparing of the sigmoid and rectum (Figure 2). Biopsy of the cecum, ascending colon, and transverse colon revealed diffuse infiltrate of pleomorphic large cells in the lamina propria and submucosa with focal ulcerations and necrosis, consistent with PTLD of monoclonal diffuse large-B cell morphology. The biopsy was negative for EBV and CMV. Immunohistochemistry was positive CD45RB, CD79a, CD30 and BCl2. He was referred to hematology-oncology and followed-up as an outpatient to begin chemotherapy. DISCUSSION: Though PTLD is classically described as an early complication of solid organ transplant, this case presents the development of colonic PTLD after over 15 years since last transplant. This finding supports the notion that there is a bimodal peak in incidence. This case also demonstrates the insidious, non-specific gastrointestinal findings of colonic PTLD. Because of this, and as survival after organ transplant continues to increase, providers must have a high index of suspicion for PTLD in the colon as a late complication of transplant.

Management of post-transplant lymphoproliferative disorders.

Management of post-transplant lymphoproliferative disorders.

1580. Characteristics of Early vs. Late Onset Post-transplant Lymphoproliferative Disorder After Liver Transplant:– A Descriptive Study of the United Network of Organ Sharing (UNOS) Database

BackgroundPost-transplant lymphoproliferative disorder (PTLD) is a devastating complication of solid-organ transplant. In liver transplant, studies comparing the risk factors for early vs. late onset PTLD have been limited to single centers. Using a national database, we sought to compare early and late onset PTLD in adult and pediatric liver transplant patients in terms of patient characteristics, immunosuppressive regimens, and mortality.MethodsWe conducted a retrospective analysis of the UNOS database to compare early (<1 year) and late (1+ year) onset PTLD in pediatric (<18) and adult (18+) liver transplant patients. We compared patient demographics, co-morbid conditions, immunosuppressive regimens, Epstein-Barr virus (EBV) and cytomegalovirus (CMV) risk status, reason for transplant, and mortality. We categorized EBV and CMV risk status into high, intermediate, and low based on donor and recipient serostatus. Categorical variables were analyzed using Fisher’s exact test. The Kaplan–Meier method, log-rank test, and multivariable Cox regression were used to examine mortality.ResultsNinety-two pediatric patients and 807 adult patients met study criteria. Overall mortality was 35.87 and 53.78% for pediatric and adult patients, respectively. In adults, unadjusted survival was significantly different for early vs. late onset PTLD (P < 0.001; Figure 1); the latter was associated with a 64.33% decreased mortality risk (95% CI: 51.17–73.95%; P < 0.001). There was no difference in mortality in pediatric patients (P = 0.549). In neither population was EBV risk status associated with early vs. late onset PTLD. In adults, tacrolimus, mycophenolate mofetil (MMF), and steroid maintenance therapy were associated with late onset PTLD (P < 0.001; 0.006; <0.001).Figure 1.ConclusionWe conclude the following: (1) Mortality is greater for early vs. late onset PTLD in adult patients; the converse has been shown previously. (2) Tacrolimus, MMF, and steroids are associated with late onset PTLD in adult patients. (3) EBV risk status did not differ between early and late onset PTLD in both the adult and pediatric populations. This contradicts established reports that EBV negative serostatus of the recipient at the time of transplant is a risk factor for early onset PTLD.Disclosures All authors: No reported disclosures.

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.

Donor-specific Antibodies, Immunoglobulin-free Light Chains, and BAFF Levels in Relation to Risk of Late-onset PTLD in Liver Recipients.

BackgroundPosttransplant lymphoproliferative disorder (PTLD) is a neoplastic complication of transplantation, with early cases largely due to immunosuppression and primary Epstein-Barr virus infection. Etiology may differ for later-onset cases, but the contributions of immunosuppression, immune reactivity to the donor organ, and chronic B cell activation are uncertain.MethodsWe conducted a case-control study of late-onset PTLD (diagnosed >1 year posttransplant) in a cohort of liver recipients. We assessed serum samples (obtained >6 months before diagnosis in cases) from N = 60 cases and N = 166 matched controls for donor-specific antibodies (DSAs, evaluable for N = 221 subjects), immunoglobulin kappa and lambda free light chains (FLCs, N = 137), and B cell activating factor (BAFF, N = 226). Conditional or unconditional logistic regression was used to calculate adjusted odds ratios (aORs).ResultsCirculating DSAs were less common in PTLD cases than controls (18% vs 30%), although this difference was borderline significant (aOR, 0.51; 95% confidence interval [CI], 0.24-1.10; P = 0.09). Donor-specific antibodies against class II HLA antigens predominated and likewise showed a borderline inverse association with PTLD (aOR, 0.58; 95% CI, 0.27-1.24). The FLC levels were less frequently abnormal in cases than controls, but measurements were available for only a subset and confidence intervals were wide (elevated kappa: aOR, 0.57; 95% CI, 0.15-2.12; P = 0.40; elevated lambda: aOR, 0.68; 95% CI, 0.30-1.50; P = 0.34). B cell–activating factor levels were not associated with PTLD.ConclusionsOur results suggest that circulating DSAs are associated with decreased risk of late-onset PTLD. Because DSAs may develop in the setting of underimmunosuppression, the inverse association with DSAs supports a role for immunosuppression in the etiology of late-onset PTLD.

Retrospective analysis of prognostic factors influencing very late onset PTLD.

e19561Background: Post-transplant lymphoproliferative disorder (PTLD), is a very rare complication following transplant (solid organ or allogeneic) due to proliferation of lymphoid cells in immunos...

An unusual presentation of Burkitt's lymphoma in a renal allograft recipient

Posttransplant lymphoproliferative disorders (PTLDs) are rare complication encountered in solid organ transplantation. They can be fatal and often occur within 1 year of transplantation. Often, they are associated with Epstein–Barr virus (EBV) reactivation occurring in a setting of immunosuppression. Among PTLDs, Burkitt's lymphoma is uncommon. In this report, we present a renal allograft recipient who presented with late-onset PTLD like Burkitt's lymphoma, 12 years after renal transplantation, and was negative for EBV markers. The clinical presentation of PTLD is often subtle as it usually involves the extranodal sites. The gastrointestinal system is one of the frequent sites involved by PTLD. The diagnosis is confirmed by histopathological analysis including immunohistochemistry (IHC) of the suspected lesion. Analysis for the EBV status of the tumor is of major significance in predicting prognosis. Late-onset PTLD is usually monomorphic and the prognosis is poor if the EBV status is negative. Reduction or even withdrawal of immunosuppression is the pivotal step in the treatment of PTLD along with the use of chemotherapeutic agents and rituximab.

Posttransplant Lymphoproliferative Disorder in Adults Receiving Kidney Transplantation in British Columbia: A Retrospective Cohort Analysis.

Background:Posttransplant lymphoproliferative disorder (PTLD) is a major complication following kidney transplantation.Objective:We undertook this study to characterize PTLD in kidney transplant patients in British Columbia with regard to incidence, patient and graft survival, histological subtypes, treatment modalities, and management of immunosuppression.Design:Retrospective cohort analysis.Setting:British Columbia.Patients:All adult patients who underwent kidney transplantation in British Columbia between January 1, 1996, and December 31, 2012, were included. Patients less than 18 years of age at the time of first transplant and multiple organ transplant recipients were excluded from analysis.Measurements:Patients with lymphoproliferative disorders that occurred subsequent to kidney transplantation were considered to have developed PTLD.Methods:Cases of PTLD were identified by cross-referencing data abstracted from the provincial transplant agency’s clinical database with the provincial cancer agency’s lymphoma registry. Patients were followed up for the development of PTLD until December 31, 2012, and for outcomes of death and graft failure until December 31, 2014. Data collection was completed via an electronic chart review.Results:Of 2217 kidney transplant recipients, 37 (1.7%) developed PTLD. Nine cases were early-onset PTLD, occurring within 1 year of transplant; of these cases, 6 were known/presumed Epstein-Barr virus mismatch, compared with only 2 of 28 late-onset cases. Patient survival for early-onset PTLD was 100% at 2 years post diagnosis. Late-onset PTLD had survival rates of 71.4% and 67.9% at 1 and 2 years, respectively. PTLD was associated with significantly decreased patient survival (P = .031) and graft survival (uncensored for death, P = .017), with median graft survival of PTLD and non-PTLD patients being 9.5 and 16 years, respectively. Immunosuppressant therapy was reduced in the majority of patients; additional therapies included rituximab monotherapy, CHOP-R, radiation, and surgery.Limitations:Limitations to this study include its retrospective nature and the unknown adherence of patients to prescribed immunosuppressant regimens. In addition, cumulative doses of immunosuppression received and the degree of immunosuppression reduction for PTLD management were not effectively captured.Conclusions:The incidence of PTLD in British Columbia following kidney transplantation was low and consistent with rates reported in the literature. The incidence of late-onset PTLD and its association with reduced patient and graft survival warrant further analysis of patients’ long-term immunosuppression.

Post-transplant lymphoproliferative disease in lung transplantation: A nested case-control study.

Post-transplant lymphoproliferative disorder (PTLD) may compromise long-term outcome of lung transplant (LTx) recipients. A case-control study was performed, comparing LTx recipients with PTLD (n=31) to matched recipients without PTLD (Controls, n=62). Risk factors for PTLD and post-transplant outcomes were assessed. PTLD prevalence was 3.9%, time to PTLD 323 (166-1132) days; and 54.8% had early-onset PTLD versus 45.2% late-onset PTLD. At LTx, more Epstein-Barr virus (EBV)-seronegative patients were present in PTLD (42%) compared to Controls (5%) (P<.0001); most of whom had undergone EBV seroconversion upon PTLD diagnosis. EBV viral load was higher in PTLD versus Controls (P<.0001). Overall, lower hemoglobin and higher C-reactive protein levels were present in PTLD versus Controls (P<.0001). EBV status at LTx (P=.0073) and EBV viral load at PTLD (P=.0002) were the most important risk determinates for later PTLD. Patients with PTLD demonstrated shorter time to onset of chronic lung allograft dysfunction (CLAD) (P=.0006) and poorer 5-year survival post-LTx (66.6% versus 91.5%), resulting in worse CLAD-free survival (HR 2.127, 95%CI 1.006-4.500; P=.0483) and overall survival (HR 3.297 95%CI 1.473-7.382; P=.0037) compared to Controls. Late-onset PTLD had worse survival compared to early-onset PTLD (P=.021). Primary EBV infection is a risk for PTLD; which is associated with worse long-term outcome post-LTx.

Remission of late-onset post-heart transplantation lymphoproliferative disorder following treatment with rituximab and modified mini-CHOP chemotherapy: A case report.

Post-transplant lymphoproliferative disorder (PTLD) is one of the most frequent secondary malignancies that can follow immunosuppressive therapy for solid organ transplantation, and may result in severe morbidities and even mortality. A middle-aged Han Chinese patient, prescribed with immunosuppressive cyclosporine and prednisone, developed PTLD that manifested as a painless cervical lymph node enlargement, 12 years following heart transplantation. Histology revealed monomorphic B-cell PTLD (diffuse large-cell lymphoma); as a result the immunosuppressive regimen of the patient was changed to tacrolimus and mycophenolate mofetil. In addition, the patient was changed to 6-cycle rituximab with a modified mini-CHOP (R-mini-CHOP) regimen for induction, and 8-cycle quarterly rituximab treatment and maintenance therapy. R-mini-CHOP therapy was well tolerated, and no allograft rejection occurred. The patient exhibited clinical remission as demonstrated by the results of the positron emission tomography-computed tomography at the 5-year follow-up visit following R-mini-CHOP therapy. In conclusion, R-mini-CHOP therapy following reduced immunosuppression is effective and safe for the treatment of late-onset PTLD following heart transplantation.

Post-Transplant Lymphoproliferative Disorder in Kidney Transplant Recipients: A Single-Center Experience in Japan.

Post-transplant lymphoproliferative disorder is a serious complication of solid organ transplantation; however, few large studies have been performed in Asian institutions. We review our single-center experience with post-transplant lymphoproliferative disorder patients in Japan. We retrospectively evaluated patients with post-transplant lymphoproliferative disorder following kidney transplantation between January 1985 and December 2013. The patients were divided into early-onset post-transplant lymphoproliferative disorder (<1 year) and late-onset post-transplant lymphoproliferative disorder (≥1 year) groups. Thirteen patients had the disorder, an incidence rate of 0.75% (13/1730). Early-onset post-transplant lymphoproliferative disorder (N = 3) had not occurred for the last two decades. In the late-onset group (N = 10), the median time of onset was 108.7 months. The Kaplan-Meier 10-year overall survival rates were 76.9% and 95.4% in patients with and without the disorder, respectively (P = 0.0001). Post-transplant lymphoproliferative disorder significantly affected transplant recipients' mortality. Late-onset occurred even > 10 years after transplantation; therefore, long-term monitoring of patients is needed.

Persistent Epstein-Barr viral load in Epstein-Barr viral naïve pediatric heart transplant recipients: Risk of late-onset post-transplant lymphoproliferative disease.

AIMTo examine the risk of late-onset post-transplant lymphoproliferative disorder (PTLD) in the presence of persisting high Epstein-Barr virus (EBV) in EBV naïve pediatric heart transplant (HT) recipients.METHODSA retrospective review of the medical records of the 145 pediatric HT recipients who had serial EBV viral load monitoring at our center was performed. We defined EBV naive patients whose EBV serology either IgM or IgG in the blood were negative at the time of HT and excluded passive transmission from mother to child in subjects less than 6 mo of age.RESULTSPTLD was diagnosed in 8 out of 145 patients (5.5%); 6/91 (6.5%) in those who were EBV seropositive and 2/54 (3.7%) in the EBV naïve group at the time of HT (P = 0.71). We found 32/145 (22%) patients with persistently high EBV load during continuing follow-up; 20/91 (22%) in EBV seropositive group vs 12/54 (22%) in EBV naïve group (P = 0.97). There was no significant association between pre-HT serostatus and EBV load after transplant (P > 0.05). In the EBV seropositive group, PTLD was diagnosed in 15% (3/20) of patients with high EBV vs 4.2% (3/71) of patients with low or undetectable EBV load (P = 0.14) whereas in EBV naïve patients 8.3% (1/12) of those with high EBV load and 2.3% (1/42) with low or undetectable EBV load (P = 0.41). There was a highly significant association between occurrence of PTLD in those with high EBV load and duration of follow up (4.3 ± 3.9 years) after HT by Cochran-Armitage test for the entire cohort (P = 0.005). At least one episode of acute rejection occurred in 72% (23/32) of patients with high EBV vs 36% (41/113) patients with low or undetectable EBV after HT (P < 0.05).CONCLUSIONThere is an association between persistently high EBV load during post-HT follow up and the occurrence of late-onset PTLD in pediatric HT recipients irrespective of serostatus at the time of transplant. The occurrence of allograft rejection increased in patients with high EBV load presumably due to reduction in immunosuppression.

CD8+ T Cell Transcriptional Profiles of Pediatric Heart Transplant Recipients That Carry EBV Loads in Peripheral Blood.

Pediatric heart transplant (HTx) recipients display impaired CD8+ T cellular immune surveillance due to chronic immunosuppression and thus are at increased risk of EBV-associated post-transplant lymphoproliferative disorders (PTLD). Approximately 70% of asymptomatic pediatric HTx patients who seroconvert after HTx carry EBV loads in peripheral blood. One third of these patients display high chronic EBV loads (> 16,000 genomic copies/ml), and have up to 45% rate of progression to late onset PTLD. Here we used microarray analyses to investigate the hypothesis that CD8+ T cell transcriptional signatures are different between asymptomatic pediatric HTx patients that carry EBV loads vs. asymptomatic patients that do not carry EBV loads in peripheral blood. Six EBV seropositive asymptomatic, gender-, age-, and immunosuppression-matched pediatric HTx recipients were recruited to the study and consisted of: (i) undetectable viral load (UVL, n=2) carriers, resembling “normal” EBV latency; (ii) low viral load (LVL n=2) carriers; (iii) high viral load (HVL n=2) carriers. RNA was extracted from highly purified CD8+ T cells, amplified and hybridized to the Affymetrix H133 2.0 Plus Array. Perfect match data were normalized using the RMA method as implemented in BRB Array Tools. Differentially expressed genes were found for each comparison using the J5 test at threshold |J5|>12. Impacted pathways were studied using Pathway Express. Transcriptional signatures (transcripts, pathways, and networks) for pro-inflammatory cytokines and chemokines were significantly increased in CD8+ T cells from LVL and HVL carriers as compared to UVL carriers. In addition, CD8+ T cell from HVL carriers uniquely revealed up-regulation of transcripts relevant for apoptosis and for cross-talk to B lymphocytes, as well as macrophage-specific transcripts critical for cell migration and inflammation. These results indicate significant differences in the transcriptional profiles of CD8+ T cells from patients that carry EBV loads suggesting that these transcriptional signatures could be used as early surrogate biomarkers to monitor and assess patients at risk of complications that may benefit for prompt clinical intervention.

A population-based study of 135 lymphomas after solid organ transplantation: The role of Epstein-Barr virus, hepatitis C and diffuse large B-cell lymphoma subtype in clinical presentation and survival

Background. Epstein-Barr virus (EBV) plays a major role in the development of post-transplant lymphoproliferative disorder (PTLD), but there is an increasing awareness of EBV-negative PTLD. The clinical presentation of EBV-negative PTLD has not been as well characterised as EBV-positive cases. Further, there is limited knowledge on the clinical importance of diffuse large B-cell lymphoma (DLBCL) cell of origin subtype post-transplant. Materials and methods. We studied the role of EBV, hepatitis C (HCV) and DLBCL subtype in clinical presentation and survival in 135 post-transplant lymphomas diagnosed 1980–2006 in a population-based cohort of 10 010 Swedish solid organ transplant recipients. The lymphomas were re-evaluated according to WHO 2008, examined for EBV, and clinical data were collected from medical records. Results. Lymphoma incidence rate was 159/100 000 person-years and is also reported by lymphoma subtype. EBV-negative lymphomas constituted 48% and were associated with HCV infection (p = 0.02), bone marrow involvement (p < 0.001), and T-cell phenotype (p = 0.002). Among DLBCL, 78% were of non-germinal centre subtype, which was associated with EBV-positivity (69%, p = 0.001), early occurrence (p = 0.03), heart/liver/lung/pancreas recipients (p = 0.02), anti-T-cell globulin (p = 0.001), and tacrolimus treatment (p = 0.02). DLBCL subtypes had similar overall survival. Five-year overall survival was 42% in all treated patients. Independent poor prognostic factors were older age, B symptoms, ECOG 2-4, kidney/pancreas/heart recipients, T-cell lymphoma, and HCV-infection. Conclusions. With long follow-up, a large part of PTLD is EBV-negative, due to a high proportion of T-cell lymphomas and low of polymorphic PTLD. EBV-negative PTLD have a different clinical presentation. HCV may play an aetiological role in late-onset PTLD and was revealed as a new prognostic factor for inferior survival that needs to be confirmed in larger studies. The heavier immunosuppression in non-kidney transplantations seems to play a role in the development of non-germinal centre DLBCL. DLBCL cell of origin subtype lacks prognostic importance in the transplant setting.

Post-Transplant Lymphoproliferative Disorder in Lung Transplant Recipients – a Shift Lo Late Onset Disease

AbstractAbstract 5075 Background:Post-transplant lymphoproliferative disorder (PTLD) is a well-recognized complication after solid organ transplantation. Most cases of PTLD arise within the first year from transplantation and are associated with EBV infection. However, there are increasing reports on a late onset form of PTLD. Methods:We reviewed all charts of patients undergoing either lung or heart-lung transplantation in a tertiary center in Israel between the years 1997 and 2012. PTLD was defined according to the WHO criteria. We analyzed baseline characteristics, clinical and pathological parameters as well as transplantation outcomes. Results:We identified 9 PTLD patients among cohort of 336 lung and heart-lung transplant recipients (incidence=2. 7%). Additional PTLD patient from another hospital was added for the clinical analysis (10 patients overall). Median age at transplantation of the PTLD patients was 50 (range 11–63) years, compared to 56 (2–69) among the non-PTLD patients (p=0. 04). Idiopathic pulmonary fibrosis was the leading etiology for transplantation among both PTLD and non-PTLD patients (50% vs. 37. 2%, respectively, p=0. 5), while relatively less COPD patients were observed among PTLD patients (10% vs. 34%, respectively, p=0. 28). Median time from transplantation to PTLD diagnosis was 41 (range 3–128) months, being among the longest to be reported in the literature among lung transplant recipients. Three patients developed early PTLD in our cohort, all were pre-transplant EBV seronegative and all were asymptomatic, diagnosed during surveillance chest imaging. In contrast, the seven late-onset PTLD cases were all EBV seropositive prior to transplantation, and were diagnosed after presenting with various symptoms, mainly B symptoms (71%). Overall extra-nodal involvement at presentation was very common for both PTLD forms (90%). While early onset PTLD uniformly involved the transplanted lung, this was relatively rare in the late-PTLD (100% vs. 14%, p=0. 03). According to the WHO classification, all PTLD specimens were monoclonal, based on molecular or light chain immuno-histochemistry. Eight (80%) cases were CD20 positive B cell lymphomas. EBV staining in the specimens was positive in 7 patients, including the 3 early-onset PTLD cases.All patients were treated with reduction of immunosuppression (Table). Other treatment modalities were diverse, including combination chemotherapy (6 patients), rituximab (6 patients), surgery (1 patient) and antiviral treatment (2 patients). 8 (80%) patients attained complete remission. With a median follow-up of 23 months, 6 patients died (3 from chronic rejection of the transplant, 1 from late chemotherapy toxicity, 1 from disease progression and 1 from unrelated cause). The median time from PTLD diagnosis to death was 19 months. Of the 8 patients attaining complete remission, only three patients are alive at the end of follow-up. Conclusion:Our cohort of lung transplant recipients demonstrates a trend of late-onset PTLD. This might be related to the high pre-transplant sero-prevalence to EBV in our cohort (96. 3%), as late-onset PTLD has been reported to be less associated with EBV proliferation. The majority of PTLD patients in our cohort died of treatment-related causes rather than disease progression.OutcomeStatus at end of treatmentTreatment givenHistologyStageExtranodal involvementPrimary site of involvementPresenting symptomsTime from transplantation to PTLD Dx (months)Age at transplantationSexCaseAliveCRRIS, RituximabMonoclonal PTLDIEYesTransplanted lungNone311F1AlivePDRIS, RituximabDLBCLIVEYesTransplanted lung, GITNone421F2DeadCRRIS, surgery, AcyclovirDLBCLIEYesTransplanted lungNone1049M3DeadCRRIS, AcyclovirDLBCLIEYesColonAbdominal pain, GI bleeding1863M4DeadCRRIS, R-CHOPDLBCLIEBYesTransplanted lungB symptoms, cough1860F5AliveCRRIS, R-CHOPDLBCLIIIAYeslymph nodesBack pain6453F6DeadPDRIS, CHOPPlasmabalstic lymphomaIEYesChest wallPalpable mass8926F7DeadCRRIS, GMALL 2002 protocol+rituximabDLBCLIVBYesBone marrowB symptoms, bone pain9153M8AliveCRRIS, R-CHOPDLBCLIEAYesStomachAbdominal pain10852M9DeadCRRIS, CHOPAnaplastic T cell lymphoma, ALK negativeIIIBNolymph nodesB symptoms, neck pain12815M10 Disclosures:No relevant conflicts of interest to declare.