Epstein-Barr Virus Post-transplant Lymphoproliferative Disorder Research Articles

Does CMV Mismatch Status Modify the Risk of PTLD Due to EBV Mismatch Status in Lung and Heart Transplant Recipients?

Purpose Epstein-Barr virus (EBV) mismatch is a known risk factor for posttransplant lymphoproliferative disorders (PTLD) in lung and heart transplant recipients (LTx and HTx). We evaluated the potential modifying effect of cytomegalovirus (CMV) mismatch on the relation between EBV mismatch and PTLD in LTx and HTx. Methods and Materials We performed a study of U.S. LTx and HTx recipients from 2000-2011 in the Scientific Registry of Transplant Recipient (SRTR). Adjustment for sextiles of the propensity score (based on the probability of being an EBV mismatch) was used to account for confounding in Cox proportional hazards models stratified for organ type. Results The study population included 5957 LTx (61 PTLDs; 1.02%) and 7870 HTx (39 PTLDs; 0.5%) with complete data on CMV and EBV serostatus. A total of 272 LTx and 457 HTx were concurrently CMV and EBV mismatches. After adjustment for sextiles of the propensity score, the hazard ratio (HR) for PTLD was 4.4 (95% CI: 2.9-6.7) and 1.6 (95% CI: 1.1-2.5) in EBV and CMV mismatch recipients, respectively. When compared to patients who were neither CMV nor EBV mismatch, the adjusted HR for PTLD in patients who were CMV mismatch only, EBV mismatch only, and both CMV/EBV mismatch were 1.8 (95% CI: 1.1-3.3), 4.8 (95% CI: 2.9-8.1), and 7.0 (95% CI: 3.9-12.7), respectively. However, the HRs for the association of EBV mismatches and PTLD in CMV mismatch and non-mismatch patients did not significantly differ (P value for interaction=0.6). [ figure 1 ] Conclusions EBV mismatch status is significantly associated with risk for PTLD in LTx and HTx. Concomitant CMV mismatch status in EBV mismatch patients does not significantly modify the relative hazard of PTLD.

Unexpected Higher Tacrolimus Levels at the Onset of Epstein-Barr Virus Associated Post-Transplantation Lymphoproliferative Disorder in Living Donor Liver Transplant Infants

Introduction: Post-transplantation lymphoproliferative disorder (PTLD) is a life threatening disease, which occurs as high as 20% of liver transplanted children. Especially, liver transplanted infants are high risk group of Epstein-Barr virus (EBV) associated PTLD because of their immature immunity and primary EBV transmission from EBV positive graft implantation. In this study, we investigated relationship between changes of tacrolimus (Tac) trough levels and symptomatic infectious episodes associated with EBV. Patients and methods: From July 1991 to June 2011, 85 pediatric living donor liver transplantations (LDLT) were performed at Tohoku University Hospital. Of these patients, there were 32 infants, who received Tac and steroids as a primary induction therapy, with an age of less than 2 years old at LDLT. In this study, a retrospective review of the transplant records of these 32 patients was conducted. The indication for LDLT included biliary atresia (n=31) and fulminant hepatitis (n=1). 32 infants were all survived for over 1-year. The definition of PTLD was infectious episodes with peripheral-blood mononuclear cells and/or serum EBV DNA positivity (cut-off value>102.5 copies/μg DNA) and with persisting abnormal nodal swelling with/without extranodal findings confirmed by contrast enhanced computed tomography images. Results: 21 (66%) of 32 patients experienced symptomatic viral infection. 8 (25%) of these patients were EBV seronegative at the onset of viral infectious episode. Of the remaining 13 patients, 8 (25%) experienced infectious episodes with sudden positive change of blood EBV DNA load without the development of PTLD at a median of 358 (161-580) posttransplant days (non-PTLD group). 5 (16%) patients developed PTLD at a median of 198 (112-447) posttransplant days (PTLD group). All 13 patients resolved their symptoms and signs associated with EBV disorders and all have maintained good allograft function during a median follow-up time of 2264 (157-4024) days after the development of symptomatic EBV infection or PTLD. The clinical characteristics of these patients were summarized in Table 1. Although the averages of Tac trough levels for 2 months before the onset of infectious episodes were similar in both patients, those levels at the onset in PTLD group patients were significantly higher than those of non-PTLD group. Moreover, most of the patients developing PTLD showed more than twice trough levels of Tac before infectious episodes.Conclusions: Among infants with an age of less than 2 years old at LDLT, an unexpected increase of Tac trough level at the onset of infectious episodes with sudden positive change of blood EBV DNA load may predict the development of PTLD. In such clinical settings, we need to perform frequent EBV load monitoring and imaging studies.

Strategy of pre-emptive management of Epstein-Barr virus post-transplant lymphoproliferative disorder after stem cell transplantation: results of European transplant centers survey

Aim of the studyEpstein-Barr virus-related post-transplant lymphoproliferative disorder (EBV-PTLD) is a serious complication after stem cell transplantation (SCT) and the number of patients at risk is increasing over time. Available data do not reflect general practice of diagnosis and treatment of this complication.Material and methodsIn 2009 a survey on management of the pre-emptive strategy of EBV infection was done and results from 74 European transplant centers were registered and analyzed.ResultsRegular monitoring for EBV after SCT is done by most of the participating centers (73%). In 68% of them the monitoring is performed in all alloSCT patients, while in remaining centers it is done in high-risk patients only. Quantitative EBV-DNA is performed in 97% of centers, mainly in whole blood (78%) and usually repeated once a week (60.9%). The monitoring for EBV reactivation is performed for a period of 3 months (37%) to 6 months (30%) or adjusted to risk factors (20%). Rituximab as a pre-emptive therapy for EBV-PTLD is routinely administered in 80% of responding centers. The number of EBV-DNA copies as an indicator for pre-emptive therapy with rituximab varies between the centers.ConclusionsThe strategy of management of EBV infection exists in most of the responding centers. Different approaches regarding indications for preemptive therapy are seen between centers: rituximab is administered as pre-emptive therapy in most participating transplant centers.

Rituximab Treatment for Epstein-Barr Virus DNAemia after Alternative-Donor Hematopoietic Stem Cell Transplantation

We report 55 patients undergoing an alternative-donor hematopoietic stem cell transplantation (HSCT) who developed Epstein-Barr virus (EBV) DNAemia, with >1000 EBV copies/10(5) peripheral blood mononuclear cells (PBMCs), and were treated with rituximab (375 mg/m(2)). The median patient age was 47 years (range, 20-65 years), and graft sources were mismatched family members (n = 4), unrelated donors (n = 46), and unrelated cord blood (n = 5). The conditioning regimen included antithymocyte globulin (ATG) in all patients. The median time to development of EBV DNAemia was day 27 post-HSCT (range, day 5 to day 242), with a median of 60 EBV copies/10(5) PBMCs (range, 1-5770 copies/10(5) PBMCs). The number of EBV copies was reduced to <1000/10(5) PBMCs on day +7 after initiation of rituximab therapy in 51% of the patients, on day +14 in 73% of the patients, and on +21 in 92% of the patients. Overall, 50 of 55 patients (91%) cleared EBV after one dose (n = 25) or more than one dose (n = 25) of rituximab. Factors predicting transplantation-related mortality (TRM) in multivariate analysis were a reduction to <1000 EBV copies/10(5) PBMCs by day +7 of treatment (relative risk [RR], 0.2; P = .01) and disease phase in remission (RR, 0.3; P = .05). TRM was 23% in the 40 patients with none or one of the negative predictors and 60% in the 15 patients with both negative predictors (P = .001). Of these latter 15 patients, 3 developed clinical posttransplantation lymphoproliferative disorder (PTLD). All 3 of these patients had a high EBV load on day +7 of rituximab therapy. This study confirms the effectiveness of rituximab in controlling EBV DNAemia in patients undergoing allogeneic HSCT. Patients with increasing EBV copies despite rituximab therapy are at high risk for EBV PTLD and may be considered for alternative therapies.

Epstein-Barr virus-associated posttransplant lymphoproliferative disorder: Strategies for prevention and cure

KEY POINTS (1) No therapies for the treatment of Epstein-Barr virus (EBV)–associated posttransplant lymphoproliferative disorder (PTLD) are based on data from randomized clinical trials. (2) Published clinical experience suggests that implementation of a systematic, stepwise approach to the treatment of EBV-associated PTLD can result in improved outcomes. (3) Several new second-line therapies, including monoclonal antibody therapies against B cell surface antigens and low-dose chemotherapy for pediatric organ recipients with PTLD, have emerged over the last decade. (4) A variety of potential approaches to the prevention of EBV disease and PTLD, including chemoprophylaxis with antiviral therapy, immunoprophylaxis, and viral load monitoring to inform preemptive strategies, are currently under consideration. (5) Although many centers have endorsed the use of the antiviral agents acyclovir and ganciclovir for the prevention of EBV/PTLD, there are few data to support this practice. (6) At present, the use of serial monitoring of EBV viral loads as a stimulus for reducing immunosuppression appears to be the most promising strategy for the prevention of EBV disease and PTLD in liver transplant recipients. Liver Transpl 16:S54-S59, 2010. © 2010 AASLD.

EBV-Negative Post-Transplant Lymphoproliferative Disorder (PTLD): A Retrospective Case-Control Study of Clinical and Pathological Characteristics, Response to Treatment and Survival

PTLD is a heterogeneous group of neoplasms arising in patients after solid-organ or allogeneic stem-cell transplantation. Although most cases of PTLD are related to Epstein - Barr virus (EBV) infection, a subset (10–20%) shows no association with EBV infection. Anecdotal uncontrolled studies have described EBV-negative PTLD as appearing late in the post-transplant period and having poor response to reduction of immunosuppression and poor outcome in general. We identified 30 patients who were diagnosed with EBV-negative PTLD in the University of Pennsylvania between November 1990 and April 2008. We compared the clinical and pathological characteristics, response to therapy and survival of these patients with 51 control patients matched by organ type who had EBVpositive PTLD. The average age at diagnosis was 53.1 in the EBV (−) group and 49.2 in the EBV (+) group (p=NS). 3/30 (10%) of the EBV (−) cases and 16/51 (31.4%) appeared within the first year after transplant (p<0.05). 7/30 (23%) of the EBV (−) patients and none of the EBV (+) patients had multiple transplants in their history (p<0.005). Presenting signs and symptoms, stage at diagnosis, extranodal involvement and involvement of the allograft were similar in both groups but patients with EBV (−) PTLD were more likely to present with “allograft failure”. Pathological characteristics were significantly different. 27/30 (90%) of EBV(−) cases and 25/38 (66%) of EBV (+) cases had monomorphic PTLD (p<0.05). The majority of the EBV (−) cases were subtyped as diffuse large B-cell lymphoma. 23/30 (76.7%) of EBV (−) PTLD cases and 41/51 (80.4%) of EBV (+) PTLD cases were treated with reduction of immunosuppression (RI) alone as initial therapy. Overall response rates to RI were 47.6% and 58.5% in the EBV (−) and EBV (+) groups respectively (p=NS). Overall response rates to the monoclonal anti-CD-20 antibody rituximab when it was used as a single agent were 47% and 48% in the EBV(−) and EBV (+) groups respectively. In both groups, less than 20% of the patients encountered allograft rejection during therapy and a total of 6 patients (3 in each group) underwent another transplant without having a relapse of their PTLD. 2-year survival rates for EBV (−) and EBV (+) PTLD were 48% and 67% respectively (p<0.05). Kaplan-Meier survival analysis showed a trend towards higher early mortality in EBV (−) patients; however overall survival and disease-free survival were not affected by EBV status by log-rank test (p=0.35 & p=0.84 respectively). Median follow-up on living patients was 60 months (range 3.9–196.9 months). Univariate analysis using the Cox proportional hazards model revealed that stage at diagnosis, B symptoms, initial albumin level, bulky disease and age>60 were significant predictors for poor prognosis in both groups, verifying that some of the classic risk factors for lymphoid malignancies are valid in PTLD. The strongest predictor of mortality was the type of transplanted organ, where lung transplant recipients had the worst outcome and kidney transplant recipients did well (log rank p-value=0.02 for both overall survival and disease-free survival). We conclude that in our single-center series, EBV-negative PTLD is a distinct subtype which appears later in the post-transplant period. Compared with EBV-positive PTLD, it is more likely to be monomorphic and similar to common B-cell malignancies; however it still responds well to reduction of immunosuppression and specific anti-B-cell immunotherapy without compromising allograft survival. It does not necessarily require chemotherapy and can be cured similarly to EBV-positive PTLD. [Display omitted]

Impact of Epstein-Barr Virus in Monomorphic B-cell Posttransplant Lymphoproliferative Disorders

The heterogeneity of the posttransplant lymphoproliferative disorders (PTLDs) is well recognized. However, in contrast to other immunodeficiency-associated lymphomas or diffuse large B-cell lymphomas in general, studies of the histogenetic spectrum of the large category of monomorphic B-cell cases have been more limited, produced conflicting results, and have paid little attention to the impact of Epstein-Barr virus (EBV). Therefore, 30 monomorphic B-cell PTLD from 27 patients were analyzed using EBER in situ hybridization for EBV and a panel of antibodies directed against CD20, CD3/bcl-6, CD10, MUM-1/IRF4, CD138, and bcl-2. The results were correlated with the histopathologic features and clinical outcome. All PTLD were CD20 with 23% CD10, 53% bcl-6, 67% MUM-1/IRF4, 13% CD138, 83% bcl-2 and 67% EBV. 30% of the PTLD had a germinal center (GC) profile (CD10, bcl-6, MUM-1/IRF4, CD138), 53% a "late GC/early post-GC" profile (CD10, bcl-6, MUM-1/IRF4, CD138), 13% a post-GC profile (CD10, bcl-6, MUM-1/IRF4, CD138) and 3% an indeterminate profile (all markers negative). EBV positivity was associated with MUM-1/IRF4 expression (P=0.005) and with a non-GC phenotype (P=0.01). All CD138 cases were EBV. The cases with a GC phenotype were the most likely to resemble transformed GC cells (P=0.023). No statistically significant survival differences could be documented between those with a GC versus non-GC phenotype. These results highlight the broad histogenetic spectrum of monomorphic B-cell PTLD. They demonstrate the association of EBV positivity with a non-GC phenotype and suggest that EBV PTLD are more like lymphomas that arise in immunocompetent individuals. The lack of a demonstrable correlation with survival may relate to the relatively small number of cases studied.

Marked increased risk of Epstein-Barr virus-related complications with the addition of antithymocyte globulin to a nonmyeloablative conditioning prior to unrelated umbilical cord blood transplantation

AbstractUmbilical cord blood (UCB) is increasingly used as an alternative source of hematopoietic stem cells for transplantation for patients who lack a suitable sibling donor. Despite concerns about a possible increased risk of Epstein-Barr virus (EBV) posttransplantation lymphoproliferative disorder (PTLD) after UCB transplantation, early reports documented rates of PTLD comparable to those reported after HLA-matched unrelated marrow myeloablative (MA) transplantations. To further investigate the incidence of EBV PTLD after UCB transplantation and potential risk factors, we evaluated the incidence of EBV-related complications in 335 patients undergoing UCB transplantation with an MA or nonmyeloablative (NMA) preparative regimen. The incidence of EBV-related complications was a 4.5% overall, 3.3% for MA transplantations, and 7% for NMA transplantations. However, the incidence of EBV-related complications was significantly higher in a subset of patients treated with an NMA preparative regimen that included antithymocyte globulin (ATG) versus those that did not (21% vs 2%; P < .01). Nine of 11 patients who developed EBV PTLD were treated with rituximab (anti-CD20 antibody), with the 5 responders being alive and disease free at a median of 26 months. Use of ATG in recipients of an NMA preparative regimen warrants close monitoring for evidence of EBV reactivation and potentially preemptive therapy with rituximab.

EBV Kidney Allograft Infection: Possible Relationship with a Peri-Graft Localization of PTLD

Post-transplant lymphoproliferative disorder (PTLD) is a grave complication of transplantation and the result of uncontrolled proliferation of B lymphocytes infected with Epstein-Barr virus (EBV). Herein we assess whether EBV infects renal grafts and whether there is a relationship between EBV kidney infection and PTLD. Allograft biopsies from 23 patients with PTLD were studied for the presence of EBV DNA and RNA (EBER-1, -2) by in situ hybridization and for CD21 by immunohistochemistry. Results were compared to 43 transplants from people without PTLD. EBV DNA and RNA were detected in 11/43 patients without PTLD (26%), and in 15/23 (65%) patients with PTLD (p = 0.004). EBV DNA and RNA localized to proximal tubular cells and these cells showed up-regulation of the EBV receptor CD21. EBV-infected allografts were noted in 12/12 patients with PTLD located near the allograft and in 3/11 (27%) of patients with PTLD distant from the graft. Multiple biopsies in eight patients showed that graft EBV infection can precede the diagnosis of PTLD by as long as 42 months. It is concluded that EBV can infect kidney allografts, and there appears to be a relationship between this infection and the presence of PTLD near the graft.

Lymphoproliferative disorders in heart transplant recipients: role of hepatitis C virus (HCV) and Epstein-Barr virus (EBV) infection

Abstract Post-transplant lymphoproliferative disorders (PTLD) are a well known complication after orthotopic heart transplantation (OHT). Although Epstein-Barr virus (EBV) infection has long been implicated in the pathogenesis of such disorders, other factors may play a part. Because of its lymphotropic properties, hepatitis C virus (HCV) may induce clonal expansion of B-lymphocytes and lead to PTLD. The aim of this study was to evaluate the potential association between HCV and EBV infection and PTLD in OHT patients. The retrospective study considered 404 adult patients screened for HCV. EBV serology, histology, and molecular analysis on tissue biopsies were performed in the PTLD patients (10/404, 2.5%). HCV positivity was found in 36/404 (8.9 %) patients. The EBV genome was expressed on all neoplastic tissue samples analyzed. A higher proportion of HCV-positive patients developed PTLD than the HCV-negative cases (8 % vs 2%, P = 0.017). EBV has a demonstrated role in the onset of PTLD, but HCV infection probably has to be considered as well.

Lymphoproliferative disorders in heart transplant recipients: role of hepatitis C virus (HCV) and Epstein-Barr virus (EBV) infection.

Post-transplant lymphoproliferative disorders (PTLD) are a well known complication after orthotopic heart transplantation (OHT). Although Epstein-Barr virus (EBV) infection has long been implicated in the pathogenesis of such disorders, other factors may play a part. Because of its lymphotropic properties, hepatitis C virus (HCV) may induce clonal expansion of B-lymphocytes and lead to PTLD. The aim of this study was to evaluate the potential association between HCV and EBV infection and PTLD in OHT patients. The retrospective study considered 404 adult patients screened for HCV. EBV serology, histology, and molecular analysis on tissue biopsies were performed in the PTLD patients (10/404, 2.5%). HCV positivity was found in 36/404 (8.9%) patients. The EBV genome was expressed on all neoplastic tissue samples analyzed. A higher proportion of HCV-positive patients developed PTLD than the HCV-negative cases (8% vs 2%, P = 0.017). EBV has a demonstrated role in the onset of PTLD, but HCV infection probably has to be considered as well.