Early-onset Post-transplant Lymphoproliferative Disorder Research Articles

Non-invasive monitoring associated with B lymphoma cells in post-transplant lymphoproliferative disorder (PTLD) patients: Systematic review.

One of the most severe side effects of solid-organ transplantation is posttransplant lymphoproliferative disease (PTLD). People with human immunodeficiency virus infection (HIV), an immunosuppressive disease comparable to HIV, have a higher chance of developing lymphoma when their peripheral blood contains elevated levels of the immunoglobulins kappa and lambda free light chains (FLCs). This systematic review's objective was to monitor associated B lymphoma cells in PTLD patients. In order to find relevant studies published between 1/1/2000 and 1/9/2022, two independent researchers conducted searches (MT, AJ). A literature search of English language publications was conducted using MEDLINE through PubMed, EMBASETM through Ovid, the Cochrane Library, and Trip. In addition to Magiran and SID, we searched KoreaMed and LILACS for literature published in other languages. sFLC or PTLD, transplant, or Electrophoresis are terms used in the search strategy. A total of 174 studies were selected. After analyzing their correspondence with the required criteria, a final review of five studies was conducted. The manuscript presents current findings on the potential benefits of the clinical applicability of sFLCs in PTLD. While the preliminary results appear promising, the only consistent result is that early-onset PTLD is predicted within the first two years after transplant, a biomarker that could be used to diagnose the condition. Therefore, PTLD has been predicted by using the sFLCs. There have been contradictory results to date. Future research could include assessing the quantity of sFLCs and their quality in transplant recipients. In addition to PTLD and complications after transplantation, sFLCs may provide insight into other diseases. To confirm the validity of sFLCs, more studies are needed.

Short-term decreased post transplant lymphoproliferative disorder risk after kidney transplantation using two novel regimens

BackgroundBelatacept is employed alongside calcineurin inhibitor (CNI) therapy to prevent graft rejection in kidney transplant patients who are Epstein-Barr virus (EBV) seropositive. Preliminary data suggested that rates of post-transplant lymphoproliferative disorder (PTLD) were higher in individuals treated with belatacept compared to CNI therapy alone. MethodsThe records of 354 adults who underwent kidney only transplantation from January 2015 through September 2021 at one medical center were evaluated. Patients underwent treatment with either low-doses of mycophenolate, tacrolimus and sirolimus (B0, n = 235) or low-doses of mycophenolate, tacrolimus and belatacept (B1, n = 119). All recipients underwent induction with antithymocyte globulin and a rapid glucocorticosteroid taper. Relevant donor and recipient information were analyzed and endpoints of PTLD were assessed. ResultsThere were no cases of PTLD in either cohort within the study period. Recipients in the belatacept cohort experienced lower estimated glomerular filtration rates at 12 months (B0: 67.48 vs. B1: 59.10, p = 0.0014). Graft failure at 12 (B0: 1.28% vs. B1: 0.84%, p = 1.0) and 24 months (B0:2.55% vs. B1: 0.84%, p = 0.431) were similar. There was no difference in rejection rates at 12 (B0: 1.27% vs. B1: 2.52%, p = 0.408) or 24 months (B0: 2.12% vs. B1: 2.52%, p = 1.000). Both groups had similar rates of malignancy, mortality and CMV/BK viremia. ConclusionNon-belatacept (MMF, tacrolimus and sirolimus) and belatacept-based (MMF, tacrolimus and belatacept) regimens do not appear to pose any increased risk of early onset PTLD. Both cohorts benefited from low rates of rejection, malignancy, mortality and graft failure. Recipients will continue to be monitored as PTLD can manifest as a long-term complication.

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

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

TREATMENT AND OUTCOMES OF PATIENTS WITH POST‐TRANSPLANT LYMPHOPROLIFERATIVE DISORDER: A SINGLE CENTRE EXPERIENCE

Background: Post-transplant lymphoproliferative disorder (PTLD) is a potentially severe complication that takes place after solid (SOT) or allogeneic hematopoietic stem cell transplant (HSCT). To date, its treatment is not standardised, and choice of therapy depends on histology and clinical presentation. We report the results of a 10 years (yrs) single-centre retrospective study assessing presentation, treatment patterns and outcomes of patients with PTLD. Methods: Patients ≥18 yrs diagnosed with a PTLD between 2011 and 2020 were identified in our medical records database. Primary endpoints were 2 yrs progression-free survival (PFS), overall survival (OS), and relapse incidence (RI) estimated with Kaplan-Meier and comparison between HSCT and SOT group. Secondary endpoints were the overall response rate (ORR) and complete response rate (CRR) at the end of first line treatment. Exploratory univariate analysis for OS, PFS were investigated using Cox regression model. Results: A total of 38 patients were included. Patient's characteristics and treatment strategies are presented in Table 1. HCST patients present a significantly higher prevalence of early onset PTLD (90% in HCST group vs 0% in SOT group), positive EBER immunostaining (100% vs 22%) and detectable Epstein Bar Virus (EBV) viremia (100% vs 28%), higher LDH (95% vs 66%), IPI score 3-5 (50% vs 33%), with a remarkable higher use of single agent Rituximab as first line therapy in HSCT patients (65% vs 11%). 2 yrs PFS was 54% (95%CI 36-73%) for the entire cohort, 42% (95%CI 16-67%) for HSCT and 67% (95%CI 41-92) for SOT; p-value 0.23. 2 yrs OS was 53% (95%CI 41-66%) for the entire cohort, 42% (95% CI 16-67%) for HSCT and 65% (95% CI 39-91) for SOT; p-value 0.22. 2 yrs RI was 9% (95% CI: 0-21%) for the entire cohort, 0% for HSCT and 14% (95% CI 0-33%) for SOT; p-value 0.26. ORR and CRR were similar with 82% (75% for HSCT, 89% for SOT, p-value 0.41) at the end of first line treatment. High IPI score (3-5) demonstrated worse outcome for PFS (HR: 2.5, 95%CI 0.95-6.65, p-value 0.063) and OS (HR: 2.4, 95%CI 0.92-6.48, p-value 0.07). A total of 17 patients died during follow-up: 7 during first line treatment of PTLD complication and multiorgan failure (5 in the HSCT group, 2 in the SOT group; p-value 0.41); 2 following PTLD relapse after first CR (0 in the HSCT group, 2 in the SOT group; p-value 0.22). Conclusion: This study highlights the clinical and therapeutic heterogeneity of PTLD. We observe a worse 2 yrs PFS and OS in patients with high IPI score. CRR after first line treatment is almost 90% in the SOT group, with a 2 yrs OS of 53%, consistent with previous studies (Trappe et al, JCO 2017). The higher mortality observed in the HSCT group suggests that serious treatment-related toxicities remain main challenges in this fragile patient population. New tools to guide therapeutic approaches in PTLD patients are warranted. Keywords: Lymphoid Cancers - Other No conflicts of interests pertinent to the abstract.

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.

Serum free light chains in solid organ transplant recipients.

Immunoglobulin is built by a pair of identical heavy and a pair of identical light chains. Light chains are produced in excess compared to heavy chains. Free light chains (FLCs) are those which are not combined with heavy chains. Currently, numerous assays are available for the measurement of serum FLCs (sFLCs). These assays cannot be used interchangeably, and renal function should be taken into account in interpreting test results. Levels of kappa and lambda sFLCs are usually used to diagnose and monitor plasma cell dyscrasias. However, the clinical relevance of sFLCs is being investigated in patients with a variety of diseases, including patients after transplantation. There are contradictory results regarding the usefulness of sFLCs in the prediction of post-transplant lymphoproliferative disorder (PTLD). However, it seems that sFLCs may be helpful in the prediction of early-onset PTLD. Some studies have shown that low levels of sFLCs are associated with a higher risk of infection in patients after transplantation. This review summarizes and highlights recent advances in the utility of sFLCs in the prediction of PTLD and infection, and inflammation assessment in patients after solid organ transplantation. Moreover, the influence of immunosuppressive treatment on sFLCs levels is described briefly.

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.

Small Bowel Perforation as the Initial Manifestation of Post-Transplant Lymphoproliferative Disorder in a Kidney and Pancreas Transplant Recipient: A Case Report

Post-transplant lymphoproliferative disorder (PTLD) comprises a broad spectrum of diseases and is a rare but serious complication of solid organ transplantation. We report the case of a 45-year-old simultaneous pancreas and kidney (SPK) transplant recipient with diffuse, early-onset PTLD, manifesting as jejunal perforation at 6 months after transplantation. The patient underwent urgent small bowel resection of the affected portion of jejunum. The surgical pathology report was significant for diffuse large B-cell lymphoma. Subsequently, the patient underwent a full workup, including upper and lower endoscopy and whole-body positron emission tomography that revealed involvement of the axial skeleton and multiple abdominal organs with sparing of the grafts. He was treated with rituximab and intrathecal methotrexate for central nervous system prophylaxis. The patient experienced complete resolution of disease by positron emission tomography 8 months after initial presentation. We found no previous report in the literature of intestinal perforation as the initial presentation of PTLD in SPK transplant recipients.

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.

EBV-MEDIATED POSTTRANSPLANT LYMPHOPROLIFERATIVE DISORDER PRESENTING AS A PLEURAL EFFUSION AND ACUTE CELLULAR REJECTION: A CASE REPORT

SESSION TITLE: Tuesday Fellows Case Report Posters SESSION TYPE: Fellow Case Report Posters PRESENTED ON: 10/22/2019 01:00 PM - 02:00 PM INTRODUCTION: Post-transplant lymphoproliferative disorder (PTLD) is a rare complication following adult lung transplantation, but carries a three-fold increase in the risk of death compared to non-sufferers (1). Described manifestations of PTLD include lung nodules & infiltrates, thoracic adenopathy, GI involvement and CNS mass lesions (2). CASE PRESENTATION: A 59 year-old male with a history of cystic fibrosis underwent bilateral lung transplantation for progressive hypoxic respiratory failure needing VV-ECMO; he suffered no significant complications until he developed fatigue and a 600mL drop in FEV1 two months post-transplant. A right lung opacity was found on CXR; he received antibiotics for pneumonia, but his symptoms persisted. Chest CT demonstrated mediastinal and hilar lymphadenopathy, and a large right sided effusion (Image 1). Flow cytometry on pleural fluid obtained from thoracentesis showed kappa-light-chain restricted plasmacytic cells, consistent with PTLD. An EBV PCR returned positive (584cpy/mL). He underwent bronchoscopy with transbronchial lung biopsy, endobronchial ultrasound-guided transbronchial lymph node sampling and tunneled pleural catheter placement for recurrent effusion. Pleural fluid again showed plasmacytoid cells. The transbronchial biopsy showed perivascular mononuclear cell infiltrates with endothelialitis and septal extension, concerning for grade A3 rejection. His EBV viremia worsened (2660cpy/mL). After a multidisciplinary discussion, it was decided his pathologic findings were due to PTLD; he was treated with reduction of immunosuppression and four weeks of rituximab. After the first dose, his EBV load dropped by almost half, and his FEV1 recovered. After four doses, his serum EBV was undetectable, and repeat CT showed near-resolution of the adenopathy (Image 2). DISCUSSION: Cystic fibrosis patients are at higher risk for PTLD, likely because they are younger at transplant and therefore tend to be EBV seronegative when transplanted (3). Adult EBV seropositivity is pervasive, and lung tissue is lymphoid-rich (2); transplanted lungs may carry a high load of infected B-cells to the recipient, who then receive therapies to suppress host immunity (including cytotoxic T-cells that check the infected lytic-phase B-cells which perpetuate infection) (2). While treatments differ by center, the anti-CD20 monoclonal antibody rituximab is often used to deplete B-cells, in tandem with reducing immunosuppression (2). Remission rates range from 52-66%, with better outcomes for early-onset PTLD and EBV positive patients (2). CONCLUSIONS: Our patient was unique in manifesting with a pleural effusion as a primary site of his PTLD, though he also had lymphadenopathy that regressed with therapy. While older and a cystic fibrosis patient, he had positive prognostic factors (early presentation, EBV-positivity), and ultimately had a good outcome from rituximab and reduced immunosuppresion. Reference #1: Zaffiri L, Neely M, Cherikh W, et al. Incidence and Outcomes of Post-lymphoproliferative Disorder in Lung Transplant Recipients. Analysis of the ISHLT Registry. J Heart Lung Transplant 2018; 37(4): S450. Reference #2: Green M and Michaels MG. Epstein-Barr Virus Infection and Posttransplant Lymphoproliferative Disorder. Am J Transplant 2013; 13: 41-45. Reference #3: Lowery EM, Adams W, Grim SA, et al. Increased risk of PTLD in lung transplant recipients with cystic fibrosis. J Cyst Fibrosis 2017; 16: 727-734. DISCLOSURES: No relevant relationships by Luis Angel, source=Web Response No relevant relationships by Melissa Lesko, source=Web Response No relevant relationships by Sunil Nair, source=Web Response

Post-transplant lymphoproliferative disorder presenting on post-transplant Day 35 as a pulmonary parenchymal infiltrate—a case report

Post-transplant lymphoproliferative disorder (PTLD), a rare but serious complication of solid organ transplantation, is classified into early-onset and late-onset subtypes. Early-onset PTLD occurs a median of 4–11 months after lung transplantation. It rarely presents in the first 2 months post-transplant. Early-onset PTLD usually presents as a solitary pulmonary nodule. We present a unique case of early-onset PTLD that was diagnosed on post-operative Day 35 and presented as a pulmonary parenchymal infiltrate. This case is also exceptional in that the patient had a significant clinical response to only a single dose of rituximab.

Systematic review and meta-analysis of post-transplant lymphoproliferative disorder in lung transplant recipients.

A systematic review of papers in English on post-transplant lymphoproliferative disorder (PTLD) in lung transplant recipients (LTR) using MEDLINE, EMBASE, SCOPUS, and Cochrane databases was performed. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) recommendations were strictly adhered to. Pooled odds ratios (pOR) were calculated from a random-effects model, and heterogeneity among studies was quantitated using I2 values. Fourteen studies published from 2005 to 2015 were included in the meta-analysis. One hundred and sixty-four lung transplant recipients were included. LTRs who received single vs bilateral were associated with a 7.67-fold risk of death after PTLD (6 studies with 64 LTRs; pOR 7.67 95% CI 1.98-29.70; P=.003). pOR of death for early onset PTLD (<1year post-LT) vs late onset (>1year post-LT) was not different (3 studies with 72 LTRS; pOR 0.62, 95% CI 0.20-1.86, P=.39). Standardized mean difference (SMD) in time from transplant to PTLD onset between LTRs who died vs alive was not different (9 studies with 109 LTRs; SMD 0.03, 95% CI -0.48-0.53, P=.92). Survival in polymorphic vs monomorphic PTLD and extranodal vs nodal disease was similar (4 studies with 31 LTRs; pOR 0.44, 95% CI 0.08-2.51; P=.36. 6 studies with 81 LTRs; pOR 1.05 95% CI 0.31-3.52, P=.94). This meta-analysis demonstrates that single LTRs are at a higher risk of death vs bilateral LTRs after the development of PTLD.

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.

Unilateral Facial Swelling as a Sign of Post-Transplant Lymphoproliferative Disorder: A Case Series

Introduction: Post-Transplant Lymphoproliferative Disorder (PTLD) is an unfortunate but increasingly common complication in the transplant era, occurring in up to 20% of post-transplant patients. PTLD has a strong association with Epstein-Barr Virus (EBV) and commonly presents with fatigue, fever, pharyngitis, and lymphadenopathy. It rarely manifests in the head, neck and oral cavity. We present two post-transplant patients who reported unilateral facial swelling leading to a diagnosis of PTLD. Case Description: Case 1: This is a 48 year old female with past medical history of orthotopic liver transplant due to cirrhosis from biliary hypoplasia 7 months prior who presented with left-sided facial swelling and fevers. Examination showed left buccal mucosa edema and a purulent left palate lesion. Urgent surgical exploration showed a polypoid necrotic mass infiltrating the left maxilla and palate; pathology showed monomorphic B-cell lymphoproliferation. Her course was complicated by EBV and cytomegalovirus (CMV) viremia. She was treated with ganciclovir, started on rituximab for PTLD and responded well. Case 2: This is a 60 year old female with a past medical history of living unrelated donor kidney transplant due to polycystic kidney disease 9 years prior, who presented with right-sided facial swelling. She was treated with Augmentin for presumed cellulitis, however did not improve. She then presented to Otorhinolaryngology outpatient and underwent right cheek biopsy. Pathology showed diffuse large B-cell lymphoma. She was started on R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) for PTLD and responded well. Discussion: PTLD can occur in up to 20% of post-transplant patients. Risk factors for early-onset PTLD include seronegative EBV status, type of transplantation, young age at transplantation, Caucasian population, and CMV viremia. As shown, Case 1 had EBV and CMV viremia however Case 2 was EBV- and CMV-seronegative. Most commonly, PTLD presents with non-specific or gastrointestinal symptoms. In one study, PLTD in the head and neck comprised only 6% of the study population, and there have only been case reports detailing oral and gingival lesions as well as skin lesions. Although the mortality of PLTD can be as high as 60%, early detection will lead to improved survival. We postulate that post-transplant patients with unilateral facial swelling should be further evaluated for PTLD.

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.

Posttransplant Lymphoproliferative Disorders in Irish Renal Transplant Recipients: Insights From a National Observational Study.

Posttransplant lymphoproliferative disorders (PTLD) are a common malignancy after renal transplantation with a high incidence of PTLD described in the first posttransplant year. We sought to determine incidence and risk determinants of PTLD in Irish kidney transplant recipients. Retrospective observational study of 1996 adult first kidney transplant recipients between 1991 and 2010 in the Republic of Ireland. Recipients were cross-referenced with the National Cancer Registry to determine incidence of PTLD. Kaplan-Meier analysis was performed for PTLD-free survival, allograft survival, and patient survival after PTLD. Cox proportional hazards models were used to identify independent risk factors for PTLD in our population. We identified 31 cases of PTLD during the study period. Histological subgroups included: early lesions (n = 1); polymorphic PTLD (n = 1); monomorphic PTLD (n = 27), Hodgkin disease (n = 2). Median time to PTLD diagnosis was 8.3 (range, 1.2-13.9) years. Cumulative incidence (95% CI) of PTLD at 1, 2, 3, 5, 10, and 15 years was 0%, 0.16% (0.05-0.5%), 0.21% (0.08-0.57%), 0.21% (0.08-0.57%), 1.76% (1.15-2.69%), and 3.07% (2.1-4.43%), respectively. Allograft survival after PTLD diagnosis was 94.4% (66.6-99.2%) at 5 years. Patient survival after PTLD diagnosis was 64% at 1 year, 53% at 2 years, 48% at 5 years, and 37% at 10 years. No risk factors for PTLD were identified. We found a paucity of early onset PTLD in our cohort with no cases in the first posttransplant year. Potential contributing factors included a high prevalence of previous Epstein-Barr virus exposure and a relatively low immunological risk profile in our recipient cohort compared with prior studies. Further studies are required to reevaluate the epidemiology of PTLD in the modern era of transplant immunosuppression.

Post-Transplant Lymphoproliferative Disorders in Transplant Recipients: 14-Yr Experience at the Hospital Israelita Albert Einstein - Brazil

Introduction: The number of patients who have undergone organ and bone marrow transplantation continues to increase, as does long-term survival. Post-transplant lymphoproliferative disorders (PTLD) are potentially life-threatening complications after solid organ transplantation. Epstein-Barr virus (EBV) infection that leads to uncontrolled B cell proliferation and tumor formation. PTLD is relatively common malignancy after transplantation and is seen up to 10% of all solid organ transplant recipients, and varies considerably among the different types of organs transplanted. We sought to determine incidence and mortality risk of PTLD in recipients of Hospital Israelita Albert Einstein, Sao Paulo, Brazil.Patient and Methods: We conducted a retrospective observational study of 3006 recipients of lung, kidney, liver, pancreas, heart and bone marrow between 2002 and 2015. A total of 26 cases (0.8%) of PTLD were identified in 3006 transplants. Kaplan-Meier analysis was performed for PTLD patient survival after PTLD.Results: Median interval from transplantation to diagnosis was 49 (4-150) months. Median age was 49 years (12-73) and 73% were men. Histological subgroups included: Monomorphic PTLD (50%), Hodgkin Lymphoma (11,5%), Burkitt (15,3%), Anaplastyc large cell (7,6%) and Plasmacytic Hyperplasia (15,3%). Sixteen patients (61,5%) were EBV (+) and eleven (42,3%) were IPI III-IV only two had bone marrow infiltration. Treatment of PTLD varied according to stage and clinical circumstances: six patients (23%) were treated with Rituximab only and seventeen (65,3%) treated with R-chemotherapy. Nine (34,6%) patients died. Changing immunosuppression (IS) from calcineurin inhibitor to sirolimus at the time of diagnosis may have improved survival, since 5 patients remain alive. The median overall survival was 1260 days, and 2-years overall survival was 65,4%.Conclusion: PTLD after solid organs transplantation remains a challenge as a result of its frequency, complexity and disappointing outcome. We found a paucity of early onset PTLD in our cohort with only one case in the first posttransplant year. Potential contributing factors included a high prevalence of previous EBV virus exposure. The rate of PTLD malignancies in our group is comparable to that reported in other centers in Europe and North American, since it is the largest series reported by a single institution in South America. Consistent with the known antiproliferative effect of sirolimus, switching IS from calcineurin inhibitor to sirolimus may improve survival. DisclosuresNo relevant conflicts of interest to declare.

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.

A meta-analysis of potential relationship between Epstein-Barr-Encoded-RNA (EBER) and onset time of post-transplant lymphoproliferative disorders.

Epstein-Barr virus (EBV) encodes two non-polyadenylated RNAs termed EBV-encoded RNAs (EBERs). In this study, we tried to find series in which data of EBER and onset time of post-transplant lymphoproliferative disorder (PTLD) for patients have been documented to conduct a meta-analysis. A comprehensive search of the literature was performed by Pubmed and Google scholar to find reports indicating test results for EBER and PTLD onset in transplant patients. PTLD was considered "early onset" when it develops within the first post-transplant year. Finally, 265 patients from 15 studies have been included in the meta-analysis. The overall meta-analysis also showed a significant relation between EBER test positivity and early-onset PTLD development [relative risk (RR): 1.36; 95% CI: 1.16-1.59; P <0.001]. The i2 index was 49.8%. Our study suggests that PTLD lesions with positive EBER test are more likely to develop within the early post-transplant period. Since early-onset PTLD is supposed to have better prognosis, having a positive EBER test might not be a bad news. However, for having a precise conclusion, prospective studies are needed to be conducted.

In vivo intratumoral Epstein–Barr virus replication is associated with XBP1 activation and early-onset post-transplant lymphoproliferative disorders with prognostic implications

Post-transplant lymphoproliferative disorders are life-threatening complications following hematopoietic or solid organ transplantation. They represent a spectrum of mostly EBV-driven lymphoplasmacytic proliferations. While the oncogenic effect of EBV is related to latent infection, lytic infection also has a role in lymphomagenesis. In vitro, EBV replication is linked to plasma cell differentiation and XBP1 activation, although this phenomenon has never been addressed in vivo. We analyzed for the first time latent and lytic intratumoral EBV infection in a series of 35 adult patients with a diagnosis of post-transplant lymphoproliferative disorder (26M/9F, median age 54 years). A complete EBV study was performed including the analysis of the latent EBER, latent membrane protein-11, and EBV nuclear antigens as well as the immediate-early BZLF1/ZEBRA and early BMRF1/EADE31 lytic genes. XBP1 activation was assessed by nuclear protein expression. EBV infection was observed in 28 (80%) cases being latency II and III the most frequently observed 22 (79%). Intratumoral EBV replication was detected in 17 (60%) cases. Among these, XBP1 activation was observed in 11/12 evaluable cases associated with strong cytoplasmic immunoglobulin expression consistent with plasma cell differentiation. Intriguingly, the combination of latency III infection and EBV replication identified a high-risk subgroup of patients with significantly shorter survival (overall survival at 1 year 18% vs 48%) and early-onset (median of 7 vs 26 months) post-transplant lymphoproliferative disorder. Moreover, these patients appear to be more heavily immunosuppressed, so they exhibit lower rates of rejection and graft vs host disease but higher rates of cytomegalovirus reactivation. In conclusion, EBV replication is associated with plasma cell differentiation and XBP1 activation with prognostic implications. Both latency III and lytic EBV infection are related to aggressive and early-onset post-transplant lymphoproliferative disorder. These results suggest that immunohistochemical study of latent and lytic EBV genes in the clinical practice may help to select higher-risk patients to new therapies including antiviral treatments.