EBV-associated Lymphoproliferative Disorders Research Articles

Antitumor activity of cyclin-dependent kinase inhibitor alsterpaullone in Epstein-Barr virus-associated lymphoproliferative disorders.

Epstein‐Barr virus (EBV) is a well‐established tumor virus that has been implicated in a wide range of immunodeficiency‐associated lymphoproliferative disorders (LPDs). Although rituximab, a CD20 mAb, has proven effective against EBV‐associated LPDs, prolonged use of this drug could lead to resistance due to the selective expansion of CD20− cells. We have previously shown that cyclin‐dependent kinase (CDK) inhibitors are able to specifically suppress the expression of viral late genes, particularly those encoding structural proteins; however, the therapeutic effect of CDK inhibitors against EBV‐associated LPDs is not clear. In this study, we examined whether CDK inhibitors confer a therapeutic effect against LPDs in vivo. Treatment with alsterpaullone, an inhibitor of the CDK2 complex, resulted in a survival benefit and suppressed tumor invasion in a mouse model of LPDs. Inhibition of CDK efficiently induced G1 cell cycle arrest and apoptosis in EBV‐positive B cells. These results suggest that alsterpaullone suppresses cell cycle progression, resulting in the antitumor effect observed in vivo.

Genomic Characterization of a Pediatric Cohort with Non-Malignant Lymphoproliferative Disorders

Introduction: Pediatric non-malignant lymphoproliferative disorders (LPDs) are a clinically and genetically heterogeneous. While transient lymphadenopathy is extremely common and rarely dangerous, long-standing immune dysregulation and lymphoproliferation in children may be life-threatening. Data to guide evaluation and treatment of children with benign LPD are lacking. The primary objective of this study was to define the genomic spectrum and clinical characteristics of a cohort of children with nonmalignant LPD. Identification of the underlying pathogenic mechanisms may facilitate timely interventions and potentially guide optimal therapeutic strategies. Method s: Patients at Texas Children's Hospital and collaborating referral centers who met criteria for non-malignant LPD were offered participation in this study, approved by the Baylor College of Medicine Institutional Review Board. LPD was defined as persistent lymphadenopathy, lymph organ involvement, or lymphocytic infiltration for more than 3 months, with or without chronic or significant EBV infection. Chronic or significant EBV infection was defined as recurrent or persistent EBV viremia more than 3 months, invasive EBV disease, or EBV PCR copies >100,000. All subjects and/or family members provided written informed consent to have their clinical and genetic information published. Genetic testing was performed clinically or through research-based whole-exome sequencing (WES). Results : Fifty-one subjects from 47 different families with non-malignant LPD were identified. Median age at disease presentation was 3.3 years (range 3.9 weeks - 21 years) with nearly equal proportions of males (n = 26) and females (n = 25). Almost half of subjects were Hispanic (49%), and 29% were non-Hispanic white. Fifteen subjects (29%) met HLH-2004 diagnostic criteria for HLH. Twenty-one patients had EBV-associated lymphoproliferative disorders (EBV-LPD) and 6 of the 51 ultimately developed malignancy. Clinical genetic testing was performed in 29 patients, and research-based WES was performed in 44 patients. Potential disease-causing genetic defects were identified in 62% of families. Of these pathogenic variants, targeted therapies may be effective for treatment in at least 10 of the conditions (17 subjects, 33%). Furthermore, genetic results supported potential for curative HSCT in 35% of the patients. Mechanistically, all of the LPD-associated genes could be placed into 1 of 3 categories: 1) defective control of lymphocyte activity; 2) impaired lymphocyte activation, cytoskeletal organization, and apoptosis; and 3) dysregulated inflammation. Ten-year survival for the entire cohort was 72.4% with a median 5.6 years of follow-up (range 0.10 - 26.6). Patients without evidence of a genetic explanation had a lower ten-year survival compared to those patients for whom a genetic explanation was identified (48% versus 82%, respectively, p=0.03). When both EBV-LPD and genetic explanation were considered, the ten-year survival estimate for those with EBV-associated disease and no genetic explanation was significantly worse than those with EBV-associated disease and a genetic explanation (17% vs. 90%; p =0.002). Patients without EBV-associated disease were at lower risk of death than those with EBV-LPD. Evaluating outcomes associated with maximum treatment received, ten-year survival was lowest (25% survival) among those who underwent HSCT. Conclusion s: Pediatric non-malignant LPD represents a group of conditions with high risk of death. WES identified actionable mutations in the majority of LPD cases in this cohort. Early identification of these mutations can guide therapy by confirming diagnosis, revealing molecular targets and/or supporting definitive therapy with stem cell transplant. Disclosures Forbes: Takeda: Consultancy. Jolles:CSL Behring: Consultancy, Honoraria, Research Funding, Speakers Bureau; LFB: Consultancy, Honoraria, Research Funding, Speakers Bureau; UCB Pharma: Consultancy, Other: Drug Safety Committee; Shire/Takeda: Consultancy, Honoraria, Research Funding, Speakers Bureau; Pharming: Consultancy, Honoraria, Research Funding, Speakers Bureau; Octapharma: Consultancy, Honoraria, Research Funding, Speakers Bureau. Heslop:Marker Therapeutics: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Allovir: Equity Ownership; Gilead Biosciences: Membership on an entity's Board of Directors or advisory committees; Kiadis: Membership on an entity's Board of Directors or advisory committees; Tessa Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Cell Medica: Research Funding. Rouce:Novartis: Consultancy, Honoraria; Tessa Therapeutics: Research Funding; Kite, a Gilead Company: Consultancy, Honoraria.

Novel Immune Checkpoint Deficiency and Susceptibility to EBV-Associated Lymphoma

Background: Understanding genetic predisposition to cancer is of paramount importance to tailor therapeutic strategies. Several defects in immune checkpoint regulators have been discovered in patients with EBV-induced lymphoma (e.g. CD27, PRKCD, RASGRP1, MAGT1, SH2D1A, ITK). Here, we describe the clinical and immune phenotype of 2 unrelated patients from consanguineous families presenting with a primary immune deficiency (PID) and EBV-associated lymphoproliferation due to biallelic mutations in CD137 (TNFRSF9/4-1BB). Methods: One patient of Turkish origin (P1) and Palestinian origin (P2), respectively were evaluated. Genetic analysis using whole exome sequencing was conducted. Immunological and biochemical assays were performed on primary patient material. Results: Clinical findings included recurrent sinopulmonary and herpes virus infections from childhood on. One patient suffered from auto-immunity (AIHA and auto-immune thrombocytopenia). Abnormal immunoglobulin levels were documented (IgG 413-1670, IgM 105-714, IgA 49-68 mg/dL). Both patients developed EBV-associated lymphoproliferative disorders: P1 developed Burkitt lymphoma and was treated according to NHL-BFM2000 regimen in combination with rituximab. He is currently in remission. P2 had monoclonal EBV-positive lymphoproliferation and was successfully treated with immunosuppressive therapy (e.g. cellcept, glucocorticoids). To shed light on the underlying genetic etiology, we performed whole exome sequencing. A large homozygous deletion in CD137 (c.1_545+1716del) was identified for P1, while P2 harbored a homozygous missense mutation (c.C452T, p.Thr151Met). Impaired anti-CD3 T cell lymphocyte activation and proliferation were observed, amenable to correction upon addition of anti-CD28 monoclonal antibodies. In an attempt to provide definitive proof that the CD137 gene variant causes the activation defect of T-cells, we designed a genetic rescue experiment in patient T cells. Upon retrovirus-mediated recombinant expression of WT CD137, proliferation and activation defects in T cells were restored. Conclusions: In sum, we here show that a genetic defect in the immune checkpoint molecule CD137 causes a new primary immunodeficiency disorder with susceptibility to EBV-induced lymphomagenesis. Disclosures No relevant conflicts of interest to declare.

EBV-associated lymphoproliferative disorder involving the gastrointestinal tract which mimic IBD in immunocompetent patients: case reports and literature review

IntroductionEpstein-Barr virus (EBV)–associated lymphoproliferative diseases (LPD) with digestive tract involvement in immunocompetent patients is rather rare. Since the symptoms of EBV-associated LPD involving the gastrointestinal tract in immunocompetent patients are similar to those of inflammatory bowel disease (IBD), most patients are initially misdiagnosed.Case presentationIn this paper, we present two cases of EBV-associated T cell LPD involving the colon in immunocompetent patients and review the relevant literature.ConclusionEBV serological testing may help in detecting this disease, and our findings suggest that histopathological evidence of EBV, such as the Epstein-Barr encoding region, is very important to establish the diagnosis.

A Patient with Primary Immunodeficiency/Activated PI3Kdelta Syndrome, who Developed Epstein-Barr Virus-Associated Lymphoproliferative Disorder at the Age of 1 year and Malignant B Cell Lymphoma at the Age of 38 years

A Patient with Primary Immunodeficiency/Activated PI3Kdelta Syndrome, who Developed Epstein-Barr Virus-Associated Lymphoproliferative Disorder at the Age of 1 year and Malignant B Cell Lymphoma at the Age of 38 years

INCREASED SUSCEPTIBILITY TO HERPESVIRUS COMPLICATIONS IN PULMONARY FIBROSIS LUNG TRANSPLANT RECIPIENTS WITH SHORT TELOMERES

SESSION TITLE: Late Breaking Pulmonary Fibrosis SESSION TYPE: Original Investigations PRESENTED ON: 10/22/2019 08:45 AM - 09:45 AM PURPOSE: Idiopathic Pulmonary Fibrosis (IPF) is the leading indication for lung transplantation in North America, however transplant survival rates in this population lag behind all other end-stage lung diseases. Herpesvirus infectious complications are common causes of morbidity and mortality among lung transplant recipients (LTRs). We recently demonstrated that a high percentage of IPF lung transplant recipients (IPF-LTRs) have short lymphocyte telomere length (short TL) using flow cytometry and fluorescence in situ hybridization. Cytomegalovirus (CMV) infection continues to be one of the most common opportunistic infections in LTRs and is associated with chronic lung allograft dysfunction (CLAD). Epstein Barr virus (EBV)-associated post-transplant lymphoproliferative disorder (PTLD) is a herpesvirus transplant complication that is associated with significant mortality. METHODS: We performed retrospective outcomes analyses combined with genetic analyses in a single institution LTR cohort. RESULTS: We have shown that IPF-LTRs with short TL have increased susceptibility to CMV viremia and other CMV complications post-transplant, compared to age-matched non-IPF-LTRs (P < 0.01). In addition, we find that IPF-LTRs with short TL demonstrate impaired CMV-specific T cell immunity compared to non-IPF-LTRs. We evaluated a cohort of 611 LTRs at our institution from 2010-2016 for EBV-associated post-transplant lymphoproliferative disorder (PTLD) and found 28 cases of PTLD (4.6% incidence). Of these, 12/28 patients (43%) were IPF-LTRs and IPF was a risk factor associated with PTLD (Odds ratio: 2.9; 95% CI: 1.2-6.9; P<0.02). Kaplan Meier analyses demonstrated a significant decreased freedom from EBV-associated PTLD among IPF-LTRs (P<0.02), as well as decreased survival with PTLD in IPF-LTRs with PTLD (P<0.05). In addition, EBV mismatch (donor+/recipient-), a known risk factor for PTLD, carried an increased risk (Odds ratio: 6.9; 95% CI 2.3-20.9; P<0.001), while other factors such as male sex or age (risk factors for IPF) were not associated with increase risk for PTLD. Using both targeted exome sequencing and whole genome sequencing approaches, we found genetic mutations in either telomere or telomere-maintenance genes associated with the short telomere syndrome among both the CMV cohort and IPF-LTRs with EBV-PTLD. CONCLUSIONS: Together, these data highlight a predominance of short TL among current IPF-LTRs, along with increased susceptibility to herpesvirus complications in IPF-LTRs as manifestations of the short telomere syndrome. The identification of IPF-LTRs at increased risk for herpesvirus complications using telomere length and genome sequencing, may allow the development of clinical strategies to mitigate these post-transplant complications. CLINICAL IMPLICATIONS: Short telomeres are common in IPF LTRs. Stratification of risk for CMV and EBV-PTLD can advance strategies to mitigate adverse clinical outcomes. DISCLOSURES: No relevant relationships by Jonathan Alder, source=Web Response No relevant relationships by Stefanie Hannan, source=Web Response No relevant relationships by Carlo Iasella, source=Web Response No relevant relationships by Ritchie Koshy, source=Web Response No relevant relationships by John McDyer, source=Web Response No relevant relationships by Matthew Morrell, source=Web Response No relevant relationships by Seyed Mehdi Nouraie, source=Web Response No relevant relationships by Joseph Pilewski, source=Web Response No relevant relationships by Iulia Popescu, source=Web Response No relevant relationships by Pablo Sanchez, source=Web Response no disclosure on file for Fernanda Silveira; No relevant relationships by Spencer Winters, source=Web Response

Virome capture sequencing does not identify active viral infection in unicentric and idiopathic multicentric Castleman disease.

Castleman disease (CD) describes a spectrum of heterogeneous disorders defined by characteristic lymph node histopathology. Enlarged lymph nodes demonstrating CD histopathology can occur in isolation (unicentric CD; UCD) sometimes accompanied by mild symptoms, or at multiple sites (multicentric CD, MCD) with systemic inflammation and cytokine-driven multi-organ dysfunction. The discovery that Kaposi sarcoma herpesvirus/human herpesvirus (HHV)-8 drives MCD in a subset of patients has led to the hypotheses that UCD and MCD patients with negative HHV-8 testing by conventional methods may represent false negatives, or that these cases are driven by another virus, known or unknown. To investigate these hypotheses, the virome capture sequencing for vertebrate viruses (VirCapSeq-VERT) platform was employed to detect RNA transcripts from known and novel viruses in fresh frozen lymph node tissue from CD patients (12 UCD, 11 HHV-8-negative MCD [idiopathic MCD; iMCD], and two HHV-8-positive MCD) and related diseases (three T cell lymphoma and three Hodgkin lymphoma). This assay detected HHV-8 in both HHV-8-positive cases; however, HHV-8 was not found in clinically HHV-8-negative iMCD or UCD cases. Additionally, no novel viruses were discovered, and no single known virus was detected with apparent association to HHV-8-negative CD cases. Herpesviridae family members, notably including Epstein-Barr virus (EBV), were detected in 7 out of 12 UCD and 5 of 11 iMCD cases with apparent correlations with markers of disease severity in iMCD. Analysis of a separate cohort of archival formalin-fixed, paraffin-embedded lymph node tissue by In situ hybridization revealed significantly fewer EBV-positive cells in UCD and iMCD compared to tissue from HHV-8-positive MCD and EBV-associated lymphoproliferative disorder. In an additional cohort, quantitative testing for EBV by PCR in peripheral blood during disease flare did not detect systemic EBV viremia, suggesting detection lymph node tissue is due to occult, local reactivation in UCD and iMCD. This study confirms that HHV-8 is not present in UCD and iMCD patients. Further, it fails to establish a clear association between any single virus, novel or known, and CD in HHV-8-negative cases. Given that distinct forms of CD exist with viral and non-viral etiological drivers, CD should be considered a group of distinct and separate diseases with heterogeneous causes worthy of further study.

Opportunities to Target the Life Cycle of Epstein-Barr Virus (EBV) in EBV-Associated Lymphoproliferative Disorders.

Many lymphoproliferative disorders (LPDs) are considered “EBV associated” based on detection of the virus in tumor tissue. EBV drives proliferation of LPDs via expression of the viral latent genes and many pre-clinical and clinical studies have shown EBV-associated LPDs can be treated by exploiting the viral life cycle. After a brief review of EBV virology and the natural life cycle within a host we will discuss the importance of the viral gene programs expressed during specific viral phases, as well as within immunocompetent vs. immunocompromised hosts and corresponding EBV-associated LPDs. We will then review established and emerging treatment approaches for EBV-associated LPDs based on EBV gene expression programs. Patients with EBV-associated LPDs can have a poor performance status, multiple comorbidities, and/or are immunocompromised from organ transplantation, autoimmune disease, or other congenital or acquired immunodeficiency making them poor candidates to receive intensive cytotoxic chemotherapy. With the emergence of EBV-directed therapy there is hope that we can devise more effective therapies that confer milder toxicity.

Cutaneous Lymphoproliferative Disorders: What's New in the Revised 4th Edition of the World Health Organization (WHO) Classification of Lymphoid Neoplasms.

Cutaneous lymphoproliferative disorders remain a challenging aspect of dermatopathology, in part due to the rarity of the entities and extreme variability in clinical outcomes. Although many of the entities remain unchanged, the approach to some of them has changed in the new 2016 classification scheme of the World Health Organization. Chief among these are Epstein-Barr virus-associated lymphoproliferative disorders such as Epstein-Barr virus-associated mucocutaneous ulcer and hydroa vacciniforme-like lymphoproliferative disorder, primary cutaneous CD8+ aggressive epidermotropic cytotoxic T-cell lymphoma, primary cutaneous acral CD8+ T-cell lymphoma, primary cutaneous CD4+ small/medium T-cell lymphoproliferative disorder, and breast implant-associated anaplastic large cell lymphoma. In addition, translocations and gene rearrangements such as those involving the 6p25.3 locus have started to inform diagnosis and classification of anaplastic large cell lymphoma and lymphomatoid papulosis. In this review, we will examine what is new in the diagnostic toolbox of cutaneous lymphoproliferative disorders.

Evaluation of PD1/PDL1 Expression and Their Clinicopathologic Association in EBV-associated Lymphoproliferative Disorders in Nonimmunosuppressed Patients.

Epstein-Barr virus (EBV)-associated lymphoproliferative disorders (LPD)/lymphomas in nonimmunosuppressed patients represent a unique entity and have been proposed to be related to immune senescence. Engagement of programmed cell death 1 (PD1) by its ligand programmed death ligand 1 (PDL1) inhibits T-cell activation, and leads to T-cell exhaustion. In clinical trials, therapeutic antibodies that block the PD1-PDL1 axis have shown promising therapeutic activity in certain types of lymphomas. Although PD1/PDL1 has been extensively studied in variety of lymphomas, there are few reports characterizing their expression in EBV-positive LPD. As these group of patients are presumed to be associated with immunosenescence/immune dysregulation, we hypothesize that the immune checkpoint pathway might be relevant in this entity. We explored the expression of PD1, PDL1 and its clinicopathologic association in 6 patients with a total of 8 independent specimens of EBV-positive LPD/lymphomas. We also applied proximity assay, a novel technique, which can identify intermolecular interaction, to evaluate physical interaction or in situ engagement of PD1 and PDL1. We found that the malignant cells in the EBV-positive LPDs express PDL1. PD1-positive tumor-infiltrating lymphocytes can be seen in these tumors. Proximity assay suggests there is active engagement between PD1 and PDL1. To our knowledge, this is the first report on the utility of proximity assay to test the active engagement between PD1 and PDL1 in lymphomas. As some EBV-positive LPDs were positive for PDL1, this subgroup of EBV-positive LPDs might be suitable for PD1/PDL1 antibody therapies.

Inherited lymphoproliferative disorders

Lymphoproliferative disorders (LPDs) are caused by dysregulated lymphocyte proliferation and include polyclonal benign and monoclonal malignant diseases. LPDs frequently occur in immunocompromized patients, particularly those with primary immunodeficiency disease (PID), a monogenic disease. PID-associated LPD corresponds to inherited LPD. Here, we describe inherited LPD and focus on IKZF1-associated diseases and Epstein-Barr virus-associated LPD, such as ZAP70 deficiency and X-linked lymphoproliferative syndrome type 1 with somatic reversion mosaicism. Disclosing the pathogenesis of inherited LPDs would lead to a broad understanding of LPDs and development of new treatment strategies.

EBV-Associated Post-Transplantation B-Cell Lymphoproliferative Disorder in Patient after Allogenic Stem Cell Transplantation

Epstein-Barr virus (EBV)-associated B-cell post-transplantation lymphoproliferative disorder (PTLD) is a severe complication following solid-organ transplantation (SOT) and allogeneic hematopoietic stem cell transplantation (HSCT). We present a case of a 15-year-old male developing a monomorphic B-cell PTLD after receiving an allogenic stem cell transplant for acute acute myeloid leukemia. A diagnostic lymph node biopsy revealed monomorphic type, B cell phenotype, associated with Epstein-Barr virus, consistent with post-transplant lymphoproliferative disorder (PTLD). The morbidity and mortality of PTLD are high, and there is no standard protocol for treatment of PTLD. To prevent the occurrence of PTLD and early intervention are important for the prognosis of patients.

Randomized Trial of Two Dosages of Rabbit Antithymocyte Globulin in Patients with Aplastic Anemia

Randomized Trial of Two Dosages of Rabbit Antithymocyte Globulin in Patients with Aplastic Anemia

The First 100 Cases of Epstein-Barr Virus-Positive Mucocutaneous Ulcers

In 2016, the World Health Organization provisionally classified Epstein-Barr virus (EBV)-positive mucocutaneous ulcer (EBVMCU) as a lymphoid neoplasm under the subcategory of mature B-cell neoplasms. Here we describe a 59-year-old Chinese woman with a long history of recurrent sinus and oropharyngeal infections and was diagnosed initially with EBVMCU and later, diffuse large B-cell lymphoma (DLBCL). She had sought medical attention after a particularly long bout of increased facial pressure and nasal obstruction. As a young adult she had undergone a tonsillectomy, adenoidectomy, and received innumerable treatments for bronchiectasis and recurrent sinopulmonary infections. A sinus computerized tomography (CT) scan showed mucosal thickening and swellings of the left frontal posterior sinus. A subsequent 18fludeoxyglucose (18FDG) positron emission tomography (PET)-CT scan showed a large hypermetabolic mass (standardized uptake value [SUV] 30.6) centered in the left half of the nasopharynx and sinus processes and extending across the mid-line. She underwent an endoscopic turbinate reduction with removal of a polypoid soft-tissue mass. Immunohistochemical studies indicated large atypical lymphoid cells that stained positively for CD20, CD30, EBER-1, MUM-1, OCT-2, and PAX-5 and variably for BCL-6, CD15, CD45, and CD79a. The Ki-67 proliferation index was 100% in the atypical cells. Tissue blocks were reviewed locally and at the National Institute of Health and were felt to be most consistent with EBVMCU. She received 4000 cGy involved-field external-beam radiation therapy over 20 fractions. At completion of treatment, no residual abnormalities were identified and no additional adjuvant therapy was pursued.Three years later she presented to medical attention with shortness of breath and a non-productive cough. A PET-CT scan showed whiteout of the left lung and intense 18FDG uptake in a left perihilar nodule (SUV of 18). Bronchoscopy revealed many reactive polypoid bronchial wall masses and a complete collapse of the lower left lobe due to an obstructing mass. The left lower lobe intraluminal mass biopsies however showed EBV-positive DLBCL of non-germinal center phenotype. She received six cycles of conventional R-CHOP therapy (rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine, and prednisone) and 36 months later she remains cancer free but with persistent bronchial inflammatory nodules and recurrent infections.Using the key words “EBV mucocutaneous ulcers,” “EBV-associated lymphoproliferative disorders,” and “lymphoproliferative disorders,” we identified 100 cases of EBVMCU in the literature. EBVMCU is manifested as a well-circumscribed ulcer typically unifocal (90%) and of the oropharynx (58%), gastrointestinal (GI) tract (20%), and skin (20%). Immunohistochemical studies of the ulcers reveal monoclonal B-immunoblasts staining positively for CD20, CD30, EBER-1, MUM-1, OCT-2, and PAX-5 and staining variably for BCL-6, CD15, CD45, and CD79a. EBVMCU is most commonly associated with medication-induced (iatrogenic) immunosuppression (65%), advanced age-associated immunosenescence (27%), and primary (3%) and acquired (3%) immunodeficiencies. The median age for all EBVMCU cases is 68.5 (range, 16 -101) years. Of the 65 cases where medication-induced immunosuppression contributed to EBVMCU, 45 (69%) were in patients greater than 60 years-old. EBVMCU is a predominantly indolent disease reminiscent of post-transplant lymphoproliferative disorders in which conservative strategies are primarily employed with potential escalation to B-cell targeted therapy with or without cytotoxic chemotherapy, resection, and/or radiotherapy. Surveillance for EBVMCU should follow B-cell directed therapies and should be considered in the differential diagnosis in cases of suspected lymphoma relapse. Additionally, other LPDs, including lymphomas, should be monitored after resolution of EBVMCU. Due to overlap of the immunohistochemical profiles and risk factors associated with EBVMCU and other ulcerative LPDs of the oral and sinus cavities, nasopharynx, or GI tract, EBVMCU should be considered in the differential diagnosis to prevent under- or over-diagnosis and their associated potential repercussions. DisclosuresNo relevant conflicts of interest to declare.

EBV/LMP-specific T cells maintain remissions of T- and B-cell EBV lymphomas after allogeneic bone marrow transplantation

AbstractAutologous T cells targeting Epstein-Barr virus (EBV) latent membrane proteins (LMPs) have shown safety and efficacy in the treatment of patients with type 2 latency EBV-associated lymphomas for whom standard therapies have failed, including high-dose chemotherapy followed by autologous stem-cell rescue. However, the safety and efficacy of allogeneic donor-derived LMP-specific T cells (LMP-Ts) have not been established for patients who have undergone allogeneic hematopoietic stem-cell transplantation (HSCT). Therefore, we evaluated the safety and efficacy of donor-derived LMP-Ts in 26 patients who had undergone allogeneic HSCT for EBV-associated natural killer/T-cell or B-cell lymphomas. Seven patients received LMP-Ts as therapy for active disease, and 19 were treated with adjuvant therapy for high-risk disease. There were no immediate infusion-related toxicities, and only 1 dose-limiting toxicity potentially related to T-cell infusion was seen. The 2-year overall survival (OS) was 68%. Additionally, patients who received T-cell therapy while in complete remission after allogeneic HSCT had a 78% OS at 2 years. Patients treated for B-cell disease (n = 10) had a 2-year OS of 80%. Patients with T-cell disease had a 2-year OS of 60%, which suggests an improvement compared with published posttransplantation 2-year OS rates of 30% to 50%. Hence, this study shows that donor-derived LMP-Ts are a safe and effective therapy to prevent relapse after transplantation in patients with B cell– or T cell–derived EBV-associated lymphoma or lymphoproliferative disorder and supports the infusion of LMP-Ts as adjuvant therapy to improve outcomes in the posttransplantation setting. These trials were registered at www.clinicaltrials.gov as #NCT00062868 and #NCT01956084.

GRANULOMATOSE LINFOMATOIDE

ABSTRACT&#x0D; Lymphomatoid granulomatosis (LYG) is a rare extranodal Epstein-Barr virus (EBV) associated B-cell lymphoproliferative disorder. Most cases occur between the fourth and sixth decades of life and the male-to-female ratio is 2:1. The lung is the most frequently involved organ. Radiographically, pulmonary disease is characterized by multiple variable size nodules. Histologically, the lesions show angiocentricity, are rich in T cells, have large atypical B cells, lymphocytic infiltration of the vascular wall and a variable necrosis. LYG is a distinct entity that can usually be differentiated from other EBV-associated B-cell lymphoproliferative disorders on the basis of the combination of clinical presentation and histology. The authors described the case of a 53-year-old woman who was previously diagnosed with sarcoidosis, histoplasmosis, and later with non-Hodgikin B Lymphoma. The lungs presented diffuse alveolar damage, exsudative phase, and infiltration by lymphomatoid granulomatosis. The patient became unstable and died. Grading of these lesions is important because it dictates the treatment choice.&#x0D; Keywords: Lymphomatoid granulomatosis, Epstein-Barr virus, pulmonary nodules.

Epstein-Barr virus (EBV)–associated lymphoid proliferations, a 2018 update

Epstein-Barr virus (EBV) has been linked to many human neoplasms including hematopoietic, epithelial, and mesenchymal tumors. Since our original review of EBV-associated lymphoproliferative disorders in 2007, many advances and developments have been reported. In this review, we will examine the recent advances in EBV-associated lymphoid/histiocytic proliferations, dividing them into reactive, B cell, T/NK cell, immunodeficiency-related, and histiocytic/dendritic cell proliferations.

Inherited Immunodeficiencies With High Predisposition to Epstein-Barr Virus-Driven Lymphoproliferative Diseases.

Epstein–Barr Virus (EBV) is a gamma-herpes virus that infects 90% of humans without any symptoms in most cases, but has an oncogenic potential, especially in immunocompromised individuals. In the past 30 years, several primary immunodeficiencies (PIDs) associated with a high risk to develop EBV-associated lymphoproliferative disorders (LPDs), essentially consisting of virus-associated hemophagocytic syndrome, non-malignant and malignant B-cell LPDs including non-Hodgkin and Hodgkin’s types of B lymphomas have been characterized. Among them are SH2D1A (SAP), XIAP, ITK, MAGT1, CD27, CD70, CTPS1, RASGRP1, and CORO1A deficiencies. Penetrance of EBV infection ranges from 50 to 100% in those PIDs. Description of large cohorts and case reports has refined the specific phenotypes associated with these PIDs helping to the diagnosis. Specific pathways required for protective immunity to EBV have emerged from studies of these PIDs. SLAM-associated protein-dependent SLAM receptors and MAGT1-dependent NKG2D pathways are important for T and NK-cell cytotoxicity toward EBV-infected B-cells, while CD27–CD70 interactions are critical to drive the expansion of EBV-specific T-cells. CTPS1 and RASGRP1 deficiencies further strengthen that T-lymphocyte expansion is a key step in the immune response to EBV. These pathways appear to be also important for the anti-tumoral immune surveillance of abnormal B cells. Monogenic PIDs should be thus considered in case of any EBV-associated LPDs.

EBV-Positive Lymphoproliferations of B- T- and NK-Cell Derivation in Non-Immunocompromised Hosts.

The contribution of Epstein-Barr virus (EBV) to the development of specific types of benign lymphoproliferations and malignant lymphomas has been extensively studied since the discovery of the virus over the last 50 years. The importance and better understanding of the EBV-associated lymphoproliferative disorders (LPD) of B, T or natural killer (NK) cell type has resulted in the recognition of new entities like EBV+ mucocutaneous ulcer or the addition of chronic active EBV (CAEBV) infection in the revised 2016 World Health Organization (WHO) lymphoma classification. In this article, we review the definitions, morphology, pathogenesis, and evolving concepts of the various EBV-associated disorders including EBV+ diffuse large B-cell lymphoma, not otherwise specified (DLBCL, NOS), EBV+ mucocutaneous ulcer, DLBCL associated with chronic inflammation, fibrin-associated DLBCL, lymphomatoid granulomatosis, the EBV+ T and NK-cell LPD of childhood, aggressive NK leukaemia, extranodal NK/T-cell lymphoma, nasal type, and the new provisional entity of primary EBV+ nodal T- or NK-cell lymphoma. The current knowledge regarding the pathogenesis of B-cell lymphomas that can be EBV-associated including Burkitt lymphoma, plasmablastic lymphoma and classic Hodgkin lymphoma will be also explored.

Epstein–Barr Virus DNAemia and co-occurrence with cytomegalovirus DNAemia in postrenal transplant recipients from a tertiary care center

Aim: Co-occurrence of Epstein–Barr virus (EBV) with Cytomegalovirus (CMV) is associated with an increased risk of EBV-associated posttransplant lymphoproliferative disorder (PTLD). Quantitation of EBV by real-time polymerase chain reaction (PCR) can aid the clinicians in the initiation of preemptive measures to improve the survival of the graft. Methods: The study was conducted among postrenal transplant recipients (PRTRs) who were attending the nephrology department from 2011 to 2016. Real-time quantitative PCR for EBV was performed in whole blood. PRTRs were classified into asymptomatic with altered renal parameters (Group A) and symptomatic (Group B), which were further subcategorized into Group B1 (fever with anemia, leukopenia, thrombocytopenia, or altered liver enzymes (any two), Group B2 (Group B1 + end-organ disease or only end-organ disease), and Group B3 (graft dysfunction [GDF]). The posttransplant period was also defined. DNA was extracted (Qiagen, Hilden, Germany) from whole blood, and real-time PCR was performed using QuantiTect multiplex PCR kit. Unpaired t-tests and ANOVA were used to analyze the data. Results: A total of 89 PRTRs were enrolled, of which 39.3% (n = 35) had EBV DNAemia, 43.1% during very late, 41.1% in late and 28.6% in immediate post transplant periods. EBV DNAemia ranged from 324 to 32,436 copies/ml. EBV DNAemia was found in 84% (n = 75) of symptomatic (Group B) and 16% (n = 14) of asymptomatic (Group A). Among the PRTRs with GDF (Group B3), 44% (n = 11/25) had EBV DNAemia of 2893.9 ± 1869 copies/ml. EBV DNAemia was considerably higher in PRTRs without GDF (8700.2 ± 9675.6 copies/ml) than PRTRs with GDF and the difference was statistically significant (P = 0.004). EBV DNAemia with CMV DNAemia among PRTRs was found in 21.3% (n = 19). Conclusion: High EBV DNAemia may precede PTLD or GDF; therefore, regular screening of EBV DNAemia is warranted. CMV and EBV DNAemia may also co-exist in PRTRs. As CMV is an immunomodulating virus, it increases the risk of opportunistic infections, especially EBV.