Infusion Of Donor-Derived CD19-Redirected-Virus-Specific T Cells For B-Cell Malignancies Relapsed After Allogeneic Stem Cell Transplant: A Phase I Study

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 152-152 ◽  
Author(s):  
Conrad Russell Y. Cruz ◽  
Kenneth P. Micklethwaite ◽  
Barbara Savoldo ◽  
Carlos A. Ramos ◽  
Sharon Lam ◽  
...  
Keyword(s):  
T Cells ◽  
Stem Cell ◽  
T Cell ◽  
Peripheral Blood ◽  
Research Funding ◽  
Epstein Barr Virus ◽  
Barr Virus ◽  
Epstein Barr ◽  
Relapsed Disease ◽  
Anti Tumor Activity

Abstract Donor lymphocyte infusions (DLI) following hematopoietic stem cell transplantation may reduce or control opportunistic infections and leukemia/lymphoma relapse, but the associated graft versus host disease (GvHD) limits the clinical success of this procedure. Since T cell immunotherapy may be a safer alternative to DLI we have now used a single T cell platform that mediates both antileukemic and antiviral activity. Autologous T cells modified to express CD19-specific chimeric antigen receptors (CD19.CAR) have had clinical activity against CD19-expressing malignancies, but it is unknown if similarly modified allogeneic T cells will be equally effective. Allogeneic virus specific T cells (VSTs) directed to cytomegalovirus (CMV), adenovirus (Adv), and Epstein Barr virus (EBV) have been shown to be safe and effective in preventing and treating life-threatening viral infections post HSCT. Therefore, we sought to determine whether allogeneic VSTs could be engineered to express CD19.CAR and would retain the safety and effectiveness of unmodified VSTs whilst gaining anti-tumor activity. VSTs were expanded ex vivo using antigen presenting cells engineered to express adenovirus and cytomegalovirus (using an Ad5f35 adenoviral vector expressing the CMV pp65 gene), and Epstein Barr virus (using EBV-infected lymphoblastoid cell lines) antigens. After 3 stimulations, the VST’s were modified to express CD19.CAR.28ζ using a retroviral vector encoding the CAR-CD19 receptor coupled to the CD28 co-stimulatory molecule and the T cell receptor zeta (ζ) chain. Nine CD19.CAR-modified virus specific T cell (CD19.CAR-VSTs) products were generated for infusion. All VST lines recognized at least one viral antigen as determined by Elispot or chromium release assays and 20% to 48% of cells expressed the CD19.CAR. All lines killed CD19-expressing cells in vitro. We treated nine patients with these CD19.CAR-VSTs, 3 months to 13 years after HSCT. Six patients received CD19.CAR-VSTs for relapsed disease and 3 patients received the T cells as adjuvant therapy to prevent viral infection and relapse after HSCT. Safety. There were no infusion-related toxicities. One patient presented with gastrointestinal symptoms following infusion subsequently determined to be unrelated to the T cells. Persistence. VSTs persisted a median of 8 weeks in the peripheral blood and up to 9 weeks at disease sites. In three patients (#1, #3 and #5), CD19.CAR signals were detectable in the bone marrow or the lymph nodes (44.8, 25.85, and 32 copies/1000 ng DNA) even when no signal was measurable in peripheral blood, indicating preferential accumulation of the infused T cells at the disease site. Anti-Tumor Activity. During the period of CD19.CAR-VST persistence, objective anti-tumor activity was evident in 2/6 patients with relapsed disease (patient # 1 had detectable blasts in the peripheral blood which disappeared within 1-2 weeks following infusion, patient # 2 had 16% circulating CLL cells which decreased within 2 weeks of T cell infusion) but disease recurred after 3 and 2 months, respectively. The two patients who received cells while in remission remain disease-free >3 and >9 months later. Anti-Viral Activity. In two patients with EBV reactivation, donor CD19.CAR-VSTs expanded concomitant with an increase in virus-specific T cell responses, and decreased viral load. A third patient had a rise in adenovirus specific VSTs during an episode of adenovirus associated diarrhea. Although the infection was controlled, there was no concomitant rise in CD19-CAR expressing T cells in this patient. No other patient had viral disease. In conclusion, allogeneic CD19.CAR-VSTs administered after allogeneic HSCT are safe and can exert both anti-tumor and anti-viral activity in the absence of GvHD. Earlier administration of CD19.CAR-VSTs after HSCT, when the host is lymphodepleted and the incidence of viral infection is higher, may allow these cells to better capture the potential advantages of native TCR stimulation (and associated co-stimulation) for expansion and persistence, and thereby produce a higher frequency of sustained tumor responses. Alternatively, intentional stimulation of the native TCRs by viral vaccines may produce equal benefit, with greater predictability. Disclosures: Savoldo: Celgene: Patents & Royalties, Research Funding. Heslop:Celgene: Patents & Royalties, Research Funding; Cell Medica: Patents & Royalties. Rooney:Cell Medica: Membership on an entity’s Board of Directors or advisory committees, Patents & Royalties, Research Funding; Celgene: Patents & Royalties, Research Funding. Brenner:Celgene: Patents & Royalties, Research Funding. Dotti:Celgene: Patents & Royalties, Research Funding.

Rapid reconstitution of Epstein-Barr virus–specific T lymphocytes following allogeneic stem cell transplantation

Blood ◽  
2000 ◽  
Vol 96 (8) ◽  
pp. 2814-2821 ◽  
Author(s):  
Natalie A. Marshall ◽  
John Greg Howe ◽  
Richard Formica ◽  
Diane Krause ◽  
John E. Wagner ◽  
...  
Keyword(s):  
T Cells ◽  
Stem Cell ◽  
T Cell ◽  
Stem Cell Transplantation ◽  
Cd8 T Cells ◽  
Epstein Barr Virus ◽  
Hla Class I ◽  
Barr Virus ◽  
Matched Sibling ◽  
Epstein Barr

Epstein-Barr virus (EBV)–specific CD8 T lymphocytes are present at remarkably high frequencies in healthy EBV+individuals and provide protection from EBV-associated lymphoproliferative diseases. Allogeneic peripheral blood stem cell transplantation (allo-PBSCT) is a commonly used therapy in which T-cell surveillance for EBV is temporarily disrupted. Herein, human leukocyte antigen (HLA) class I tetramers were used to investigate the reestablishment of the EBV-specific CD8 T-cell repertoire in patients following allo-PBSCT. CD8+ T cells specific for lytic and latent cycle–derived EBV peptides rapidly repopulate the periphery of matched sibling allo-PBSCT patients. The relative frequencies of T cells specific for different EBV peptides in transplantation recipients closely reflect those of their respective donors. Investigation of patients at monthly intervals following unmanipulated allo-PBSCT demonstrated that the frequency of EBV-specific T cells correlates with the number of EBV genome copies in the peripheral blood and that expansion of EBV-specific T-cell populations occurs even in the setting of immunosuppressive therapy. In contrast, patients undergoing T-cell–depleted or unrelated cord blood transplantation have undetectable EBV-specific T cells, even in the presence of Epstein-Barr viremia. The protective shield provided by EBV-specific CD8 T cells is rapidly established following unmanipulated matched sibling allo-PBSCT and demonstrates that HLA class I tetramers complexed with viral peptides can provide direct and rapid assessment of pathogen-specific immunity in this and other vulnerable patient populations.

scholarly journals PD-1 Blockade Aggravates Epstein–Barr Virus+ Post-Transplant Lymphoproliferative Disorder in Humanized Mice Resulting in Central Nervous System Involvement and CD4+ T Cell Dysregulations

2021 ◽  
Vol 10 ◽  
Author(s):  
Valery Volk ◽  
Sebastian J. Theobald ◽  
Simon Danisch ◽  
Sahamoddin Khailaie ◽  
Maja Kalbarczyk ◽  
...  
Keyword(s):  
Central Nervous System ◽  
T Cells ◽  
Nervous System ◽  
Stem Cell ◽  
T Cell ◽  
Lymphoproliferative Disorder ◽  
Epstein Barr Virus ◽  
Humanized Mice ◽  
Barr Virus ◽  
Epstein Barr

Post-transplant lymphoproliferative disorder (PTLD) is one of the most common malignancies after solid organ or allogeneic stem cell transplantation. Most PTLD cases are B cell neoplasias carrying Epstein-Barr virus (EBV). A therapeutic approach is reduction of immunosuppression to allow T cells to develop and combat EBV. If this is not effective, approaches include immunotherapies such as monoclonal antibodies targeting CD20 and adoptive T cells. Immune checkpoint inhibition (ICI) to treat EBV+ PTLD was not established clinically due to the risks of organ rejection and graft-versus-host disease. Previously, blockade of the programmed death receptor (PD)-1 by a monoclonal antibody (mAb) during ex vivo infection of mononuclear cells with the EBV/M81+ strain showed lower xenografted lymphoma development in mice. Subsequently, fully humanized mice infected with the EBV/B95-8 strain and treated in vivo with a PD-1 blocking mAb showed aggravation of PTLD and lymphoma development. Here, we evaluated vis-a-vis in fully humanized mice after EBV/B95-8 or EBV/M81 infections the effects of a clinically used PD-1 blocker. Fifteen to 17 weeks after human CD34+ stem cell transplantation, Nod.Rag.Gamma mice were infected with two types of EBV laboratory strains expressing firefly luciferase. Dynamic optical imaging analyses showed systemic EBV infections and this triggered vigorous human CD8+ T cell expansion. Pembrolizumab administered from 2 to 5 weeks post-infections significantly aggravated EBV systemic spread and, for the M81 model, significantly increased the mortality of mice. ICI promoted Ki67+CD30+CD20+EBER+PD-L1+ PTLD with central nervous system (CNS) involvement, mirroring EBV+ CNS PTLD in humans. PD-1 blockade was associated with lower frequencies of circulating T cells in blood and with a profound collapse of CD4+ T cells in lymphatic tissues. Mice treated with pembrolizumab showed an escalation of exhausted T cells expressing TIM-3, and LAG-3 in tissues, higher levels of several human cytokines in plasma and high densities of FoxP3+ regulatory CD4+ and CD8+ T cells in the tumor microenvironment. We conclude that PD-1 blockade during acute EBV infections driving strong CD8+ T cell priming decompensates T cell development towards immunosuppression. Given the variety of preclinical models available, our models conferred a cautionary note indicating that PD-1 blockade aggravated the progression of EBV+ PTLD.

scholarly journals T Cell Exhaustion and Senescence in Epstein-Barr Virus-Associated Lymphoma Patients

2020 ◽  
Author(s):  
Huihui Liu ◽  
Junhui Xu ◽  
Lihong Wang ◽  
Wenjun Mao ◽  
Bingjie Wang ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Peripheral Blood ◽  
Epstein Barr Virus ◽  
T Cell Exhaustion ◽  
Cell Exhaustion ◽  
Barr Virus ◽  
Cell Counts ◽  
Healthy Donors ◽  
Epstein Barr

Abstract Background The Epstein-Barr Virus (EBV) is tumorigenic, and can be detected in many kinds of lymphomas. Some studies have shown a worse prognosis for patients with EBV-associated lymphoma. However, the mechanism is not fully understood. This study aimed to investigate the T cell signatures in patients with EBV-associated lymphoma. Methods Peripheral blood was collected from 17 patients with EBV-associated lymphoma and 19 healthy donors. We first examined the proportions of the lymphocyte subpopulations in peripheral blood mononuclear cells in patients with both groups by flow cytometry. Then we employed the enzyme-linked immunospot assay to evaluate the EBV antigen-specific response of the cytotoxic T cells in the two groups. Finally, to explore the mechanism of T cells dysfunction in EBV-associated lymphoma, we examined the expression of multiple inhibitory receptors representing T cell exhaustion and biomarkers representing T cell senescence on the surfaces of CD4+ T cells and CD8+ T cells. Results The ratio of peripheral CD4+ T cells and the absolute cell counts of CD4+ T cells and CD8+ T cells were significantly decreased in patients with EBV-associated lymphoma compared with those of healthy donors. The IFN-γ production upon stimulation of EBV mixed peptides were remarkably reduced in the patients. Higher expression levels of T cell exhaustion markers, PD1, LAG3, TIM3 and CTLA4 on T cells were found in the patients. The two subsects of exhausted T cells (T-bethiPD1mid and EOMEShiPD1hi) were higher in the patients. More importantly, CXCR5+CD8+T cells controlling viral replication decreased significantly in the patients. The fractions of senescent T cells increased in the patients. Conclusions In summary, our study demonstrated that the reduced EBV-specific T cells, the exhaustion and senescence of T cells together contributed to the T cell dysfunction in the patients with EBV-associated lymphoma.

Skewed TCR Repertoire of Vδ1+ γδT Cells in Recipients of Allogeneic Hematopoietic Stem Cell Grafts and Possible Involvement of Epstein-Barr Virus in Clonal Expansion of Vδ1+ T Cells.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2230-2230
Author(s):  
Masumi Fujishima ◽  
Makoto Hirokawa ◽  
Naohito Fujishima ◽  
Hirobumi Saitoh ◽  
Yoshikazu Ichikawa ◽  
...  
Keyword(s):  
T Cells ◽  
Stem Cell ◽  
T Cell ◽  
Clinical Outcome ◽  
Epstein Barr Virus ◽  
Clonal Expansion ◽  
Hematopoietic Stem ◽  
Barr Virus ◽  
Cdr3 Region ◽  
Epstein Barr

Abstract Background: We previously demonstrated that stable clonal expansion of Vδ1+ γδT lymphocytes persisted for several years after human allogeneic hematopoietic stem cell transplantation (allo-HSCT). These Vδ1+ T cells are derived from mature T cells in the graft. In the present study, we have extended our observation to learn whether oligoclonal expansions of Vδ1+ γδT lymphocytes might be associated with clinical outcome and GVHD, and whether consensus sequences of the CDR3 region of clonally expanded Vδ1+ T cells would be observed among different individuals. We also examined the possible role for Epstein-Barr virus (EBV) in clonal expansion of Vδ1+ T cells. Methods: Forty-two patients receiving allo-HSCT for hematological malignancies were included in this study. Grafts included bone marrow (n=33), G-CSF mobilized peripheral blood stem cells (n=7) and cord blood (n=2). Clonality of the Vδ1+ T cell subset was determined by CDR3 size spectratyping analysis. Junctional sequences were determined by DNA sequencing. In some experiments, PBMCs from healthy volunteer donors were stimulated with autologous EBV-LCL and were analyzed for clonality of TCRs. Results: CDR3 size spectratyping analysis revealed that twenty-three out of forty-two patients had highly skewed TCR repertoires of the Vδ1+ T cells. There was no apparent association between the oligoclonality of Vδ1+ TCRs and clinical outcome such as GVHD and leukemia relapse. In eight out of seventeen patients examined, the -WGI- amino acid sequence was observed in the CDR3 region of TCRs of clonally expanded Vδ1+ T cells. The -YWG- sequence was observed in four patients. All recipients examined were serologically positive for EBV-VCA IgG and EBNA. Bacterial or fungal components failed to stimulate Vδ1+ T cells to proliferate in vitro, but autologous EBV transformed B cells could induce the expansion of Vδ1+ T cells. The CDR3 size distribution patterns of Vδ1+ TCRs became skewed after stimulation with autologous EBV-LCL, and the T cell clone with the -LEEYWGLPH- CDR3 sequence predominated in the culture with autologous EBV-LCL, whereas this clone was not detectable before culture. Moreover, allogeneic EBV-positive Raji cells also induced the oligoclonal expansion of Vδ1+ T cells carrying the -WGI- or -YWG- junctional sequence. These results suggest the CDR3 structure may contribute to recognition of EBV-associated antigens by Vδ1+ T cells Conclusion: Skewing of the Vδ1+ TCR after allo-HSCT may be the result of the response to infectious antigens widely existing in humans such as EBV. Table 1. Junctional diversity of Vδ1 TCR of γδ T cells expanded in response to autologous EBV-LCL and allogeneic Burkitt lymphoma cells Stimulation δV1 N-D-N Jδ Colony frequency T cell clones appearing more than once are presented. Nil CALGE GLPHALIMWGDLAY TDKLIFGKG 3/20 EBV-LCL CALGE LEEYWGLPH TDKLIFGKG 10/27 CALGE GLPHALIMWGDLAY TDKLIFGKG 7/27 CALG GVLYWGIRR TDKLIFGKG 2/27 CALGE SLWGIRY TDKLIFGKG 2/27 CALGE LGETTPLLGGYSFA LTAQLFFGKG 2/27 Raji CALG VSGLARGGSL KLIFGKG 6/25 CALGE ADWGIRARILY TDKLIFGKG 4/25 CALGE PRAILGDTRIKRMY TDKLIFGKG 4/25 CALGE LEEYWGLPH TDKLIFGKG 3/25 CALGE DPGLPFLWY TDKLIFGKG 2/25 CALG DLNLLWGIRSILPG TDKLIFGKG 2/25

Adoptive Transfer of Epstein-Barr Virus (EBV) Nuclear Antigen 1–Specific T Cells As Treatment for EBV Reactivation and Lymphoproliferative Disorders After Allogeneic Stem-Cell Transplantation

2013 ◽  
Vol 31 (1) ◽  
pp. 39-48 ◽  
Author(s):  
Vanya Icheva ◽  
Simone Kayser ◽  
Daniel Wolff ◽  
Sebastian Tuve ◽  
Christina Kyzirakos ◽  
...  
Keyword(s):  
T Cells ◽  
Stem Cell ◽  
T Cell ◽  
Stem Cell Transplantation ◽  
Adoptive Transfer ◽  
Epstein Barr Virus ◽  
Nuclear Antigen ◽  
Barr Virus ◽  
Epstein Barr

Purpose Reactivation of Epstein-Barr virus (EBV) after allogeneic stem-cell transplantation (SCT) can lead to severe life-threatening infections and trigger post-transplantation lymphoproliferative disease (PTLD). Since EBV-specific T cells could prevent PTLD, cellular immunotherapy has been a promising treatment option. However, generation of antigen-specific T-cell populations has been difficult within a short time frame. Patients and Methods To improve availability in urgent clinical conditions, we developed a rapid protocol for isolation of polyclonal EBV nuclear antigen 1 (EBNA-1) –specific T cells by using an interferon gamma (IFN-γ) capture technique. Results We report on the use of adoptive transfer of EBNA-1–specific T cells in 10 pediatric and adult patients with EBV viremia and/or PTLD after SCT. No acute toxicity or graft-versus-host disease (GVHD) of more than grade 2 occurred as a result of adoptive T-cell transfer. In vivo expansion of transferred EBNA-1–specific T cells was observed in eight of 10 patients after a median of 16 days following adoptive transfer that was associated with clinical and virologic response in seven of them (70%). None of the responders had EBV-associated mortality. Within clinical responders, three patients were disease free by the day of last follow-up (2 to 36 months), three patients died of other infectious complications, and one patient died as a result of relapse of malignancy. EBV-related mortality was observed in two of 10 patients, and another patient had ongoing viremia without clinical symptoms at last follow-up. Conclusion Adoptive ex vivo transfer of EBNA-1–specific T cells is a feasible and well-tolerated therapeutic option, representing a fast and efficient procedure to achieve reconstitution of antiviral T-cell immunity after SCT.

Rapid reconstitution of Epstein-Barr virus–specific T lymphocytes following allogeneic stem cell transplantation

Blood ◽  
2000 ◽  
Vol 96 (8) ◽  
pp. 2814-2821 ◽  
Author(s):  
Natalie A. Marshall ◽  
John Greg Howe ◽  
Richard Formica ◽  
Diane Krause ◽  
John E. Wagner ◽  
...  
Keyword(s):  
T Cells ◽  
Stem Cell ◽  
T Cell ◽  
Stem Cell Transplantation ◽  
Cd8 T Cells ◽  
Epstein Barr Virus ◽  
Hla Class I ◽  
Barr Virus ◽  
Matched Sibling ◽  
Epstein Barr

Abstract Epstein-Barr virus (EBV)–specific CD8 T lymphocytes are present at remarkably high frequencies in healthy EBV+individuals and provide protection from EBV-associated lymphoproliferative diseases. Allogeneic peripheral blood stem cell transplantation (allo-PBSCT) is a commonly used therapy in which T-cell surveillance for EBV is temporarily disrupted. Herein, human leukocyte antigen (HLA) class I tetramers were used to investigate the reestablishment of the EBV-specific CD8 T-cell repertoire in patients following allo-PBSCT. CD8+ T cells specific for lytic and latent cycle–derived EBV peptides rapidly repopulate the periphery of matched sibling allo-PBSCT patients. The relative frequencies of T cells specific for different EBV peptides in transplantation recipients closely reflect those of their respective donors. Investigation of patients at monthly intervals following unmanipulated allo-PBSCT demonstrated that the frequency of EBV-specific T cells correlates with the number of EBV genome copies in the peripheral blood and that expansion of EBV-specific T-cell populations occurs even in the setting of immunosuppressive therapy. In contrast, patients undergoing T-cell–depleted or unrelated cord blood transplantation have undetectable EBV-specific T cells, even in the presence of Epstein-Barr viremia. The protective shield provided by EBV-specific CD8 T cells is rapidly established following unmanipulated matched sibling allo-PBSCT and demonstrates that HLA class I tetramers complexed with viral peptides can provide direct and rapid assessment of pathogen-specific immunity in this and other vulnerable patient populations.

scholarly journals High Incidence but Very Low Mortality of Epstein Barr Virus Related Post-Transplantation Lymphoproliferative Disorder after T-Cell Replete Haploidentical Peripheral Blood Stem Cell Transplantation

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 2104-2104
Author(s):  
Queralt Salas Gay ◽  
Zeyad Al-Shaibani ◽  
Wilson Lam ◽  
Fotios V. Michelis ◽  
Santhosh Thyagu ◽  
...  
Keyword(s):  
Stem Cell ◽  
T Cell ◽  
Research Funding ◽  
Lymphoproliferative Disorder ◽  
Epstein Barr Virus ◽  
Barr Virus ◽  
Ebv Reactivation ◽  
Gvhd Prophylaxis ◽  
Epstein Barr

Abstract BACKGROUND The use of immunosuppressive agents such as antithymocyte globulin (ATG) as graft-versus host disease (GVHD) prophylaxis may increase the risk of Epstein Barr Virus (EBV) related post-transplant lymphoproliferative disorder (PTLD). The aim of the present study is to report the incidence, risk factors, and outcome of PTLD in the setting of haploidentical stem cell transplant (haploSCT) combining PTCy and ATG as GVHD prophylaxis. METHODS From August 2016 to May 2018, 55 adult patients diagnosed with hematological malignancies underwent T-cell replete haploSCT. All patients received a reduced intensity conditioning regimen (RIC) with fludarabine, busulfan, and 200cGy of total body irradiation (TBI), combined with rabbit ATG, PTCy and cyclosporine (Cy). EBV titre was monitored by quantitative PCR in plasma samples. The cut-off value for test positivity was >600 copies of EBV DNA per milliliter of plasma. Testing was performed weekly from engraftment to day 100 and beyond in case the patients were on immunosuppression. Data was collected through retrospective chart review. Last follow up was updated in June 31, 2018. Median follow-up was 9.5 months (range 1-21). RESULTS Patient and donor characteristics are summarized in Table 1. Median age was 57 (22-73) years, with 23 (43%) patients ≥60 years. Overall survival of the 55 patients at 6 months was 70% (95% CI 57-83), and 51% (95% CI 46-66) at 1 year. EBV reactivation was documented in 31 (57%) patients. Median time to EBV reactivation was 54 (20-326) days. Three (5.5%) patients developed presumed PTLD with EBV-viremia higher than 1x10E6 copies and corroborative imaging. Three (5.5%) had biopsy-proven PTLD (Table 2). Median time since EBV reactivation to presumed/proven (P/P)-PTLD was 25 (3-36) days. All cases occurred early post-transplant within the first 100 days. Four patients were on therapeutic doses of cyclosporine. All 6 (11%) patients received treatment with weekly Rituximab 375 mg/m+. Five (83%) patients achieved complete clinical responses with PCR negativity with reduction of immunosuppression and single agent rituximab. One patient died of complications of viral encephalitis and bacterial pneumonia. CONCLUSION ATG based conditioning can be associated with increased viral reactivations. Frequent EBV monitoring and pre-emptive treatment may lead to rapid disease control. While no guidelines exist currently, further investigation is needed to define optimal monitoring strategies. Disclosures Lipton: BMS: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding.

Peripheral T-cell Lymphoma, NOS With Epstein-Barr Virus Positivity in an Elderly Patient With Myelodysplastic Syndrome: An Autopsy Case Report

2020 ◽  
Vol 154 (Supplement_1) ◽  
pp. S81-S81
Author(s):  
J Lanceta ◽  
W Xue ◽  
M Hurford ◽  
H Wu
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
Lymph Node ◽  
T Cell ◽  
Epstein Barr Virus ◽  
Cell Lymphoma ◽  
T Cell Lymphoma ◽  
Peripheral T Cell Lymphoma ◽  
Barr Virus ◽  
Epstein Barr

Abstract Casestudy Epstein-Barr virus (EBV)-associated peripheral T-cell lymphomas are a group of aggressive neoplasms with a geographic predilection for South America and Asia, but are very rare in Western populations. Results We report a case of a 74-year-old Caucasian female who presented with pancytopenia and B symptoms with EBV-IgG detected on admission. Past medical history included: ITP, chronic urticaria, and recently diagnosed myelodysplastic syndrome (MDS) on bone marrow biopsy one month prior to admission. Excisional biopsies of an enlarged right neck lymph node (repeated within 6 months) and right axillary lymph node five years ago were negative for a lymphoproliferative disorder at the time. Repeated bone marrow biopsy, performed during the current admission, confirmed the diagnosis of MDS, with scattered T-cells without aberrant immunophenotype. Despite aggressive treatment from multiple specialties, the patient deteriorated and expired four weeks later from complications of MDS. At autopsy, there was diffuse lymphadenopathy involving the mediastinum, axilla, pelvis and peripancreatic fat. Lymph node sections demonstrated nodal architecture effacement by diffuse, vaguely nodular lymphoid infiltrates. Histologically, the infiltrates were composed of medium to large lymphocytes with round to slight irregular nuclei, rare Reed-Sternberg-like multinucleated cells, clumped chromatin, and indistinct nucleoli. Individual cell necrosis was abundant with mitotic figures readily identifiable. Immunohistochemistry revealed CD2+ CD3+ neoplastic T-cells that co-express MUM1 and a subset of CD30, while negative for CD4, CD5, CD8, CD56, ALK1, and TDT. EBV-encoded RNA in-situ hybridization was focally positive. The final postmortem diagnosis was peripheral T-cell lymphoma, not otherwise specified (NOS), with focal EBV positivity. Conclusion Co-existence of a de-novo MDS and non-Hodgkin lymphoma without any prior chemotherapeutic exposure is a highly unusual finding, although MDS-like presentations can occur with EBV-associated lymphomas. Peripheral T-cell lymphoma, NOS is an aggressive lymphoma and EBV positivity has been found correlated with a poor prognosis. This case demonstrates how postmortem examination remains an important tool in clinical- pathological correlation and highlights the potential pathogenetic role EBV plays in MDS and T-cell lymphoma.

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