Epstein-Barr Virus-associated Post-transplant Lymphoproliferative Disease Research Articles

POSB172 A Review of the Risks of Long-Term Consequences Associated with Components of CHOP Chemotherapy Regimen

A common chemotherapy regimen in Epstein-Barr virus-associated post-transplant lymphoproliferative disease (EBV+ PTLD) following solid organ transplants is cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP). This study describes the available evidence for long-term consequences, therapy-related complications that persist or arise after treatment, associated with any components of CHOP.

Epstein-Barr Virus-Associated Post-transplant Lymphoproliferative Disease.

Epstein-Barr virus (EBV) is associated with a variety of malignancies including post-transplant lymphoproliferative disease (PTLD). These include B and T cell lymphomas, epithelial, and mesenchymal tumors. The virus is ubiquitous, transmitted in saliva, and not usually associated with the development of malignancy. PTLD is usually associated with EBV when it occurs soon after the transplant. Measurement of viral DNA in blood, especially plasma, may be useful in the diagnosis of PTLD. Treatment approaches include withdrawal of immunosuppression, monoclonal antibodies or antibody conjugates, cytotoxic chemotherapy, and a variety of virus-specific treatments such as adoptive cellular therapy with EBV-specific T cells. Approaches to prevention include selection of immunosuppressive regimens that minimize the risk. In the future, EBV vaccines may be available for potential transplant recipients.

A RARE CAUSE OF CRAZY PAVING: POSTTRANSPLANT LYMPHOPROLIFERATIVE DISEASE

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: Crazy paving on computed tomography (CT) is defined as interlobular septal thickening with areas of ground glass attenuation. It can be caused by a variety of pathologies. Here we describe an unusual cause of crazy paving in an immunosuppressed patient. CASE PRESENTATION: A 58-year old man presented for syncope. His past medical history included acute myelogenous leukemia in complete remission post stem cell transplant, and complicated by cytomegalovirus colitis. Upon arrival to the emergency department, he was found to be obtunded and was intubated. Home medications included tacrolimus, ganciclovir, sulfamethoxazole-trimethoprim, and voriconazole. Vital signs were significant for a blood pressure of 62/38mmHg and heart rate of 138/minute. Laboratory studies revealed a white blood cell count of 13.6K/mm3, with 15% lymphocytes, 5% atypical lymphocytes, 34% plasmacytes, and 44% neutrophils. Lactic acid was 10.8mmol/L, bicarbonate 15mmol/L, and creatinine 3mg/dL. Arterial blood gas was consistent with metabolic acidosis. Tacrolimus level was 6ng/mL (goal 5-10). Computed tomography (CT) of the chest (Images 1-3) revealed interlobular septal thickening with ground glass opacities, and prominent mediastinal, cervical, and axillary lymphadenopathy. The patient required vasopressor support and was started on broad spectrum antibiotics, antivirals, antifungals. Bronchoalveolar lavage showed 38% neutrophils, 52% monocytes, and 10% lymphocytes. Gram stain, cultures, stain for acid fast bacilli, cytology, galactomannan, fungal cultures, and viral respiratory panel were negative. Serum flow cytometry revealed plasmacytoid cells with positive Epstein-Barr virus (EBV) in situ hybridization. Serum EBV PCR showed >39,000,000 copies/mL. These findings were consistent with post-transplant lymphoproliferative disease (PTLD). DISCUSSION: PTLD is a category of lymphoid disorders that arise after solid organ or hematopoietic transplants in the setting of active immunosuppression, most commonly with active EBV infection. Severity is graded as early, polymorphic, or monomorphic. Treatment can involve decreasing immunosuppression, rituximab in CD20+ disease, chemotherapy (with surgery if localized disease), or EBV-targeted cytotoxic T-cell instillation. Prevention of PTLD in transplant patients has included rapid tapering of immunosuppression as appropriate, and close monitoring of EBV viral levels, with elevations prompting reduction in immunosuppression or initiation of rituximab. Given its in vitro inhibition of EBV replication, ganciclovir has been suggested prophylactically, but there is no consensus regarding antiviral prophylaxis. CONCLUSIONS: Our patient rapidly decompensated and went into multiorgan system failure; he was made comfort care and expired. This case demonstrates the need for a high index of suspicion for PTLD in all transplanted patients with crazy paving present on imaging. Reference #1: Al-Mansour Z, Nelson BP, Evens AM. Post-transplant lymphoproliferative disease: risk factors, diagnosis, and current treatment strategies. Curr Hematol Malig Rep. 2013 September; 8(3): 173-183. Reference #2: Rossi SE, Erasmus JJ, Volpacchio M, et al. "Crazy Paving” pattern at thin-section CT of the lungs: radiologic-pathologic overview. Radiographics 2003; 26 (6): 1509-1519. Reference #3: AlDabbagh, MR, Gitman MR, Kumar D et al. The Role of Antiviral Prophylaxis for the prevention of Epstein-Barr virus-associated posttransplant lymphoproliferative disease in solic organ transplant recipients: a systematic review. Am J Transplant. 2017; 17: 770-781. DISCLOSURES: No relevant relationships by Payam Nabizadeh, source=Web Response No relevant relationships by Paul Simpson, source=Web Response

350 - Hemophagocytic Lymphohistiocytosis is a Sign of Poor Outcome in Pediatric Epstein-Barr Virus-Associated Post-Transplant Lymphoproliferative Disease after Hematopoietic Stem Cell Transplantation

350 - Hemophagocytic Lymphohistiocytosis is a Sign of Poor Outcome in Pediatric Epstein-Barr Virus-Associated Post-Transplant Lymphoproliferative Disease after Hematopoietic Stem Cell Transplantation

The role of biologicals in intestinal transplantation.

This article reviews the role of biologicals in intestinal transplantation. Several biologicals have been used in intestinal and multivisceral transplantation for various indications, such as induction therapy, prevention and treatment of antibody-mediated rejection, desensitization, anti-inflammatory treatment, as well as treatment of Epstein-Barr virus-associated posttransplant lymphoproliferative disease. Particularly, the administration of biologicals in induction therapy such as T-cell depleting antibodies and interleukin-2 receptor antagonists have significantly contributed to the great improvement of patient and allograft outcome. Novel biologicals, such as B-cell, plasma-cell, and complement-directed agents have been successfully applied to treat antibody and complement-driven alloimmune processes to stabilize long-term outcome. Several other inflammatory allotransplant conditions have been addressed with anti-TNF-α antibodies, such as infliximab. Biologicals have contributed significantly to the recent success of intestinal transplantation. Novel developments in this field are supposed to aid in addressing various urgent needs in intestinal transplantation, such as preimmunization, antibody and complement-induced graft injury, as well as pathologies originating from innate immune responses.

Risk factors for Epstein-Barr virus-related post-transplant lymphoproliferative disease after allogeneic hematopoietic stem cell transplantation

Allogeneic hematopoietic stem cell transplantation is a successful treatment for hematologic malignancies and a variety of genetic and metabolic disorders. In the period following stem cell transplantation, the immune-compromised milieu allows opportunistic pathogens to thrive. Epstein-Barr virus-associated post-transplant lymphoproliferative disease can be a life-threatening complication for transplanted patients because of suppressed T-cell-mediated immunity. We analyzed possible risk factors associated with post-transplant lymphoproliferative disease in a cohort of over 1,000 patients. The incidence of post-transplant lymphoproliferative disease was 4%. Significant risk factors identified by multivariate analysis were: human leukocyte antigen-mismatch (P<0.001), serological Epstein-Barr virus mismatch recipient-/donor+ (P<0.001), use of reduced intensity conditioning (P=0.002), acute graft-versus-host disease grade II to IV (P=0.006), pre-transplant splenectomy (P=0.008) and infusion of mesenchymal stromal cells (P=0.015). The risk of post-transplant lymphoproliferative disease has increased in more recent years, from less than 2% before 1998 to more than 6% after 2011. Additionally, we show that long-term survival of patients with post-transplant lymphoproliferative disease is poor despite initial successful treatment. The 3-year survival rate among the 40 patients with post-transplant lymphoproliferative disease was 20% as opposed to 62% among patients without post-transplant lymphoproliferative disease (P<0.001). The study identifies patients at risk of post-transplant lymphoproliferative disease after transplantation in need of pre-emptive measures.

CD20-negative Epstein–Barr virus-associated post-transplant lymphoproliferative disease refractory to rituximab in a patient with severe aplastic anemia

Epstein-Barr virus-associated post-transplant lymphoproliferative disease (EBV-PTLD) is a life-threatening complication following allogeneic hematopoietic stem cell transplantation (HSCT). Monitoring of EBV DNA in high-risk patients with subsequent pre-emptive rituximab treatment is highly effective, and can prevent EBV-associated disease following HSCT. Here, we report a 10-year-old girl with aplastic anemia who developed CD20 negative EBV-PTLD after unrelated bone marrow transplantation that was refractory to rituximab treatment. Similar to other types of lymphoma, the absence of CD20 antigen is likely to be characteristic of rituximab-refractory EBV-PTLD.

Treatment advances in posttransplant lymphoproliferative disease.

Epstein-Barr virus-associated posttransplant lymphoproliferative disease (PTLD) is a life-threatening complication of organ transplantation. As we continue to observe improved outcomes of patients living after solid or hematopoietic stem cell transplantation, we can expect to see a parallel increase in the incidence of PTLD. Several innovative therapeutic approaches are currently under development to add to our arsenal of treatment strategies in this devastating disease. The past decade has witnessed significant progress in the understanding and treatment of PTLD. The tolerability and effectiveness of standard treatment regimens, such as a reduction in immunosuppression, rituximab, and chemotherapy, have been confirmed and improved upon. Newer options for treatment demonstrating significant promise include antiviral therapy with arginine butyrate, as well as Epstein-Barr virus-specific cytotoxic T-cell therapy. Both the heterogeneous PTLD population and the lack of standardized and evidence-based treatment approaches make treatment a difficult decision for the clinician. This article reviews and updates the evidence behind accepted strategies such as reduction in immunosuppression, rituximab, and chemotherapy, as well as explores novel and effective therapeutic modalities including antiviral therapy with arginine butyrate and adoptive allogeneic T-cell therapy.

Adoptive T‐cell transfer in cancer immunotherapy

Adoptive T-cell therapy has definite clinical benefit in relapsed leukaemia after allogeneic transplant and in Epstein-Barr virus-associated post-transplant lymphoproliferative disease. However, the majority of tumour targets are weakly immunogenic self-antigens and success has been limited in part by inadequate persistence and expansion of transferred T cells and by tumour-evasion strategies. Adoptive immunotherapy presents the opportunity to activate, expand and genetically modify T cells outside the tolerising environment of the host and a number of strategies to optimize the cellular product, including gene modification and modulation of the host environment, in particular by lymphodepletion, have been developed.

Murine gammaherpesvirus 68 infection is associated with lymphoproliferative disease and lymphoma in BALB beta2 microglobulin-deficient mice.

Human gammaherpesvirus infections are associated with development of lymphoproliferative disease. Understanding of the mechanisms of gammaherpesvirus lymphomagenesis during chronic infection in a natural host has been limited by the exquisite species specificity of human gammaherpesviruses and the expense of primates. Murine gammaherpesvirus gammaHV68 is genetically and biologically related to human gammaherpesviruses and herpesvirus saimiri and has been reported to be associated with lymphoproliferative disease in mice (N. P. Sunil-Chandra, J. Arno, J. Fazakerley, and A. A. Nash, Am. J. Pathol. 145:818-826, 1994). We report the development of an animal model of gammaHV68 lymphomagenesis in BALB/c beta2 microglobulin-deficient mice (BALB beta2m-/-). GammaHV68 infection induced two lymphoproliferative lesions: B-cell lymphoma and atypical lymphoid hyperplasia (ALH). ALH lesion histology resembled lesions of Epstein-Barr virus-associated posttransplant lymphoproliferative disease and was characterized by the abnormal infiltration of the white pulp with cells expressing the plasma cell marker CD138. Lymphomas observed in gammaHV68-infected animals were B220+/CD3- large-cell lymphomas. GammaHV68-infected cells were common in ALH lesions as measured by in situ hybridization with a probe specific for viral tRNAs (vtRNAs), but they were scarce in gammaHV68-infected spleens with normal histology. Unlike ALH lesions, gammaHV68 vtRNA-positive cells were rare in lymphomas. GammaHV68 infection of BALB beta2m-/- mice results in lymphoproliferation and lymphoma, providing a valuable tool for identifying viral and host genes involved in gammaherpesvirus-associated malignancies. Our findings suggest that gammaHV68 induces lymphomas via hit-and-run oncogenesis, paracrine effects, or stimulation of chronic inflammation.

Posttransplant viral syndromes in pediatric patients: a review.

The success of pediatric solid organ transplantation has been largely due to advancements in surgical techniques, technology, and preoperative and postoperative care. Potent immunosuppression continues to reduce the incidence and severity of rejection, and improve long-term survival. However, there is growing awareness of the role immunosuppression plays in contributing to the incidence of cytomegalovirus, Epstein-Barr virus, and Epstein-Barr virus-associated posttransplant lymphoproliferative disease. Herpes viruses such as these present as primary or recurrent disease and continue to be a significant source of morbidity and mortality in transplant recipients. This paper reviews the predictors of disease, clinical features, diagnosis, and methods of treatment of these major posttransplant viral syndromes. As part of the human herpes virus family, varicella-zoster virus will also be discussed. A case study shows the delicate balance of treating concomitant varicella infection at the time of transplantation.

De novo malignancies after liver transplantation: a major cause of late death.

1. Recurrent and de novo malignancies are the second leading causes of late death in liver transplant recipients, following age-related cardiovascular complications. 2. The increased incidence of de novo malignancies in liver transplant recipients compared with the general population reflects their demographic makeup, known preexistent risk factors for cancer, greater rate of chronic viral infection, and actions of exogenous immunosuppression. 3. The greatest incidence of de novo malignancies is seen in cancers associated with chronic viral infections, such as Epstein-Barr virus-associated posttransplant lymphoproliferative disease, and skin cancers, including squamous cell carcinoma and Kaposi's sarcoma. 4. Although a greater incidence of such malignancies as oropharyngeal malignancy and colorectal cancer was noted, there did not appear to be an increased risk for liver transplant recipients matched for age, sex, and length of follow-up using modified life-table technique and Surveillance Epidemiology End Result data with a similar at-risk group. However, they may present with more advanced stages of disease. 5. An increased incidence of de novo cancers in chronically immunocompromised liver transplant recipients demands careful long-term screening protocols to help facilitate diagnosis at an earlier stage of disease.

Epstein-Barr virus-associated post-transplant lympho-proliferative disease of donor origin in liver transplant recipients

Background/Aims: Post-transplant lymphoproliferative disease, a potential complication of solid organ transplantation, occurs in about 3% of orthotopic liver transplant recipients. We report the genetic and virological characterization of two cases of post-transplant lymphoproliferative disease that occurred early (4 and 6 months) after orthotopic liver transplant as large-cell non-Hodgkin's lymphomas located at the hepatic hilum. Methods: Lymphomatous tissues were analyzed for clonality and presence of Epstein-Barr virus (EBV) sequences by Southern blot, polymerase chain reaction, and in situ hybridization techniques. Results: The tumors in both cases were sustained by a clonal proliferation of B lymphocytes containing type A EBV DNA. Moreover, in situ hybridization with a digoxigenin-labeled EBV-specific probe evidenced a strong nuclear signal in most of the neoplastic cells. DNA microsatellite analysis at three different loci detected alleles of donor origin in both tumor samples, suggesting that the neoplastic B cells were of donor origin. Conclusions: EBV-infected donor B lymphocytes might be responsible for intragraft post-transplant lymphoproliferative disease in orthotopic liver transplant recipients. As 20 to 30% of post-transplant lymphomas involve the graft itself, donor-derived post-transplant lymphoproliferative disease might be more frequent than present appreciated. Prospective studies are needed to assess its real incidence and identify possible risk factors.