RESUMEN

BACKGROUND: Post-transplant lymphoproliferative disorders (PTLD) are rare but severe complications that occur after solid organ or allogeneic hematopoietic stem cell transplantations (allo-HSCT), with rapid progression and high mortality. Primary central nervous system (CNS)-PTLD are rarely recognized histo-pathologically. In addition, the diagnostic value of the Epstein-Barr virus (EBV) DNA copies in CNS-PTLD remains poorly understood. OBJECTIVES: We herein report a case of monomorphic EBV-associated CNS-PTLD (diffuse large B-cell lymphoma, DLBCL) after allo-HSCT and perform a meta-analysis to assess the efficacy of PTLD treatment strategies in recent years. METHODS: We present the case report covering clinical manifestations, diagnosis, treatment, and outcomes of a patient with primary CNS-PTLD. Additionally, we include a systematic review and meta-analysis of the clinical characteristics of 431 patients with PTLD after allo-HSCT. We evaluate the main treatment options and outcomes of PTLD management, including rituximab, chemotherapies, and autologous or human leukocyte antigen (HLA)-matched EBV-specific cytotoxic T lymphocyte infusion (EBV-CTLs)/donor lymphocyte infusion (DLI). RESULTS: The meta-analysis revealed an overall response rate of 69.0% for rituximab alone (95% CI: 0.47-0.84), 45.0% for rituximab plus chemotherapies (95% CI: 0.15-0.80), and 91.0% for rituximab plus EBV-CTLs/DLI (95% CI: 0.83-0.96). The complete response (CR) rate after treatments for PTLD was 67.0% (95% CI: 0.56-0.77). Moreover, the 6-month and 1-year overall survival (OS) rate was 64.0% (95% CI: 0.31-0.87) and 49.0% (95% CI: 0.31-0.68), respectively. CONCLUSIONS: This case highlighted the urgent need for effective, low-toxic treatment regimens for CNS-PTLD. Our meta-analysis suggested that rituximab combined with EBV-CTLs/DLI could be a favorable strategy for the management of PTLD after allo-HSCT.

Asunto(s)

Infecciones por Virus de Epstein-Barr , Trasplante de Células Madre Hematopoyéticas , Trastornos Linfoproliferativos , Humanos , Infecciones por Virus de Epstein-Barr/complicaciones , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Herpesvirus Humano 4/aislamiento & purificación , Herpesvirus Humano 4/genética , Linfoma de Células B Grandes Difuso/virología , Linfoma de Células B Grandes Difuso/terapia , Trastornos Linfoproliferativos/etiología , Trastornos Linfoproliferativos/diagnóstico , Trastornos Linfoproliferativos/terapia , Rituximab/uso terapéutico , Trasplante Homólogo/efectos adversos

RESUMEN

INTRODUCTION: This study investigated variables associated with mortality in kidney transplant recipients (KTRs) diagnosed with post-transplant lymphoproliferative disease (PTLD) and a simultaneous Epstein-Barr virus (EBV) viremia. METHODS: This was a retrospective cohort study enrolling KTRs diagnosed with PTLD between 2018 and 2020. Outcome: death within two years after diagnosis. RESULTS: Among 1,625 KTRs who collected EBV viremia (by PCR, 2018-2020) for any reason, 238 (14.6%) had a positive viral load and 41 (17.2%) simultaneous PTLD. These 41 patients were 40.1 years old at diagnosis and 8.6 years after transplantation; 26.8% were induced with rATG and 92.7% were maintained on tacrolimus and azathioprine (TAC/AZA) as immunosuppressive regimen. Lymph nodes (75.6%) was the most common site of PTLD, followed by the gastrointestinal tract (48.8%), with 61.0% at Lugano stage IV and 80.5% monomorphic PTLD. The mean EBV viral load was 12,198 IU/mL. One- and two-year patient survival post-diagnosis was 60.4% and 46.8%, respectively. In the Cox regression analysis, age at PTLD diagnosis (HR for each year = 1.039; p < 0.001) and EBV viral load (HR for each log = 1.695; p = 0.026) were associated with risk of death. CONCLUSION: This study suggests that in patients predominantly on TAC/AZA, PTLD with simultaneous EBV positive viral load is a late event, and worse survival is associated with older age and EBV viral load at diagnosis.

Asunto(s)

Infecciones por Virus de Epstein-Barr , Herpesvirus Humano 4 , Trasplante de Riñón , Trastornos Linfoproliferativos , Complicaciones Posoperatorias , Carga Viral , Humanos , Trasplante de Riñón/efectos adversos , Trastornos Linfoproliferativos/diagnóstico , Trastornos Linfoproliferativos/mortalidad , Trastornos Linfoproliferativos/virología , Trastornos Linfoproliferativos/etiología , Estudios Retrospectivos , Masculino , Femenino , Adulto , Infecciones por Virus de Epstein-Barr/diagnóstico , Infecciones por Virus de Epstein-Barr/complicaciones , Persona de Mediana Edad , Herpesvirus Humano 4/aislamiento & purificación , Herpesvirus Humano 4/genética , Factores de Edad , Complicaciones Posoperatorias/virología , Complicaciones Posoperatorias/diagnóstico , Viremia/diagnóstico , Inmunosupresores/efectos adversos , Inmunosupresores/uso terapéutico

RESUMEN

LRBA deficiency is an inborn error of immunity defined by autoimmunity, lymphoproliferation, recurrent infections, cytopenia, and inflammatory bowel disease. Despite recent advances in managing this disease with targeted biologic therapy, haematopoietic stem cell transplant (HSCT) remains the only cure. However, great variability exists between protocols used to transplant patients with LRBA deficiency. We describe a cohort of seven patients with LRBA deficiency who underwent HSCT using a myeloablative, reduced toxicity regime of fludarabine, treosulfan, and thiotepa at two transplantation centres from 2016 to 2019. Data were collected both retrospectively and prospectively, measuring time to engraftment, infectious complications, incidence of graft versus host disease, and post-transplantation chimerism. Six of seven patients survived transplantation, and four of six surviving patients achieving treatment-free survival. We thus recommend that HSCT with fludarabine, treosulfan, and thiotepa-based conditioning be considered in patients with LRBA deficiency.

Asunto(s)

Busulfano , Trasplante de Células Madre Hematopoyéticas , Tiotepa , Acondicionamiento Pretrasplante , Vidarabina , Vidarabina/análogos & derivados , Vidarabina/uso terapéutico , Humanos , Trasplante de Células Madre Hematopoyéticas/métodos , Busulfano/análogos & derivados , Busulfano/uso terapéutico , Acondicionamiento Pretrasplante/métodos , Tiotepa/uso terapéutico , Masculino , Femenino , Lactante , Preescolar , Enfermedad Injerto contra Huésped/etiología , Niño , Estudios Retrospectivos , Resultado del Tratamiento , Trastornos Linfoproliferativos/etiología , Trastornos Linfoproliferativos/terapia

RESUMEN

Epstein-Barr virus (EBV) associated post-transplant lymphoproliferative disorders (PTLD) are one of the most severe complications after hematopoietic stem cell transplantation (HSCT). This study includes 31 cases of aplastic anemia (AA) patients who developed PTLD after haploidentical transplantation, summarizing their clinical characteristics and categorizing them into either rituximab monotherapy group or combination therapy group based on whether their condition improved by 1 log after a single dose of rituximab. The incidence of PTLD after HSCT in children with AA was 10.16%, and the incidence of PTLD in patients with age >10 years was significantly increased (χ(2)=11.336, P=0.010). Of the 31 patients, 27 were clinically diagnosed and 4 were pathologically confirmed. Finally, 15 patients were classified into the rituximab treatment group and 15 patients into the combination treatment groups. Finally three patients died, and the 2-year overall survival rate was (89.7±5.6) %. Standard pre-treatment protocols and EBV reactivation are risk factors affecting the prognosis of PTLD. There was no statistically significant difference in the impact of the two treatment schemes on prognosis.

Asunto(s)

Anemia Aplásica , Infecciones por Virus de Epstein-Barr , Trasplante de Células Madre Hematopoyéticas , Trastornos Linfoproliferativos , Rituximab , Humanos , Anemia Aplásica/terapia , Niño , Masculino , Femenino , Adolescente , Preescolar , Rituximab/administración & dosificación , Rituximab/uso terapéutico , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Trastornos Linfoproliferativos/etiología , Trastornos Linfoproliferativos/terapia , Estudios Prospectivos

RESUMEN

OBJECTIVE: To analyze the risk factors of Epstein-Barr virus (EBV) infection after allogeneic hematopoietic stem cell transplantation (allo-HSCT) and its impact on survival. METHODS: The clinical data of 347 patients who underwent their first allo-HSCT in our hospital from January 2014 to June 2021 were retrospectively analyzed. Patients were divided into EBV (n =114) and Non-EBV (n =233) groups according to whether they were infected with EBV. The incidence of EBV infection after allo-HSCT was calculated, and the risk factors of EBV infection were analyzed. RESULTS: A total of 114(32.8%) patients presented EBV infection (all peripheral blood EBV-DNA were positive). EBV infection occurred in 88 patients within 100 days after transplantation, which accounted for 77.2% of all patients with EBV infection. 5 cases (1.44%) were confirmed as post-transplant lymphoproliferative disorder (PTLD). The median onset time of patients was 57(7-486) days after transplantation. Multivariate analysis showed that the use of ATG/ATG-F, occurrence of CMV viremia, and grade III-IV aGVHD were risk factors for EBV infection. Furthermore, compared to BUCY, the use of intensified preconditioning regimens containing FA/CA was significantly increased the risk of EBV infection. CONCLUSION: EBV infection is a common complication after allo-HSCT. Intensified preconditioning regimens, use of ATG/ATG-F, CMV viremia and grade III to IV aGVHD increase the risk of EBV infection after allo-HSCT.

Asunto(s)

Infecciones por Virus de Epstein-Barr , Trasplante de Células Madre Hematopoyéticas , Herpesvirus Humano 4 , Trasplante Homólogo , Humanos , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Estudios Retrospectivos , Factores de Riesgo , Trasplante Homólogo/efectos adversos , Acondicionamiento Pretrasplante/efectos adversos , Enfermedad Injerto contra Huésped/etiología , Trastornos Linfoproliferativos/etiología , Incidencia , Femenino , Masculino

RESUMEN

The acquisition or reactivation of Epstein-Barr virus (EBV) after allogeneic Hematopoietic Stem Cell Transplant (HSCT) can be associated with complications including the development of post-transplant lymphoproliferative disorder (PTLD), which is associated with significant morbidity and mortality. A number of risk factors for PTLD have been defined, including T-cell depletion, and approaches to monitoring EBV, especially in high-risk patients, with the use of preemptive therapy upon viral activation have been described. Newer therapies for the preemption or treatment of PTLD, such as EBV-specific cytotoxic T-cells, hold promise. Further studies to help define risks, diagnosis, and treatment of EBV-related complications are needed in this at-risk population.

Asunto(s)

Infecciones por Virus de Epstein-Barr , Trasplante de Células Madre Hematopoyéticas , Herpesvirus Humano 4 , Trastornos Linfoproliferativos , Trasplante Homólogo , Activación Viral , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Humanos , Infecciones por Virus de Epstein-Barr/virología , Trasplante Homólogo/efectos adversos , Trastornos Linfoproliferativos/etiología , Trastornos Linfoproliferativos/terapia , Factores de Riesgo

RESUMEN

Posttransplant lymphoproliferative disorders (PTLDs) are among the most common malignant complications after transplantation, leading to a drastic reduction in patient survival rates. The majority of PTLDs are tightly linked to Epstein-Barr virus (EBV+PTLDs) and are the result of an uncontrolled proliferation of EBV-infected cells. However, although EBV infections are a common finding in transplant recipients, most patients with high EBV loads will never develop EBV+PTLD. Natural killer cells and EBV-specific CD8+ T lymphocytes are critical for controlling EBV-infected cells, and the impairment of these cytotoxic immune responses facilitates the unfettered proliferation of EBV-infected cells. Recent years have seen a considerable increase in available literature aiming to describe novel risk factors associated with the development of EBV+PTLD, which may critically relate to the strength of EBV-specific natural killer cell and EBV-CD8+ T lymphocyte responses. The accumulation of risk factors and the increased risk of developing EBV+PTLD go hand in hand. On the one hand, most of these risk factors, such as the level of immunosuppression or the EBV donor and recipient serologic mismatch, and distinct genetic risk factors are host related and affect cytotoxic EBV-specific immune responses. On the other hand, there is growing evidence that distinct EBV variants may have an increased malignant potential and are thus more likely to induce EBV+PTLD. Here, we aim to review, from a mechanistic point of view, the risk factors for EBV+PTLD in the host and the infecting EBV variants that may explain why only a minority of transplant recipients develop EBV+PTLD.

Asunto(s)

Infecciones por Virus de Epstein-Barr , Herpesvirus Humano 4 , Células Asesinas Naturales , Trastornos Linfoproliferativos , Trasplante de Órganos , Humanos , Trastornos Linfoproliferativos/virología , Trastornos Linfoproliferativos/inmunología , Trastornos Linfoproliferativos/etiología , Infecciones por Virus de Epstein-Barr/inmunología , Infecciones por Virus de Epstein-Barr/virología , Herpesvirus Humano 4/inmunología , Factores de Riesgo , Trasplante de Órganos/efectos adversos , Células Asesinas Naturales/inmunología , Células Asesinas Naturales/virología , Linfocitos T CD8-positivos/inmunología , Animales , Inmunosupresores/efectos adversos , Interacciones Huésped-Patógeno

RESUMEN

BACKGROUND: Chronic immunosuppression following pancreas transplantation carries significant risk, including posttransplant lymphoproliferative disease (PTLD). We sought to define the incidence, risk factors, and long-term outcomes of PTLD following pancreas transplantation at a single center. METHODS: All adult pancreas transplants between February 1, 1983 and December 31, 2023 at the University of Minnesota were reviewed, including pancreas transplant alone (PTA), simultaneous pancreas-kidney transplants (SPK), and pancreas after kidney transplants (PAK). RESULTS: Among 2353 transplants, 110 cases of PTLD were identified, with an overall incidence of 4.8%. 17.3% were diagnosed within 1 year of transplant, 32.7% were diagnosed within 5 years, and 74 (67.3%) were diagnosed after 5 years. The overall 30-year incidence of PTLD did not differ by transplant type-7.4% for PTA, 14.2% for SPK, and 19.4% for PAK (p = 0.3). In multivariable analyses, older age and Epstein-Barr virus seronegativity were risk factors for PTLD, and PTLD was a risk factor for patient death. PTLD-specific mortality was 32.7%, although recipients with PTLD had similar median posttransplant survival compared to those without PTLD (14.9 year vs. 15.6 year, p = 0.9). CONCLUSIONS: PTLD following pancreas transplantation is associated with significant mortality. Although the incidence of PTLD has decreased over time, a high index of suspicion for PTLD following PTx should remain in EBV-negative recipients.

Asunto(s)

Supervivencia de Injerto , Trastornos Linfoproliferativos , Trasplante de Páncreas , Complicaciones Posoperatorias , Humanos , Trasplante de Páncreas/efectos adversos , Masculino , Trastornos Linfoproliferativos/etiología , Trastornos Linfoproliferativos/epidemiología , Femenino , Adulto , Complicaciones Posoperatorias/epidemiología , Complicaciones Posoperatorias/etiología , Estudios de Seguimiento , Factores de Riesgo , Pronóstico , Persona de Mediana Edad , Incidencia , Tasa de Supervivencia , Estudios Retrospectivos , Rechazo de Injerto/etiología , Rechazo de Injerto/mortalidad , Trasplante de Riñón/efectos adversos , Adulto Joven

RESUMEN

Background: Children undergoing allo-HCT are at high risk of EBV-related complications. The objective of the study was to analyze the impact of prophylactic post-transplant rituximab on EBV infection and EBV-PTLD in children after allo-HCT, to determine the risk factors for the development of EBV infection and EBV-PTLD and to determine their outcomes. Additionally, the impact of EBV-driven complications on transplant outcomes was analyzed. Methods: Single center retrospective analysis of EBV-related complications in pediatric population undergoing allo-HCT, based on strategy of prophylaxis with rituximab. Overall 276 consecutive children, including 122 on prophylaxis, were analyzed for EBV-driven complications and transplant outcomes. Results: Prophylaxis with rituximab resulted in significant reduction of EBV infection (from 35.1% to 20.5%; HR=2.7; p<0.0001), and EBV-PTLD (from 13.0% to 3.3%; HR=0.23; p=0.0045). A trend for improved survival was also observed (HR=0.66; p=0.068), while non-relapse mortality was comparable in both cohorts. The peak value of viral load was a risk factor in the development of EBV-PTLD: 10-fold higher peak viral load in comparison to the baseline 104 copies/mL, caused a 3-fold (HR=3.36; p<0.001) increase in the risk of EBV-PTLD. Rituximab treatment was effective as a preemptive therapy in 91.1%, and in 70.9% in EBV-PTLD. Patients who developed PTLD had dismal 5-year overall survival (29% vs 60%; p<0.001), and an increased risk of relapse (72% vs 35%; p=0.024). Conclusions: Rituximab for prophylaxis of EBV infection and EBV-PTLD was highly effective in pediatric population. Treatment of EBV-PTLD was successful in 70%, however the occurrence of EBV-PTLD was associated with an increased risk of relapse of primary malignant disease.

Asunto(s)

Infecciones por Virus de Epstein-Barr , Trasplante de Células Madre Hematopoyéticas , Herpesvirus Humano 4 , Rituximab , Trasplante Homólogo , Humanos , Rituximab/uso terapéutico , Rituximab/efectos adversos , Rituximab/administración & dosificación , Infecciones por Virus de Epstein-Barr/prevención & control , Infecciones por Virus de Epstein-Barr/etiología , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Niño , Femenino , Masculino , Preescolar , Estudios Retrospectivos , Adolescente , Herpesvirus Humano 4/inmunología , Lactante , Trasplante Homólogo/efectos adversos , Factores de Riesgo , Trastornos Linfoproliferativos/prevención & control , Trastornos Linfoproliferativos/etiología , Carga Viral , Resultado del Tratamiento

RESUMEN

Posttransplant lymphoproliferative disorder (PTLD) is a rare lymphoid and/or plasmocytic proliferation that occurs after allogeneic hematopoietic stem cell transplantation (allo-HSCT). We aimed to identify the pathologic features and clinical outcomes of T-cell PTLD, an extremely rare subtype of PTLD, after allo-HSCT. In this study, six allo-HSCT recipients with T-cell PTLD from five transplant centers in China were enrolled. All the T-cell PTLD were donor-derived, and three patients were with monomorphic and three with polymorphic types, respectively. All patients received cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP)-based chemotherapy. Five patients achieved complete response (CR), and one experienced progressive disease (PD). The median time from HSCT to onset was 4 (range: 0.6-72) months, analyzed in combination with the other 16 patients with T-cell PTLD identified from previous reports. About 56.3% of the T-cell samples (9/16) were positive for in situ hybridization with an Epstein-Barr virus (EBV)-encoded small nuclear early region (EBER ISH). CHOP-based chemotherapy might be the optimal strategy for patients who showed no response to empiric therapy with a CR rate of 87.5%. In conclusion, our study observed that T-cell PTLD has distinct clinical manifestations and morphological features, which characterized by less relation to EBV, later occurrence, and poorer prognosis when compared with B-cell PTLD.

Asunto(s)

Trasplante de Células Madre Hematopoyéticas , Trastornos Linfoproliferativos , Linfocitos T , Trasplante Homólogo , Humanos , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Trasplante de Células Madre Hematopoyéticas/métodos , Trastornos Linfoproliferativos/etiología , Masculino , Femenino , Adulto , Linfocitos T/inmunología , Trasplante Homólogo/métodos , Trasplante Homólogo/efectos adversos , Adolescente , Niño , Persona de Mediana Edad , Adulto Joven , Ciclofosfamida/uso terapéutico

RESUMEN

The most prevalent malignancy that complicates both adult and pediatric solid organ transplantation is post-transplant lymphoproliferative disorder (PTLD). This study aimed to analyze the clinical and pathological characteristics, treatments, and outcomes of Epstein-Barr virus (EBV) DNAemia and PTLD in pediatric liver transplant recipients. A retrospective chart review was performed on 112 patients less than 18 years of age who underwent isolated orthotopic liver transplantation (OLT) between 2010 and 2022 at Ege University Children's Hospital. Data gathered for 1-year post-OLT included age at OLT, EBV, immunoglobulin (Ig)M/IgG status of the donor and recipient, indication for OLT, induction regimen, all immunosuppression levels, date and result of EBV polymerase chain reaction testing, rejection episodes documented by liver biopsy, and the development of PTLD. Forty-nine patients (43.75%) developed EBV DNAemia (median interval from surgery: 2 months, min-max: 2-36), of which 43 (87.8%) grafts came from living donors, and 6 (12.2%) came from deceased donors. Nine (18.4%) patients died during follow-up, and eight (16.3%) developed PTLD. Of these 8 patients; five patients developed EBV-related disease, one child developed hemophagocytic lymphohistiocytosis, one developed aplastic anemia, and one child developed B cell lymphoma. When PTLD patients and without-PTLD patients were compared, pediatric intensive care unit hospitalization, abnormal bone marrow biopsy findings, lymphadenopathy, age at diagnosis of EBV DNAemia, EBV viral load, tacrolimus (FK 506) pre-infection, were higher and tacrolimus 1-month levels were lower in patients with PTLD (p < 0.05). In logistic regression analysis, we showed that the age at diagnosis of EBV DNAemia was significantly higher in children with PTLD (p = 0.045; OR: 1.389; 95% CI: 1.007-1.914). PTLD is a rare but severe complication associated with EBV after OLT. This study demonstrated that PTLD is associated with older age, higher tacrolimus blood levels before EBV DNAemia, and higher peak EBV viral load at 1 month of EBV DNAemia.

Asunto(s)

ADN Viral , Infecciones por Virus de Epstein-Barr , Herpesvirus Humano 4 , Trasplante de Hígado , Trastornos Linfoproliferativos , Humanos , Trastornos Linfoproliferativos/virología , Trastornos Linfoproliferativos/etiología , Trasplante de Hígado/efectos adversos , Estudios Retrospectivos , Niño , Preescolar , Masculino , Femenino , Infecciones por Virus de Epstein-Barr/virología , Infecciones por Virus de Epstein-Barr/complicaciones , ADN Viral/sangre , Lactante , Herpesvirus Humano 4/genética , Adolescente

Asunto(s)

Trastornos Linfoproliferativos , Humanos , Trastornos Linfoproliferativos/diagnóstico , Trastornos Linfoproliferativos/etiología , Trastornos Linfoproliferativos/patología , Trastornos Linfoproliferativos/terapia , Masculino , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Niño , Diferenciación Celular , Células Plasmáticas/patología , Femenino

RESUMEN

The International Pediatric Transplant Association convened an expert consensus conference to assess current evidence and develop recommendations for various aspects of care relating to post-transplant lymphoproliferative disorders (PTLD) after pediatric solid organ transplantation. This report addresses the outcomes of deliberations by the PTLD Management Working Group. A strong recommendation was made for reduction in immunosuppression as the first step in management. Similarly, strong recommendations were made for the use of the anti-CD20 monoclonal antibody (rituximab) as was the case for chemotherapy in selected scenarios. In some scenarios, there is uncoupling of the strength of the recommendations from the available evidence in situations where such evidence is lacking but collective clinical experiences drive decision-making. Of note, there are no large, randomized phase III trials of any treatment for PTLD in the pediatric age group. Current gaps and future research priorities are highlighted.

Asunto(s)

Trastornos Linfoproliferativos , Trasplante de Órganos , Complicaciones Posoperatorias , Rituximab , Humanos , Trastornos Linfoproliferativos/etiología , Trastornos Linfoproliferativos/diagnóstico , Trastornos Linfoproliferativos/terapia , Niño , Adolescente , Rituximab/uso terapéutico , Complicaciones Posoperatorias/etiología , Complicaciones Posoperatorias/prevención & control , Complicaciones Posoperatorias/diagnóstico , Inmunosupresores/uso terapéutico , Preescolar

RESUMEN

Epstein-Barr virus-related post-transplantation lymphoproliferative disorder (EBV-PTLD) is a serious complication following hematopoietic stem cell transplantation (HSCT). A pre-emptive strategy using rituximab, which aims to manage patients early at the time of EBV reactivation to avoid PTLD, has been recommended by the most recent ECIL-6 guidelines in 2016. However, there is still a great heterogeneity of viral-load monitoring protocols, targeted patient populations, and pre-emptive treatment characteristics between centers, making precise EBV monitoring recommendations difficult. We conducted a literature review from the most recent publications between 1 January 2015 and 1 August 2023, to summarize the emerging data on EBV-PTLD prevention strategies in HSCT recipients, including the EBV-DNA threshold and use of rituximab. We also present the results of a survey of current practices carried out in 12 of the main HSCT centers across Canada. We confirm that pre-emptive rituximab remains an efficient strategy for EBV-PTLD prevention. However, there is an urgent need to perform prospective, randomized, multicentric trials with larger numbers of patients reflecting current practices to determine the best clinical conduct with regards to rituximab dosing, timing of treatment, and criteria to initiate treatments. Longer follow-ups will also be necessary to assess patients' long-term outcomes.

Asunto(s)

Infecciones por Virus de Epstein-Barr , Trasplante de Células Madre Hematopoyéticas , Herpesvirus Humano 4 , Humanos , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Trasplante de Células Madre Hematopoyéticas/métodos , Canadá , Rituximab/uso terapéutico , Trasplante Homólogo/métodos , Trastornos Linfoproliferativos/etiología

RESUMEN

A 67-year-old man underwent renal transplantation in his twenties. He developed refractory pleural effusion, with many large lymphocytes with severe atypia and mitosis in the effusion, indicating malignant lymphoma. He finally died of respiratory failure. An autopsy revealed atypical lymphocytes positive for CD3, CD4, and CD30 and negative for CD8, CD20, PAX5, human herpesvirus (HHV) 8, and Epstein-Barr virus-encoded small RNAs by immunohistochemistry and in situ hybridization. Atypical lymphocytes also had T-cell receptor gene rearrangements Jß2, Jγ2, and Jδ1 and chromosomal aberrations der(8)t(1;8)(q21;p21), add(13)(q12), add(14)(q32), and add(16)(q12-13). A few atypical lymphocytes were present at other sites. We finally diagnosed this case as monomorphic T-cell post-transplant lymphoproliferative disorder with features of HHV8-negative primary effusion lymphoma. A literature review only identified six cases (four HHV8-negative, two HHV8-positive) of effusion lymphoma of T-cell type, including the present case. Interestingly, about half of HHV8-negative and HHV8-positive cases had a history of renal transplantation in their twenties. All cases showed tumor CD30 expression, whereas CD4 and CD8 expressions were inconsistent. These findings indicated that this lymphoma may be associated with post-transplant lymphoproliferative disorder by renal transplantation at a young age, although further cases need to be analyzed.

Asunto(s)

Autopsia , Herpesvirus Humano 8 , Trasplante de Riñón , Linfoma de Efusión Primaria , Humanos , Masculino , Anciano , Linfoma de Efusión Primaria/patología , Linfoma de Efusión Primaria/virología , Trasplante de Riñón/efectos adversos , Herpesvirus Humano 8/aislamiento & purificación , Herpesvirus Humano 8/genética , Linfocitos T/inmunología , Trastornos Linfoproliferativos/patología , Trastornos Linfoproliferativos/virología , Trastornos Linfoproliferativos/etiología , Resultado Fatal

RESUMEN

When Epstein-Barr virus (EBV) infection is suspected, identification of infected cells is important to understand the pathogenesis, determinine the treatment strategy, and predict the prognosis. We used the PrimeFlow™ RNA Assay Kit with a probe to detect EBV-encoded small RNAs (EBERs) and multiple surface markers, to identify EBV-infected cells by flow cytometry. We analyzed a total of 24 patients [11 with chronic active EBV disease (CAEBV), 3 with hydroa vacciniforme lymphoproliferative disorder, 2 with X-linked lymphoproliferative disease type 1 (XLP1), 2 with EBV-associated hemophagocytic lymphohistiocytosis, and 6 with posttransplant lymphoproliferative disorder (PTLD)]. We compared infected cells using conventional quantitative PCR methods and confirmed that infected cell types were identical in most patients. Patients with CAEBV had widespread infection in T and NK cells, but a small amount of B cells were also infected, and infection in patients with XLP1 and PTLD was not limited to B cells. EBV-associated diseases are believed to be complex pathologies caused by EBV infecting a variety of cells other than B cells. We also demonstrated that infected cells were positive for HLA-DR in patients with CAEBV. EBER flow FISH can identify EBV-infected cells with high sensitivity and is useful for elucidating the pathogenesis.

Asunto(s)

Infecciones por Virus de Epstein-Barr , Herpesvirus Humano 4 , Humanos , Infecciones por Virus de Epstein-Barr/virología , Herpesvirus Humano 4/genética , Niño , Masculino , Femenino , Preescolar , Hibridación Fluorescente in Situ , Adolescente , Trastornos Linfoproliferativos/virología , Trastornos Linfoproliferativos/diagnóstico , Trastornos Linfoproliferativos/etiología , ARN Viral/análisis , Citometría de Flujo/métodos , Linfocitos B/virología , Adulto , Sensibilidad y Especificidad , Lactante , Células Asesinas Naturales/virología

RESUMEN

BACKGROUND: Monomorphic post-transplant lymphoproliferative disorder (mPTLD) is a major cause of morbidity/mortality following solid organ transplant (SOT), with infection, mPTLD progression and organ rejection presenting equal risks. Balancing these risks is challenging, and the intensity of therapy required by individual patients is not defined. Although an increasing body of evidence supports the use of a stepwise escalation of therapy through reduction in immunosuppression (RIS) to rituximab monotherapy and low-dose chemo-immunotherapy, many centres still use B-cell non-Hodgkin lymphoma (B-NHL) protocols, especially when managing Burkitt/Burkitt-like (BL) PTLD. This study sought to define outcomes for children managed in the UK or Spanish centres using low-intensity first-line treatments. PROCEDURE: Retrospective data were anonymously collected on patients younger than 18 years of age, with post-SOT mPTLD diagnosed between 2000 and 2020. Only patients given low-intensity treatment at initial diagnosis were included. RESULTS: Fifty-six patients were identified. Age range was 0.9-18 years (median 10.7). Most (62.5%) had early-onset PTLD. Haematopathological analysis showed 75% were diffuse large B-cell like, 14.3% were BL and nine of 33 (27%) harboured a MYC-rearrangement. Stage III-IV disease was present in 78.6%. All but one had RIS, 26 received rituximab monotherapy and 24 low-dose chemo-immunotherapy, mostly R-COP. Intensified B-NHL chemotherapy was required in 10/56 (17.9%). There were a total of 13 deaths in this cohort, three related to PTLD progression. The 1-year overall survival (OS), event-free survival (EFS) and progression-free survival (PFS) were 92.8%, 78.6% and 80.2%, respectively. CONCLUSIONS: R-COP provides an effective low-dose chemotherapy option. Escalation to more intensive therapies in the minority of inadequately controlled patients is an effective strategy.

Asunto(s)

Trastornos Linfoproliferativos , Trasplante de Órganos , Humanos , Niño , Masculino , Femenino , Adolescente , Trastornos Linfoproliferativos/etiología , Trastornos Linfoproliferativos/mortalidad , Trastornos Linfoproliferativos/terapia , Estudios Retrospectivos , Preescolar , Lactante , Trasplante de Órganos/efectos adversos , Tasa de Supervivencia , Rituximab/uso terapéutico , Rituximab/administración & dosificación , Estudios de Seguimiento , Pronóstico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos

RESUMEN

Objective: To summarize the clinical characteristics, prognostic factors and treatment outcomes of childhood aggressive mature B-cell lymphoma after liver transplantation. Methods: This retrospective study included 18 children with newly diagnosed aggressive mature B-cell lymphoma after liver transplantation and treated from June 2018 to June 2022 in the Department of Hematology and Oncology of Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine. Clinical characteristics, treatment and outcomes of patients at last evaluation were analyzed. Overall survival (OS) and event free survival (EFS) rates were calculated by Kaplan-Meier method and Log-Rank analysis was performed to find factors of poor prognosis. Results: Among all 18 patients, there were 6 males and 12 females, and the age of onset was 40 (35, 54) months. The interval from transplant to tumor diagnosis was 21 (17, 35) months and 5 patients had early onset disease (<1 year since transplant). Seventeen patients had abdominal lesions. Diarrhea, vomiting and abdominal masses were the main clinical manifestations. All patients were Epstein-Barr virus (EBV) related posttransplant lymphoproliferative disorders (PTLD). One patient received individualized therapy due to critical sick at diagnosis, and the remaining 17 patients received CP (cyclophosphamide, methylprednisolone plus rituximab) and (or) modified EPOCH (prednisone, etoposide, doxorubicin, vincristine, cyclophosphamide plus rituximab) regimens. Of all 18 patients, 15 cases got complete response, 2 cases got partial response, 1 patient died of severe infection. The 2-year OS and EFS rates of 18 patients were (94±5)% and (83±8)%, respectively. None of age, gender or early onset disease had effect on OS and EFS rates in univariate analysis (all P>0.05). Conclusions: The symptoms of PTLD were atypical. Close surveillance of EBV-DNA for patients after liver transplantation was crucial to early stage PTLD diagnosis. CP or modified EPOCH regimen was efficient for pediatric patients with aggressive mature B cell lymphoma after liver transplantation.

Asunto(s)

Protocolos de Quimioterapia Combinada Antineoplásica , Trasplante de Hígado , Linfoma de Células B , Humanos , Trasplante de Hígado/efectos adversos , Femenino , Masculino , Estudios Retrospectivos , Preescolar , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Niño , Linfoma de Células B/etiología , Pronóstico , Ciclofosfamida/administración & dosificación , Ciclofosfamida/uso terapéutico , Infecciones por Virus de Epstein-Barr/complicaciones , Infecciones por Virus de Epstein-Barr/etiología , Vincristina/uso terapéutico , Tasa de Supervivencia , Doxorrubicina/uso terapéutico , Doxorrubicina/administración & dosificación , Resultado del Tratamiento , Prednisona/uso terapéutico , Prednisona/administración & dosificación , Herpesvirus Humano 4/aislamiento & purificación , Trastornos Linfoproliferativos/etiología , Lactante , Adolescente

RESUMEN

AIMS: With recent European Union marketing authorization, tabelecleucel is the first off-the-shelf, allogeneic Epstein-Barr virus (EBV)-specific T-cell immunotherapy approved for the treatment of relapsed/refractory EBV-positive post-transplant lymphoproliferative disease (EBV+ PTLD). In the absence of a control arm, real-world evidence can provide a comparative benchmark for single-arm studies in ultra-rare populations. This study assessed the treatment effect of tabelecleucel in the single-arm phase 3 ALLELE study (NCT03394365) versus a treatment group from a multinational, multicenter retrospective chart review study (RS002) of patients with EBV+ PTLD. METHODS: In ALLELE, patients had disease relapsed/refractory to rituximab ± chemotherapy and received tabelecleucel 2x106 cells/kg on days 1, 8, and 15 in 35-day cycles. Patients in RS002 had disease relapsed/refractory to rituximab ± chemotherapy and received next line of systemic therapy between January 2000 and December 2018. Propensity score-based standardized mortality/morbidity ratio weighting was used to achieve balance between treatment and comparator arms. Kaplan-Meier estimators and Cox regression models were used to compare overall survival (OS) in the re-weighted sample. RESULTS: 30 patients (n = 14 hematopoietic cell transplant [HCT], n = 16 solid organ transplant [SOT]) from ALLELE (data cutoff: November 2021) and 84 patients (n = 36 HCT, n = 48 SOT) from RS002 (data lock: January 2021) were included. Median time from diagnosis to first tabelecleucel dose (ALLELE) or start date of next line of systemic therapy (RS002) was 3.6 months. Tabelecleucel was associated with a substantial OS benefit compared with current treatment, with an unadjusted HR of 0.47 (95% confidence interval [CI] 0.25-0.88) and adjusted HR of 0.37 (95% CI 0.20-0.71) when using the start date of the next line of therapy as the index date. Sensitivity analyses yielded consistent results. CONCLUSIONS: In this study of real-world data, tabelecleucel was associated with an OS benefit among patients with R/R EBV+ PTLD for whom there is high unmet need.

Asunto(s)

Infecciones por Virus de Epstein-Barr , Trasplante de Células Madre Hematopoyéticas , Trastornos Linfoproliferativos , Humanos , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Trastornos Linfoproliferativos/etiología , Masculino , Femenino , Estudios Retrospectivos , Persona de Mediana Edad , Adulto , Infecciones por Virus de Epstein-Barr/complicaciones , Trasplante de Órganos/efectos adversos , Herpesvirus Humano 4/aislamiento & purificación , Herpesvirus Humano 4/genética , Rituximab/uso terapéutico , Estimación de Kaplan-Meier

Asunto(s)

Trastornos Linfoproliferativos , Humanos , Trastornos Linfoproliferativos/etiología , Trastornos Linfoproliferativos/patología , Trastornos Linfoproliferativos/diagnóstico , Masculino , Persona de Mediana Edad , Femenino , Trasplante de Células Madre Hematopoyéticas/efectos adversos