Non-Hodgkin lymphoma after liver and kidney transplantation in children. Experience from one center.

BACKGROUND: Post-transplantation lymphoproliferative disorder (PTLD) is a complication of organ transplantation and a life-threatening condition. Children who underwent organ transplantation are at risk of developing lymphoproliferative disorders and, among them, non-Hodgkin lymphoma (NHL) is the most serious. OBJECTIVES: The objective of this study was to describe the clinical course of NHL after liver and kidney transplantation. MATERIAL AND METHODS: Retrospective analysis of medical records of children who underwent liver/kidney transplantation and developed NHL. RESULTS: Nine children were identified, all girls, 6 after liver and 3 after kidney transplantations. Age at transplantation ranged from 1 year to 13 years (median: 4 years), while age at lymphoma diagnosis from 4 to 17 years (median: 12 years). Time from transplantation to lymphoma diagnosis ranged from 7 months to 12 years (median: 9 years). All but 1 patient developed mature B-cell lymphoma, 4 children - diffuse large B-cell lymphoma (DLBCL), 2 children - Burkitt's lymphoma, 1 child - mature B-cell leukemia, 1 child - Burkitt-like lymphoma, while 1 patient was diagnosed with T-cell lymphoblastic lymphoma. High levels of Epstein-Barr virus (EBV) DNA were found in blood of 3 patients, and EBV in tissue samples was detected in 4 patients. Six patients presented with stage III and 2 with stage IV disease. Two patients had graft involvement. Three children received chemotherapy according to R-CHOP, 3 LMB protocol (2 with addition of rituximab), while 1 received CHOP and 5 courses of COP. T-cell lymphoma patient was treated with Euro-LB protocol. Six out of 8 treated patients are alive with a median follow-up of 6 years. Two children died from disease progression during treatment and 1 from cerebral herniation before starting therapy. All patients experienced at least 1 toxic episode of grade 3 and 4 according to Common Toxicity Criteria Adverse Event (CTCAE). Complications of chemotherapy were manageable and there were no transplanted organ failures. CONCLUSIONS: Our study provides further data on the treatment and outcome of monomorphic PTLD and indicates that it is feasible to treat solid organ recipients with multiagent chemotherapy.

Epstein-barr virus DNAemia monitoring for the management of post-transplant lymphoproliferative disorder.

BACKGROUND: Post-transplant lymphoproliferative disorder (PTLD) is a potentially fatal complication of allogeneic hematopoietic cell transplantation (HCT). Epstein-Barr virus (EBV) reactivation (detectable DNAemia) predisposes to the development of PTLD. METHODS: We retrospectively studied 306 patients monitored for EBV DNAemia after Thymoglobulin-conditioned HCT to determine the utility of the monitoring in the management of PTLD. DNAemia was monitored weekly for ≥12 weeks post-transplantation. RESULTS: Reactivation was detected in 82% of patients. PTLD occurred in 14% of the total patients (17% of patients with reactivation). PTLD was treated with rituximab only when and if the diagnosis was established. This allowed us to evaluate potential DNAemia thresholds for pre-emptive therapy. We suggest 100,000-500,000 IU per mL whole blood as this would result in unnecessary rituximab administration to only 4-20% of patients and near zero mortality due to PTLD. After starting rituximab (for diagnosed PTLD), sustained regression of PTLD occurred in 25/25 (100%) patients in whom DNAemia became undetectable. PTLD progressed or relapsed in 12/17 (71%) patients in whom DNAemia was persistently detectable. DISCUSSION: In conclusion, for pre-emptive therapy of PTLD, we suggest threshold DNAemia of 100,000-500,000 IU/mL. Persistently detectable DNAemia after PTLD treatment with rituximab appears to have 71% positive predictive value and 100% negative predictive value for PTLD progression/relapse.

Epstein-Barr Virus-Related Post-Transplantation Lymphoproliferative Disorders After Allogeneic Hematopoietic Stem Cell Transplantation.

Epstein-Barr virus (EBV)-related post-transplantation lymphoproliferative disorders (EBV-PTLDs) are rare but potentially fatal complications of allogeneic hematopoietic stem cell transplantation (allo-HSCT), characterized by uncontrolled proliferation of EBV-infected lymphocytes. The most common risk factors include T cell depletion of graft, HLA mismatch, severe graft-versus-host disease (GVHD), and EBV seromismatch (recipient-negative/donor-positive), among others. EBV-PTLDs commonly manifest as fever and lymphadenopathy and may rapidly progress to multiorgan failure and even death. Histopathological evidence is indispensable for the diagnosis, and positive findings of EBV-DNA (EBV-DNAemia) and imaging are also very helpful. Active prophylaxis, such as optimization of the donor choice, conditioning regimen, and GVHD prevention, or passive prophylaxis, such as low dose of rituximab, unselected donor lymphocyte infusion (DLI), and EBV-specific cytotoxic T lymphocyte (EBV-CTLs) infusion, can decrease the incidence of EBV-DNAemia. Rituximab- based preemptive treatment can prevent EBV-DNAemia from developing into EBV-PTLDs, particularly benefiting recipients with higher loads of EBV-DNA, although the long-term outcome has not been significantly improved. To date, there is no consensus as to whether and when to initiate prophylactic or preemptive treatment. The current treatment strategies for probable and proven EBV-PTLDs include reduction of immunosuppression (RI), rituximab, adoptive cell therapy (DLI or EBV-CTLs), chemotherapy, radiotherapy, and surgery, among which rituximab plus RI is the mainstay. However, the mortality of EBV-PTLDs remains considerably high, and novel strategies merit exploration.

Treatment of post-transplantation lymphoproliferative disorders after kidney transplant with rituximab and conversion to m-TOR inhibitor / Tratamiento de la enfermedad linfoproliferativa post-trasplante renal con Rituximab y conversión a inhibidor m-TOR

Abstract Background: Post-transplantation lymphoproliferative disorders are serious complications of organ transplantation which treatment is not yet standardized. Objective: To describe the clinical response, overall and graft survival of patients in our center with this complication after kidney transplantation, which received rituximab as part of their treatment as well as conversion to m-TOR. Methods: Retrospective study, which included patients, diagnosed with post-transplant lymphoproliferative disorders after kidney transplantation from January 2011 to July 2014. Results: Eight cases were found with a wide spectrum of clinical presentations. Most had monomorphic histology, 85% were associated with Epstein-Barr virus, 25% of patients had tumor involvement of the renal graft, and 12.5% ​​had primary central nervous system lymphoma. All patients were managed with reduction of immunosuppression, conversion to m-TOR (except one who lost the graft at diagnosis) and rituximab-based therapy. The overall response rate was 87.5% (62.5% complete response, 25% partial response). Survival was 87.5% with a median follow-up of 34 months. An additional patient lost the graft, with chronic nephropathy already known. All the remaining patients had stable renal function. Conclusions: There are no standardized treatment regimens for lymphoproliferative disorders after kidney transplantation, but these patients can be managed successfully with reduction of immunosuppression, conversion to m-TOR and rituximab-based schemes.

Resumen Antecedente: La enfermedad linfoproliferativa post-trasplante es una complicación grave del trasplante de órganos cuyo tratamiento aún no se encuentra estandarizado. Objetivo: Describir la respuesta clínica, supervivencia global y del injerto en pacientes con esta complicación post trasplante renal en nuestro centro y que recibieron rituximab como parte de su tratamiento y la conversión a m-TOR. Métodos: Estudio retrospectivo que incluyó pacientes con diagnóstico de enfermedad linfoproliferativa postrasplante renal entre enero de 2011 y julio de 2014. Resultados: Se encontraron ocho casos, con presentaciones clínicas variables. La mayoría correspondieron a histología monomórfica, en 85% se asoció con virus de Epstein-Barr, 25% de los pacientes tenían compromiso tumoral del injerto renal y 12.5% linfoma primario de sistema nervioso central. Todos los pacientes se manejaron con reducción de inmunosupresión, conversión a m-TOR (excepto uno que perdió el injerto al diagnóstico) y tratamiento basado en rituximab. La tasa de respuesta global fue del 87.5% (62.5% respuesta completa, 25% respuesta parcial). La supervivencia fue del 87.5% con una mediana de seguimiento de 34 meses. Un paciente adicional perdió el injerto renal, con nefropatía crónica ya conocida. Los pacientes restantes con función renal estable. Conclusiones: No existen esquemas estandarizados de tratamiento para la enfermedad linfoproliferativa post-trasplante renal, pero estos pacientes pueden ser manejados de forma exitosa con reducción de la inmunosupresión, conversión a m-TOR y esquemas basados en rituximab.

[Infectious and neoplasic complications after kidney transplantation]. / Complications infectieuses et néoplasiques après transplantation rénale.

Infections and malignancies are the expected complications of immunosuppressive therapy, which non-specifically impairs cellular and humoral immune responses in renal transplant recipients. Infections were usually frequent and severe during the early post-transplant period (first year). Recent diagnostic methods (molecular biology) and availability of new antivirals, antifungal and antibiotic drugs made rapid diagnosis and systematic preventive strategies much easier and this resulted in a significant reduction of infections and infectious death in this population. However, new infectious agents like BK polyomavirus, hepatitis E virus, parvovirus (as well as Chigunkunya, West Nile and others in particular areas) were recently recognized as responsible of aggressive infections in the immunocompromised host. Malignancies are also common after transplantation, due to the intensity and duration of immunosuppression. Skin cancers and lymphoproliferative disorders are the most common and are undoubtedly caused by viral infections, but incidence of non-skin cancers is also increased. After reduction of immunosuppression, treatment is similar to non-transplant patients: Results are usually poor and cancer is now the third cause of death in transplant recipients. Due to their anti-proliferative and anti-tumoral properties, incidence of de novo cancer significantly decreased in patients receiving mTor inhibitors as maintenance immunosuppression; furthermore, in patients already diagnosed with Kaposi sarcoma or recurrent skin cancers, introduction of mTor was associated with stabilisation and/or regression of malignant lesions.

Treatment of post-transplantation lymphoproliferative disorders after kidney transplant with rituximab and conversion to m-TOR inhibitor.

BACKGROUND: Post-transplantation lymphoproliferative disorders are serious complications of organ transplantation which treatment is not yet standardized. OBJECTIVE: To describe the clinical response, overall and graft survival of patients in our center with this complication after kidney transplantation, which received rituximab as part of their treatment as well as conversion to m-TOR. METHODS: Retrospective study, which included patients, diagnosed with post-transplant lymphoproliferative disorders after kidney transplantation from January 2011 to July 2014. RESULTS: Eight cases were found with a wide spectrum of clinical presentations. Most had monomorphic histology, 85% were associated with Epstein-Barr virus, 25% of patients had tumor involvement of the renal graft, and 12.5% ​​had primary central nervous system lymphoma. All patients were managed with reduction of immunosuppression, conversion to m-TOR (except one who lost the graft at diagnosis) and rituximab-based therapy. The overall response rate was 87.5% (62.5% complete response, 25% partial response). Survival was 87.5% with a median follow-up of 34 months. An additional patient lost the graft, with chronic nephropathy already known. All the remaining patients had stable renal function. CONCLUSIONS: There are no standardized treatment regimens for lymphoproliferative disorders after kidney transplantation, but these patients can be managed successfully with reduction of immunosuppression, conversion to m-TOR and rituximab-based schemes.

ANTECEDENTE: La enfermedad linfoproliferativa post-trasplante es una complicación grave del trasplante de órganos cuyo tratamiento aún no se encuentra estandarizado. OBJETIVO: Describir la respuesta clínica, supervivencia global y del injerto en pacientes con esta complicación post trasplante renal en nuestro centro y que recibieron rituximab como parte de su tratamiento y la conversión a m-TOR. MÉTODOS: Estudio retrospectivo que incluyó pacientes con diagnóstico de enfermedad linfoproliferativa postrasplante renal entre enero de 2011 y julio de 2014. RESULTADOS: Se encontraron ocho casos, con presentaciones clínicas variables. La mayoría correspondieron a histología monomórfica, en 85% se asoció con virus de Epstein-Barr, 25% de los pacientes tenían compromiso tumoral del injerto renal y 12.5% linfoma primario de sistema nervioso central. Todos los pacientes se manejaron con reducción de inmunosupresión, conversión a m-TOR (excepto uno que perdió el injerto al diagnóstico) y tratamiento basado en rituximab. La tasa de respuesta global fue del 87.5% (62.5% respuesta completa, 25% respuesta parcial). La supervivencia fue del 87.5% con una mediana de seguimiento de 34 meses. Un paciente adicional perdió el injerto renal, con nefropatía crónica ya conocida. Los pacientes restantes con función renal estable. CONCLUSIONES: No existen esquemas estandarizados de tratamiento para la enfermedad linfoproliferativa post-trasplante renal, pero estos pacientes pueden ser manejados de forma exitosa con reducción de la inmunosupresión, conversión a m-TOR y esquemas basados en rituximab.

Lymphoproliferative disorders in inflammatory bowel disease patients on immunosuppression: Lessons from other inflammatory disorders.

Immunosuppressive agents, such as thiopurines, methotrexate, and biologics, have revolutionized the treatment of inflammatory bowel disease (IBD). However, a number of case reports, case control studies and retrospective studies over the last decade have identified a concerning link between immunosuppression and lymphoproliferative disorders (LPDs), the oncological phenomenon whereby lymphocytes divide uncontrollably. These LPDs have been associated with Epstein-Barr virus (EBV) infection in which the virus provides the impetus for malignant transformation while immunosuppression hampers the immune system's ability to detect and clear these malignant cells. As such, the use of immunosuppressive agents may come at the cost of increased risk of developing LPD. While little is known about the LPD risk in IBD, more is known about immunosuppression in the post-transplantation setting and the development of EBV associated post-transplantation lymphoproliferative disorders (PTLD). In review of the PTLD literature, evidence is available to demonstrate that certain immune suppressants such as cyclosporine and T-lymphocyte modulators in particular are associated with an increased risk of PTLD development. As well, high doses of immunosuppressive agents and multiple immunosuppressive agent use are also linked to increased PTLD development. Here, we discuss these findings in context of IBD and what future studies can be taken to understand and reduce the risk of EBV-associated LPD development from immunosuppression use in IBD.