Supportive Care During Pediatric Hematopoietic Stem Cell Transplantation: Prevention of Infections. A Report From Workshops on Supportive Care of the Paediatric Diseases Working Party (PDWP) of the European Society for Blood and Marrow Transplantation (EBMT)

Terapia profiláctica antibiótica; Niños; VacunaciónTeràpia profilàctica antibiòtica; Nens; VacunacióAntibiotic prophylactic therapy; Children; VaccinationSpecific protocols define eligibility, conditioning, donor selection, graft composition and prophylaxis of graft vs. host disease for children and young adults undergoing hematopoietic stem cell transplant (HSCT). However, international protocols rarely, if ever, detail supportive care, including pharmaceutical infection prophylaxis, physical protection with face masks and cohort isolation or food restrictions. Supportive care suffers from a lack of scientific evidence and implementation of practices in the transplant centers brings extensive restrictions to the child's and family's daily life after HSCT. Therefore, the Board of the Pediatric Diseases Working Party (PDWP) of the European Society for Blood and Marrow Transplantation (EBMT) held a series of dedicated workshops since 2017 with the aim of initiating the production of a set of minimal recommendations. The present paper describes the consensus reached within the field of infection prophylaxis

Desarrollo de neoplasias secundarias después del trasplante de progenitores hematopoyéticos realizado en edad pediátrica /

INTRODUCCIÓN: El trasplante de progenitores hematopoyético (TPH) es un procedimiento médico que permite la curación de numerosas enfermedades en edad pediátrica. Se ha descrito un riesgo aumentado de desarrollar una neoplasia secundaria en esta población de pacientes que representa una importante causa de mortalidad tardía. El objetivo de este estudio es analizar la incidencia de neoplasias secundarias y los posibles factores de riesgo asociados. PACIENTES Y MÉTODOS: Hemos analizado la evolución a largo plazo de 371 pacientes sometidos en edad pediátrica a un trasplante hematopoyético (alogénico o autólogo) en el Hospital de la Santa Creu i Sant Pau entre 1984 y 2013. Se ha calculado la incidencia acumulada de neoplasias secundarias a 30 años de seguimiento. Se ha realizado análisis univariante y multivariante de los factores de riesgo mediante test de Chi-cuadrado y el modelo de regresión logística binaria (Odds Ratio). Se ha analizado el exceso de riesgo de segundas neoplasias mediante comparación del número de casos observados en nuestra cohorte con el número de casos esperados en la población general utilizando el test de Chi-cuadrado. RESULTADOS: Hemos observado 19 casos de segundas neoplasias malignas, con una incidencia acumulada de 6% a 15 años, 12% a 20 años y 36% a 30 años de seguimiento. El riesgo ha sido superior a lo esperado en la población general por cada tipo de tumor y en los diferentes intervalos de edad. La enfermedad de injerto contra el huésped crónica, la irradiación corporal total durante el acondicionamiento y la radioterapia previa al trasplante han sido los factores que se han asociados con un aumento del riesgo. La mortalidad entre los pacientes que han desarrollado la neoplasia secundaria maligna ha sido del 42% siendo la causa de muerte en todos los casos. CONCLUSIONES: Hemos observado una incidencia de segundas neoplasias post-TPH del 5,1%, siendo significativamente más alta de lo esperado (p=0,000). Los factores que se han relacionado con un aumento del riesgo han sido la EICH crónica, la TBI y la RDT previa al TPH.INTRODUCCIÓN El trasplante de progenitores hematopoyético (TPH) es un procedimiento médico que permite la curación de numerosas enfermedades en edad pediátrica. Se ha descrito un riesgo aumentado de desarrollar una neoplasia secundaria en esta población de pacientes que representa una importante causa de mortalidad tardía. El objetivo de este estudio es analizar la incidencia de neoplasias secundarias y los posibles factores de riesgo asociados. PACIENTES Y MÉTODOS Hemos analizado la evolución a largo plazo de 371 pacientes sometidos en edad pediátrica a un trasplante hematopoyético (alogénico o autólogo) en el Hospital de la Santa Creu i Sant Pau entre 1984 y 2013. Se ha calculado la incidencia acumulada de neoplasias secundarias a 30 años de seguimiento. Se ha realizado análisis univariante y multivariante de los factores de riesgo mediante test de Chi-cuadrado y el modelo de regresión logística binaria (Odds Ratio). Se ha analizado el exceso de riesgo de segundas neoplasias mediante comparación del número de casos observados en nuestra cohorte con el número de casos esperados en la población general utilizando el test de Chi-cuadrado. RESULTADOS Hemos observado 19 casos de segundas neoplasias malignas, con una incidencia acumulada de 6% a 15 años, 12% a 20 años y 36% a 30 años de seguimiento. El riesgo ha sido superior a lo esperado en la población general por cada tipo de tumor y en los diferentes intervalos de edad. La enfermedad de injerto contra el huésped crónica, la irradiación corporal total durante el acondicionamiento y la radioterapia previa al trasplante han sido los factores que se han asociados con un aumento del riesgo. La mortalidad entre los pacientes que han desarrollado la neoplasia secundaria maligna ha sido del 42% siendo la causa de muerte en todos los casos. CONCLUSIONES Hemos observado una incidencia de segundas neoplasias post-TPH del 5,1%, siendo significativamente más alta de lo esperado (p=0,000). Los factores que se han relacionado con un aumento del riesgo han sido la EICH crónica, la TBI y la RDT previa al TPH.INTRODUCTION Hematopoietic stem cell transplantation (HSCT) is a medical procedure that allows the cure of many paediatric diseases. It has been described an increased risk of new malignancies in this population and it represents an important cause of late mortality. The purpose of this study is to analyse the incidence of secondary malignancies and the associated risk factors. PATIENTS AND METHODS We analyzed the late evolution of 371 patients submitted at pediatric age to hematopoietic transplantation (HSCT) (allogeneic or autologous) in Santa Creu i Sant Pau Hospital between 1984 and 2013. It has been calculated the cumulative incidence of secondary malignancies at 30 years of follow-up. It has been done univariate and multivariate analysis of risk factors through Chi-squared test and binary logistic regression method (Odds Ratio). It has been studied the risk excess for new malignancies through comparison of observed cases in our cohort with the expected cases in the general population by using Chi-squared test. RESULTS We observed 19 cases of secondary malignancies with a cumulative incidence of 6% at 15 years, 12% at 20 years and 36% at 30 years of follow-up. The risk was higher of expected in general population for each tumor type and in the different range of age. Chronic graft versus host disease, total body irradiation of conditioning and previous radiotherapy were the factors related with an increased risk. Mortality was 42% between patients with a new malignancy and it was the cause of death for all the cases. CONCLUSION We observed an incidence of secondary malignancies after HSCT of 5.1% that is significantly higher compared to the expected in the general population (p=0,000). The factors that have been related to an increased risk were chronic GvHD (graft versus host disease), TBI and radiotherapy administered previously

Supportive Care During Pediatric Hematopoietic Stem Cell Transplantation : Prevention of Infections. A Report From Workshops on Supportive Care of the Paediatric Diseases Working Party (PDWP) of the European Society for Blood and Marrow Transplantation (EBMT)

Specific protocols define eligibility, conditioning, donor selection, graft composition and prophylaxis of graft vs. host disease for children and young adults undergoing hematopoietic stem cell transplant (HSCT). However, international protocols rarely, if ever, detail supportive care, including pharmaceutical infection prophylaxis, physical protection with face masks and cohort isolation or food restrictions. Supportive care suffers from a lack of scientific evidence and implementation of practices in the transplant centers brings extensive restrictions to the child's and family's daily life after HSCT. Therefore, the Board of the Pediatric Diseases Working Party (PDWP) of the European Society for Blood and Marrow Transplantation (EBMT) held a series of dedicated workshops since 2017 with the aim of initiating the production of a set of minimal recommendations. The present paper describes the consensus reached within the field of infection prophylaxis.Peer reviewe

Immunotherapy with CAR-T cells in paediatric haematology-oncology

Despite being a rare disease, cancer is the first cause of mortality due to disease during the paediatric age in the developed countries. The current, great increase in new treatments, such as immunotherapy, constitutes a new clinical and regulatory paradigm. Cellular immunotherapy is one of these types of immunotherapy. In particular, the advanced therapy drugs with chimeric antigen receptors in the T-lymphocytes (CAR-T), and particularly the CAR-T19 cells, has opened up a new scenario in the approach to haematology tumours like acute lymphoblastic leukaemia and the B-Cell lymphomas. The approval of tisagenlecleucel and axicabtagene ciloleucel by the regulatory authorities has led to the setting up of the National Plan for Advanced Therapies-CAR-T drugs in Spain. There is evidence of, not only the advantage of identifying the centres most suitable for their administration, but also the need for these to undergo a profound change in order that their healthcare activity is extended, in some cases, to the ability for the in-house manufacture of these types of therapies. The hospitals specialised in paediatric haematology-oncology thus have the challenge of progressing towards a healthcare model that integrates cellular immunotherapy, having the appropriate capacity to manage all aspects relative to their use, manufacture, and administration of these new treatments.A pesar de ser una enfermedad rara, el cáncer es la primera causa de mortalidad por enfermedad durante la edad pediátrica en los países desarrollados. En este momento, la irrupción de nuevos tratamientos como la inmunoterapia constituye un nuevo paradigma clínico y regulatorio. Uno de estos tipos de inmunoterapia es la inmunoterapia celular. En particular, los medicamentos de terapia avanzada con receptores antigénicos quiméricos en los linfocitos T (CAR-T), y en concreto las células CAR-T19, han supuesto un nuevo escenario en el abordaje de los tumores hematológicos, como la leucemia aguda linfoblástica y los linfomas de células tipo B. La aprobación por las autoridades regulatorias de tisagenlecleucel y axicabtagene ciloleucel,ha impulsado la puesta en marcha del Plan Nacional de Terapias Avanzadas-Medicamentos CAR-T en España, evidenciándose no solo la conveniencia de identificar los centros más adecuados para su administración, sino la necesidad de que estos sufran una profunda transformación para que su actividad asistencial se extienda en algunos casos a la capacidad de fabricación propia de este tipo de terapias. Los hospitales especializados en hematooncología pediátrica tienen por tanto el reto de evolucionar hacia un modelo asistencial que integre la inmunoterapia celular,dotándose de capacidad propia para gestionar todos los aspectos relativos al uso, fabricación y administración de estos nuevos tratamientos.Fundación CRIS contra el cáncer

Risk factors and outcome of COVID-19 in patients with hematological malignancies

Background: Prognostic factors of poor outcome in patients with hematological malignancies and COVID-19 are poorly defned. Patients and methods: This was a Spanish transplant group and cell therapy (GETH) multicenter retrospective observational study, which included a large cohort of blood cancer patients with laboratory-confrmed SARS-CoV-2 infection through PCR assays from March 1st 2020 to May 15th 2020. Results: We included 367 pediatric and adult patients with hematological malignancies, including recipients of autologous (ASCT) (n=58) or allogeneic stem cell transplantation (allo-SCT) (n=65) from 41 hospitals in Spain. Median age of patients was 64 years (range 1-93.8). Recipients of ASCT and allo-SCT showed lower mortality rates (17% and 18%, respectively) compared to non-SCT patients (31%) (p=0.02). Prognostic factors identifed for day 45 overall mortality (OM) by logistic regression multivariate analysis included age>70 years [odds ratio (OR) 2.1, 95% con‑ fdence interval (CI) 1.2-3.8, p=0.011]; uncontrolled hematological malignancy (OR 2.9, 95% CI 1.6-5.2, p20 mg/dL (OR 3.3, 95% CI 1.7-6.4, p<0.0001). In multivariate analysis of 216 patients with very severe COVID-19, treatment with azithromycin or low dose corticosteroids was associated with lower OM (OR 0.42, 95% CI 0.2-0.89 and OR 0.31, 95% CI 0.11-0.87, respectively, p=0.02) whereas the use of hidroxycloroquine did not show signifcant improvement in OM (OR 0.64, 95% CI 0.37-1.1, P=0.1). Conclusions: In most patients with hematological malignancies COVID-19 mortality was directly driven by older age, disease status, performance status, as well as by immune (neutropenia) parameters and level of infammation (high CRP). Use of azithromycin and low dose corticosteroids may be of value in very severe COVID-19

Desarrollo de neoplasias secundarias después del trasplante de progenitores hematopoyéticos realizado en edad pediátrica

INTRODUCCIÓN El trasplante de progenitores hematopoyético (TPH) es un procedimiento médico que permite la curación de numerosas enfermedades en edad pediátrica. Se ha descrito un riesgo aumentado de desarrollar una neoplasia secundaria en esta población de pacientes que representa una importante causa de mortalidad tardía. El objetivo de este estudio es analizar la incidencia de neoplasias secundarias y los posibles factores de riesgo asociados. PACIENTES Y MÉTODOS Hemos analizado la evolución a largo plazo de 371 pacientes sometidos en edad pediátrica a un trasplante hematopoyético (alogénico o autólogo) en el Hospital de la Santa Creu i Sant Pau entre 1984 y 2013. Se ha calculado la incidencia acumulada de neoplasias secundarias a 30 años de seguimiento. Se ha realizado análisis univariante y multivariante de los factores de riesgo mediante test de Chi-cuadrado y el modelo de regresión logística binaria (Odds Ratio). Se ha analizado el exceso de riesgo de segundas neoplasias mediante comparación del número de casos observados en nuestra cohorte con el número de casos esperados en la población general utilizando el test de Chi-cuadrado. RESULTADOS Hemos observado 19 casos de segundas neoplasias malignas, con una incidencia acumulada de 6% a 15 años, 12% a 20 años y 36% a 30 años de seguimiento. El riesgo ha sido superior a lo esperado en la población general por cada tipo de tumor y en los diferentes intervalos de edad. La enfermedad de injerto contra el huésped crónica, la irradiación corporal total durante el acondicionamiento y la radioterapia previa al trasplante han sido los factores que se han asociados con un aumento del riesgo. La mortalidad entre los pacientes que han desarrollado la neoplasia secundaria maligna ha sido del 42% siendo la causa de muerte en todos los casos. CONCLUSIONES Hemos observado una incidencia de segundas neoplasias post-TPH del 5,1%, siendo significativamente más alta de lo esperado (p=0,000). Los factores que se han relacionado con un aumento del riesgo han sido la EICH crónica, la TBI y la RDT previa al TPH.INTRODUCTION Hematopoietic stem cell transplantation (HSCT) is a medical procedure that allows the cure of many paediatric diseases. It has been described an increased risk of new malignancies in this population and it represents an important cause of late mortality. The purpose of this study is to analyse the incidence of secondary malignancies and the associated risk factors. PATIENTS AND METHODS We analyzed the late evolution of 371 patients submitted at pediatric age to hematopoietic transplantation (HSCT) (allogeneic or autologous) in Santa Creu i Sant Pau Hospital between 1984 and 2013. It has been calculated the cumulative incidence of secondary malignancies at 30 years of follow-up. It has been done univariate and multivariate analysis of risk factors through Chi-squared test and binary logistic regression method (Odds Ratio). It has been studied the risk excess for new malignancies through comparison of observed cases in our cohort with the expected cases in the general population by using Chi-squared test. RESULTS We observed 19 cases of secondary malignancies with a cumulative incidence of 6% at 15 years, 12% at 20 years and 36% at 30 years of follow-up. The risk was higher of expected in general population for each tumor type and in the different range of age. Chronic graft versus host disease, total body irradiation of conditioning and previous radiotherapy were the factors related with an increased risk. Mortality was 42% between patients with a new malignancy and it was the cause of death for all the cases. CONCLUSION We observed an incidence of secondary malignancies after HSCT of 5.1% that is significantly higher compared to the expected in the general population (p=0,000). The factors that have been related to an increased risk were chronic GvHD (graft versus host disease), TBI and radiotherapy administered previously

Desarrollo de neoplasias secundarias después del trasplante de progenitores hematopoyéticos realizado en edad pediátrica

INTRODUCCIÓN El trasplante de progenitores hematopoyético (TPH) es un procedimiento médico que permite la curación de numerosas enfermedades en edad pediátrica. Se ha descrito un riesgo aumentado de desarrollar una neoplasia secundaria en esta población de pacientes que representa una importante causa de mortalidad tardía. El objetivo de este estudio es analizar la incidencia de neoplasias secundarias y los posibles factores de riesgo asociados. PACIENTES Y MÉTODOS Hemos analizado la evolución a largo plazo de 371 pacientes sometidos en edad pediátrica a un trasplante hematopoyético (alogénico o autólogo) en el Hospital de la Santa Creu i Sant Pau entre 1984 y 2013. Se ha calculado la incidencia acumulada de neoplasias secundarias a 30 años de seguimiento. Se ha realizado análisis univariante y multivariante de los factores de riesgo mediante test de Chi-cuadrado y el modelo de regresión logística binaria (Odds Ratio). Se ha analizado el exceso de riesgo de segundas neoplasias mediante comparación del número de casos observados en nuestra cohorte con el número de casos esperados en la población general utilizando el test de Chi-cuadrado. RESULTADOS Hemos observado 19 casos de segundas neoplasias malignas, con una incidencia acumulada de 6% a 15 años, 12% a 20 años y 36% a 30 años de seguimiento. El riesgo ha sido superior a lo esperado en la población general por cada tipo de tumor y en los diferentes intervalos de edad. La enfermedad de injerto contra el huésped crónica, la irradiación corporal total durante el acondicionamiento y la radioterapia previa al trasplante han sido los factores que se han asociados con un aumento del riesgo. La mortalidad entre los pacientes que han desarrollado la neoplasia secundaria maligna ha sido del 42% siendo la causa de muerte en todos los casos. CONCLUSIONES Hemos observado una incidencia de segundas neoplasias post-TPH del 5,1%, siendo significativamente más alta de lo esperado (p=0,000). Los factores que se han relacionado con un aumento del riesgo han sido la EICH crónica, la TBI y la RDT previa al TPH.INTRODUCTION Hematopoietic stem cell transplantation (HSCT) is a medical procedure that allows the cure of many paediatric diseases. It has been described an increased risk of new malignancies in this population and it represents an important cause of late mortality. The purpose of this study is to analyse the incidence of secondary malignancies and the associated risk factors. PATIENTS AND METHODS We analyzed the late evolution of 371 patients submitted at pediatric age to hematopoietic transplantation (HSCT) (allogeneic or autologous) in Santa Creu i Sant Pau Hospital between 1984 and 2013. It has been calculated the cumulative incidence of secondary malignancies at 30 years of follow-up. It has been done univariate and multivariate analysis of risk factors through Chi-squared test and binary logistic regression method (Odds Ratio). It has been studied the risk excess for new malignancies through comparison of observed cases in our cohort with the expected cases in the general population by using Chi-squared test. RESULTS We observed 19 cases of secondary malignancies with a cumulative incidence of 6% at 15 years, 12% at 20 years and 36% at 30 years of follow-up. The risk was higher of expected in general population for each tumor type and in the different range of age. Chronic graft versus host disease, total body irradiation of conditioning and previous radiotherapy were the factors related with an increased risk. Mortality was 42% between patients with a new malignancy and it was the cause of death for all the cases. CONCLUSION We observed an incidence of secondary malignancies after HSCT of 5.1% that is significantly higher compared to the expected in the general population (p=0,000). The factors that have been related to an increased risk were chronic GvHD (graft versus host disease), TBI and radiotherapy administered previously

Subsequent malignancies after long-term follow-up of pediatric hematopoietic stem cell transplantation Neoplasias malignas secundarias después de un trasplante de progenitores hematopoyéticos en edad pediátrica

Survival after hematopoietic stem cell transplantation has improved dramatically in recent years. Unfortunately, there is an increased risk of subsequent malignant neoplasms (SMN) in this population and this represents a significant cause of late mortality. In this study, we analyzed the incidence of SMN and the associated risk factors in patients referred at a pediatric age for hematopoietic stem cell transplantation (allogeneic or autologous) in our center. We observed 19 cases of SMN in a cohort of 371 patients, with a cumulative incidence of 6, 12, and 36% at 15, 20, and 30 years of follow-up, respectively. The solid tumors were the most prevalent malignancies. The risk was significantly higher than expected in the general population for each tumor type and in the different age ranges (p<.0001). Radiotherapy and chronic GvHD were the main risk factors for the development of SMN in our series. We observed a high incidence of SMN among hematopoietic stem cell transplantation survivors highlighting the need for life-long surveillance

High Incidence of Early Human Herpesvirus-6 Infection in Children Undergoing Haploidentical Manipulated Stem Cell Transplantation for Hematologic Malignancies

Human herpesvirus-6 (HHV-6) infection is increasingly recognized among allogeneic hematopoietic stem cell transplantation (HSCT) recipients, with 30% at risk of reactivation in the haploidentical setting. It has been associated with encephalitis, acute graft-versus-host disease, and graft failure. Here we report 2 cohorts of pediatric haploidentical manipulated HSCT in which, despite many differences, HHV-6 reactivation and disease occurred with very high incidence compared with data reported in the literature and represented the main early post-transplant infectious complication compared with other viral, bacterial, or fungal infections. The 2 cohorts were recruited at the pediatric transplant centers of Perugia (n\u202f=\u202f13), Barcelona (n\u202f=\u202f10), and Madrid (n\u202f=\u202f15). All patients received myeloablative conditioning regimens and 2 different types of ex vivo graft manipulation: CD34+ selection and regulatory T cell/conventional T cell infusion in 13 patients and CD45RA T cell depletion in 25 patients. Antiviral prophylaxis was acyclovir in 33 and foscarnet in 5 patients. HHV-6 DNAemia was checked by quantitative or qualitative PCR. In vitro experiments demonstrated that donor CD4+ T cells are the reservoir of HHV-6 and suggested a role of the graft composition in both transplant settings (rich in CD4+ T cells) in the high rate of HHV-6 infections. All patients presented very early HHV-6 DNAemia after transplantation, and although viremic, 9 patients (24%) developed symptomatic limbic encephalitis. All patients responded to antiviral treatment, and none died of infection, although 2 experienced long-term neurologic sequelae (22%). Moreover, 6 patients presented organ involvement in absence of other causes: 1 hepatitis, 1 pneumonia, 2 gastroenteritis, and 2 multiorgan involvement(1 encephalitis, pneumonia, and gastritis; 1 pneumonia and enteritis). Incidences of other viral, bacterial, and fungal diseases were lower in both cohorts. In vitro, HHV-6 was found to infect only CD4+ fraction of the graft. Co-culturing CD4+ T cells with CD56+ natural killer (NK) cells eliminated the virus, demonstrating the main role of NK cells in the antiviral immune response. All 38 pediatric patients undergoing these manipulated haploidentical HSCTs showed HHV-6 reactivation, and 14 of 38 developed HHV-6 disease with similar features in terms of timing, morbidity, response to treatment, and outcome. The graft composition in both transplant platforms, rich in CD4+ T cells and poor in NK cells, seems to play a key role. HHV-6 DNAemia surveillance was useful to diagnose and treat preemptively HHV-6 infection

Impact of Human Herpes Virus (HHV)-6 infection in manipulated haploidentical stem cell transplantation in children

Retrospective study of HHV-6 infection and disease after haploidentical stem cell transplan