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The main advantages of haploidentical hematopoietic stem cell transplantation (haplo-HSCT) are the immediate availability of donors, the possibility of developing cell therapy approaches with different novel transplant platforms, and the procedure's cost savings.We retrospectively analyzed the pediatric haplo-HSCT activity of the Spanish hematopoietic stem-cell transplantation group (GETH) between 1999 and 2016, aiming to study clinical characteristics and outcomes by describing patient groups with non-malignant disease (NMD) or malignant disease (MD) and the impact of 2 different periods (1999-2009 and 2010-2016) on long-term outcomes.Twelve centers performed 232 haplo-HSCTs in 227 children, representing 10% of all pediatric allogeneic HSCT activity in Spain from 1999 to 2016, with a notable increase since 2013. Most haplo-HSCTs (86.7%) were performed in patients with MD; 95% received peripheral blood stem cells from donors, and 78.9% received ex vivo T-cell depleted grafts. Non-manipulated grafts using post-transplantation cyclophosphamide have been incorporated since 2012. We observed a higher percentage of graft failure in NMD versus MD (32% vs. 15.6%; p=0.029). Relapse and transplant-related mortality were the procedure's main limitations in MD and NMD, respectively. Five-year overall survival was 48.5% (SE 3.9), with no statistically significant difference when comparing the MD and NMD cohorts. Patients who received previously a HSCT the overall survival was significantly decreased. We observed no survival improvement over time.Although haplo-HSCT is an increasingly employed treatment option, our patients' results need improvement. We need to develop reference centers, especially for NMD whose rarity makes it difficult to gain experience.

Resumen Introduccion Los resultados de los pacientes con diagnostico de leucemia linfoblastica aguda con cromosoma de Philadelphia (LLA-Ph) continuan siendo desfavorables comparados con los otros tipos de leucemias linfoblasticas agudas, pese a las mejoras en los tratamientos farmacologicos y los avances del trasplante de progenitores hematopoyeticos (TPH). Pacientes y metodos Se ha analizado el papel del TPH alogenico en pacientes diagnosticados de LLA-Ph mediante un estudio multicentrico donde se recogen datos pertenecientes a 70 pacientes reportados por el Grupo Espanol de Trasplante Hematopoyetico (GETH), diagnosticados de esta enfermedad trasplantados en distintos hospitales espanoles entre los anos 1998 y 2014. Resultados La realizacion del TPH a partir del ano 2004, en primera remision completa (RC) y con el empleo de timoglobulina (ATG) como parte del acondicionamiento, impacto favorablemente en la supervivencia global (SG). El TPH a partir del ano 2004 en primera RC, asi como el tratamiento con ATG y el desarrollo de enfermedad de injerto contra receptor aguda (EICRa), aumentaron la supervivencia libre de eventos (SLE). La administracion de imatinib, asi como la ausencia de enfermedad minima residual previas al TPH, junto con la EICRa redujeron la probabilidad de recaida. La edad del paciente inferior a 10 anos, el estado de primera RC y el empleo de ATG en el acondicionamiento disminuyeron la mortalidad relacionada con el TPH. Conclusiones Los pacientes en primera RC que han recibido ATG durante el acondicionamiento presentan mayores SG y SLE. La indicacion de TPH deberia considerarse en estas situaciones.

[Objective]: Describe the GETH haploidentical stem cell transplantation (haplo‐HSCT) activity in non‐malignant disease (NMDs)., [Methods]: We retrospectively analyzed data from children with NMDs who underwent haplo‐HSCT., [Results]: From January 2001 to December 2016, 26 pediatric patients underwent 31 haplo‐HSCT through ex vivo T cell‐depleted (TCD) graft platforms or post‐transplantation cyclophosphamide (PT‐Cy) at 7 Spanish centers. Five cases employed unmanipulated PT‐Cy haplo‐HSCT, 16 employed highly purified CD34+ cells, and 10 employed ex vivo TCD grafts manipulated either with CD3+CD19+ depletion, TCRαβ+CD19+ selection or naive CD45RA+ T‐cell depletion. Peripheral blood stem cells were the sole source for patients following TCD haplo‐HSCT, and bone marrow was the source for one PT‐Cy haplo‐HSCT. The most common indications for transplantation were primary immunodeficiency disorders (PIDs), severe aplastic anemia, osteopetrosis, and thalassemia. The 1‐year cumulative incidence of graft failure was 27.4%. The 1‐year III‐IV acute graft‐versus‐host disease (GvHD) and 1‐year chronic GvHD rates were 34.6% and 16.7%, respectively. The 2‐year overall survival was 44.9% for PIDs, and the 2‐year graft‐versus‐host disease‐free and relapse‐free survival rate was 37.6% for the other NMDs. The transplantation‐related mortality at day 100 was 30.8%., [Conclusion]: Although these results are discouraging, improvements will come if procedures are centralized in centers of expertise., This work was supported in part by the National Health Service of Spain, Carlos III Health Institute (ISCIII), FONDOS FEDER grant (FIS) PI18/01301, the CRIS Cancer Foundation (http://criscancer.org), and the Association Pablo Ugarte (http://www.asociacionpablougarte.es/).

A total of 192 pediatric patients, median age 8.6 years, with high‐risk hematological malignancies, underwent haploidentical stem cell transplantation (haplo‐HSCT) using post‐transplantation cyclophosphamide (PT‐Cy), or ex vivo T cell‐depleted (TCD) graft platforms, from January 1999 to December 2016 in 10 centers in Spain. Some 41 patients received an unmanipulated graft followed by PT‐Cy for graft‐vs‐host disease (GvHD) prophylaxis. A total of 151 patients were transplanted with CD3‐depleted peripheral blood stem cells (PBSCs) by either CD34+ selection, CD3+CD19+ depletion, TCRαβ+CD19+ depletion or CD45RA+ depletion, added to CD34+ selection for GvHD prophylaxis. The PBSCs were the only source in patients following ex vivo TCD haplo‐HSCT; bone marrow was the source in 9 of 41 patients following PT‐CY haplo‐HSCT. Engraftment was achieved in 91.3% of cases. A donor younger than 30 years, and the development of chronic GvHD were positive factors influencing survival, whereas positive minimal residual disease (MRD) before transplant and lymphoid disease were negative factors. The probability of relapse increased with lymphoid malignancies, a donor killer‐cell immunoglobulin‐like receptor (KIR) haplotype A and positive MRD pretransplant. No difference was found in overall survival, disease‐free survival or relapse incidence between the two platforms. Relapse is still of concern in both platforms, and it should be the focus of future efforts. In conclusion, both platforms for haplo‐HSCT were effective and could be utilized depending on the comfort level of the center., Research funding: National Health Service of Spain, Instituto de Salud Carlos III (ISCIII), FONDOS FEDER grant (FIS). Grant Number: PI18/01301, the CRIS Cancer Foundation, the Association Pablo Ugarte.

Background and objectives The treatment of childhood cancers has increased survival rates, but also the risk of sequelae, such as endocrine complications. The objective of this study is to evaluate the endocrine disorders in survivors of childhood malignant tumours within the first years after treatment and analyse the variables related to their appearance. Subjects and methods A retrospective medical record review of patients referred to paediatric endocrinology after treatment of malignancy. Outcome measures were frequency and types of endocrine dysfunction and new-onset obesity. Clinical and laboratory evaluations were performed every 6 months. Statistics tests were: chi square and multiple logistic regression . Results Fifty five patients (26 women) were included with an age at diagnosis of tumour (mean ± standard deviation) 6.0 ± 4.4 years and followed up for 6.8 ± 3.6 years. Thirty endocrine disorders were diagnosed in 26 patients (47.3%), 17 women ( p = 0.01). Eleven adolescents had primary hypogonadism (26.2% to 0.6 ± 0.5 years of follow-up) in relation to local irradiation (adjusted odds ratio [OR] 3.99, p = 0.005). Eleven patients had a pituitary disorder (20.0%) 5.2 ± 2.4 years after diagnosis in relation to brain irradiation (OR 1.54, p = 0.039). Six children (10.9%) had primary hypothyroidism from 3.2 ± 1.0 years of follow-up. Two children developed obesity. Conclusions Endocrine disorders are frequently seen within the first years after diagnosis of a childhood cancer, so hormonal evaluation should start early and be repeated periodically.

Resumen Fundamento y objetivos El tratamiento de las neoplasias infantiles ha aumentado las tasas de supervivencia, pero tambien el riesgo de desarrollar complicaciones tardias, muchas de tipo endocrino. El objetivo de este estudio es describir las endocrinopatias que se presentan en los primeros anos de seguimiento de las neoplasias infantiles y analizar las variables relacionadas con su aparicion. Sujetos y metodos Estudio retrospectivo de los pacientes remitidos a Endocrinologia Pediatrica tras el tratamiento de una neoplasia maligna. Como endocrinopatias se incluyeron las afecciones hormonales por exceso o por defecto y la obesidad de nueva aparicion. Las evaluaciones clinicas y analiticas se realizaron semestralmente. Pruebas estadisticas: chi cuadrado y regresion logistica multiple . Resultados Se incluyen 55 pacientes (26 mujeres) con una edad en el momento del diagnostico del tumor (media ± desviacion estandar) de 6,0 ± 4,4 anos y un seguimiento de 6,8 ± 3,6 anos. Se diagnosticaron 30 endocrinopatias en 26 pacientes (47,3%), de los que 17 eran mujeres (p = 0,01). Once adolescentes presentaron hipogonadismo primario (26,2%, a los 0,6 ± 0,5 anos de seguimiento), relacionandose su aparicion con la radioterapia pelvica ( odds ratio ajustada [OR] 3,99, p = 0,005). Once pacientes presentaron algun trastorno hipofisario (20,0%, a los 5,2 ± 2,4 anos tras el diagnostico) en relacion con radioterapia cerebral (OR 1,54, p = 0,039). Seis ninos (10,9%) presentaron hipotiroidismo primario a los 3,2 ± 1,0 anos de seguimiento. Dos ninos desarrollaron obesidad. Conclusiones Los ninos supervivientes de neoplasias malignas presentan diversas endocrinopatias ya en los primeros anos tras el tratamiento oncologico, por lo que la evaluacion hormonal debe iniciarse precozmente y repetirse de forma periodica.

Respiratory syncytial virus (RSV) is a potential cause of serious morbidity and even mortality among children undergoing hematopoietic SCT (HSCT). Contrary to the available information regarding the aerosolized formulation of ribavirin, there is a paucity of published studies using i.v. ribavirin in adults, and very few single reports on pediatric patients. Aerosolized drug administration has been limited by potential toxicity and special air-flow requirements. In this regard, i.v. ribavirin could prevent these disadvantages, but its efficacy and safety remain controversial in the pediatric HSCT setting. The present study describes the outcome of six pediatric patients undergoing HSCT with nine episodes of proven RSV. Four episodes corresponded to lower respiratory tract infection (LRTI) and five presented with upper respiratory tract infection (URTI). All LRTI patients showed favorable clinical responses, with 100% survival and no progression to LRTI in the remaining five URTI. No side effects were documented during ribavirin administration. We conclude that ribavirin was well tolerated intravenously, without associated side effects, and was effective in the treatment of RSV in this limited number of pediatric HSCT patients. The role and efficacy of i.v. ribavirin needs to be further clarified by prospective controlled trials in pediatric populations.

To address the prognostic value of minimal residual disease (MRD) before unrelated cord blood transplantation (UCBT) in children with acute lymphoblastic leukemia (ALL), we analyzed 170 ALL children transplanted in complete remission (CR) after myeloablative conditioning regimen. In all, 72 (43%) were in first CR (CR1), 77 (45%) in second CR (CR2) and 21 (12%) in third CR (CR3). The median interval from MRD quantification to UCBT was 18 days. All patients received single-unit UCBT. Median follow-up was 4 years. Cumulative incidence (CI) of day-60 neutrophil engraftment was 85%. CI of 4 years relapse was 30%, incidence being lower in patients with negative MRD before UCBT (hazard ratio (HR)=0.4, P=0.01) and for those transplanted in CR1 and CR2 (HR=0.3, P=0.002). Probability of 4 years leukemia-free survival (LFS) was 44%, (56, 44 and 14% for patients transplanted in CR1, CR2 and CR3, respectively (P=0.0001)). Patients with negative MRD before UCBT had better LFS after UCBT compared with those with positive MRD (54% vs 29%; HR=2, P=0.003). MRD assessment before UCBT for children with ALL in remission allows identifying patients at higher risk of relapse after transplantation. Approaches that may decrease relapse incidence in children given UCBT with positive MRD should be investigated to improve final outcomes.

Introduccion La leucemia mielomonocitica cronica juvenil (LMMC-j) es una entidad muy infrecuente durante la infancia. Su etiopatogenia, biologia y curso evolutivo no son bien conocidos. El mejor tratamiento para esta enfermedad es el trasplante alogenico de progenitores hematapoyeticos (TPH). Si se produce una recidiva con posterioridad a un TPH las opciones terapeuticas son ya muy limitadas. Presentamos nuestra experiencia utilizando infusiones secuenciales de linfocitos T del donante para el tratamiento de un nino afectado de una LMMC-j con perdida de quimerismo y recidiva biologica con cultivo de CFU-GM patologico a los 5 meses de habersele realizado un TPH alogenico de donante no relacionado. Caso clinico Lactante varon de 8 meses y 10 kg de peso diagnosticado en octubre de 2004 de LMMC-j. Cariotipo 46XY. Cultivo de CFU-GM patologico con crecimiento de colonias en ausencia de citocinas y abundantes macrolidos. Crupo sanguineo AD. No tenia donante familiar identico por lo que en junio de 2005 se le realizo un TPH de donante no relacionado de celulas progenitoras de sangre periferica, estando su enfermedad en el momento del TPH en actividad dado que no habia respondido previamente a un ciclo ICE. El TPH se acondiciono con busulfan, ciclofosfamida y melfalan. Profilaxis de EICH con ciclosporina y metotrexato. Tras el TPH alcanzo su primera remision completa citologica y ademas un cultivo de CFU-GM normal. El dia + 35 se objetivo un quimerismo completo, 100 %, por PCR en tiempo real de la serie leucocitaria y el dia + 65 presentaba el grupo sanguineo del donante (0 cde). El dia + 152 se aprecia perdida de quimerismo en serie leucocitaria y serie roja. Persistia en remision citologica pero de nuevo el cultivo de CFU-GM era patologico. Se realizaron dos infusiones de linfocitos T del donante separadas por 2 meses. Tras la primera (CD3 1,2 × 107/kg) se obtuvo el dia + 174 un quimerismo mixto del 2% en serie leucocitaria sin que presentara EICH aguda. Se decidio una segunda infusion de linfocitos T el dia + 222 por persistir identicos resultados en los sucesivos controles de quimerismo. La dosis de CD3 infundida fue 4,8 × 107/kg. El dia + 237 sufre una EICH aguda en piel grado II/III que se ha tratado con tacrolimus topico con buena respuesta. Se alcanzo un quimerismo mixto del 62% leucocitario. Adicionalmente el cultivo de CFU-GM en medula osea volvia a ser normal y de nuevo el grupo sanguineo era el del donante. En la actualidad persiste en igual situacion con una EICH cutanea de grado I. Conclusiones La hasta ahora evolucion favorable de nuestro paciente sugiere que esta enfermedad puede ser subsidiaria de tratamiento inmunologico con infusiones de linfocitos T del donante para el control de la perdida de quimera post-TPH. El hecho de que en este caso el cultivo de CFU-GM fuera patologico previamente a dichas infusiones no impidio que se restableciera la quimera tras las mismas. No ha sido necesario por tanto administrar quimioterapia para intentar conseguir la normalizacion del cultivo antes de las infusiones y la recuperacion de la quimera se ha obtenido en este caso con un procedimento que ha sido poco toxico y muy bien tolerado por nuestro paciente.

Abstract 532 Intensive and risk-adapted chemotherapy protocols may cure more than 80% of children with acute lymphoblastic leukemia (ALL). The detection of a positive minimal residual disease (MRD) in childhood ALL, is an independent prognostic factor of poor outcomes after chemotherapy treatment and has been used recently as a tool for risk stratification in most ALL treatment protocols. Its value before allogeneic related or unrelated hematopoietic stem cell transplantation (HSCT) has been described in small series of patients and it has been associated with outcomes. With the aim to investigate the prognostic significance of MRD before unrelated cord blood transplantation (UCBT) for ALL, we retrospectively analyzed children reported to the Eurocord registry. From 2000 to 2009, 316 children and adolescents with ALL in remission underwent a first single UCBT after a myeloablative conditioning regimen in 38 EBMT centers. Among these patients, 170 had an assessment of MRD before UCBT and were considered in this analysis. Of those, 72 patients underwent UCBT in first complete remission (CR), 77 in CR2 and 21 in CR3. The MRD assay was based on PCR (71%) or multiparameter flow cytometric analysis (FC) (29%). A positive MRD was defined according to treatment protocols of the various participating centers. MRD test before UCBT was positive (MRD+) in 74 patients (44%) and negative (MRD-) in 96 (56%). MRD was positive in 32 out of 72 patients in CR1, 31 out of 77 patients in CR2 and 11 out of 21 patients in CR3. The median interval from the last MRD test to UCBT was 18 days (12-42 days). The median follow-up was 46 months (4-104 months) and the median age at UCBT was 6.5 years (0.6-17 years). The most common immunephenotype was B-cell precursor ALL (83%). Of 72 patients transplanted in CR1, 56% had poor risk cytogenetics (t4;11 or t9;22). For patients in CR2 and CR3, the median interval between remission to relapse was 22 months (3-130 months). All patients received a TBI-based (63%) or Busulfan-based (37%), myeloablative conditioning regimen. GVHD prophylaxis consisted of cyclosporin (CSA) ± steroids in 75%. Sixty percent of cord blood units had 0–1 HLA mismatches with recipients and 40% had 2–3 mismatches (antigen level for HLA-A and B, allelic level for DRB1). Median infused TNC cell dose was 4.8 ×107/kg (1.30-18×107/kg) and median CD34+ was 1.8× 105/kg (1-10×105/kg). Cumulative incidence (CI) of day-60 neutrophil recovery (>500 mm3) and grade II-IV acute GVHD were 85±3% and 26±4%, respectively. Fifty-eight patients developed acute GVHD (grade 2, n=39, grade 3, n=14, grade 4, n= 5). The overall incidence of cGVHD was 17% at 4 years. Twenty-four patients had chronic GVHD (limited involvement, n=15, extensive disease, n=9). Overall CI of non-relapse mortality (NRM), relapse incidence (RI) and probability of leukemia free survival (LFS) at 4 years were 22±3%, 30±3%, and 44±4, respectively. In a univariate analysis, CI of NRM, RI and LFS at 4 years were 26±5%, 39±6%, and 29±5% in children with MRD+ and 20±4%, 24±3% and 54±5% in children with MRD- (p=0.08, p=0.05, p=0.006) respectively. In a multivariate analysis adjusted, a positive MRD before UCBT was an independent factor statistically associated with higher RI and decreased LFS (RI, HR=2.15, p=0.01, LFS, HR=1.97, p=0.003) (Figure 1). Also patients transplanted in more advanced status of disease at UCBT had higher RI and decreased LFS (RI, HR=4.25, p=0.002, LFS, HR=3.7, p= Estimated 4-year Leukemia free Survival according to MRD status before UCBT [(••• MRD negative) (— MRD positive)] Disclosures: No relevant conflicts of interest to declare.