Survival and toxicity outcomes of hematopoietic stem cell transplantation for pediatric patients with Fanconi anemia: a unified multicentric national study from the Spanish Working Group for Bone Marrow Transplantation in Children.

Hematopoietic stem cell transplantation (HSCT) is currently the only curative option for hematological manifestations in patients with Fanconi anemia (FA). We report the outcome of 34 patients with FA inside a collaborative multicenter national study based on recommendations of Spanish Working Group for Bone Marrow Transplantation in Children (GETMON) between 2009 and 2016. Fludarabine-based conditioning regimen was carried out in all patients, with low dose total body irradiation in unrelated transplants. Disease status before HSCT was bone marrow failure (BMF) in 30 patients and myelodysplastic syndrome (MDS) in four. Donors were matched siblings donors (MSD) in 18, matched unrelated donors (MUD) in 15, and one haploidentical donor. All except one patient engrafted. Cumulative incidence of grades II-IV acute graft-versus-host disease (GVHD) was 29% and 11% for chronic GVHD. Median follow-up after HSCT was 6.5 years. Seven patients (21%) died due to transplant-related causes, two (6%) because of MDS relapse, and one (3%) after a squamous cell carcinoma. Overall survival (OS) was 73% at 5 years post-transplant, with no differences between MSD and MUD transplants. OS for patients with BMF was 80% while for MDS was 25%. Our data suggest HSCT can cure hematologic manifestations of most FA patients with BMF.

[Severe acquired aplastic anemia: historical outcome of patients treated by allogeneic bone marrow transplantation from matched sibling donors. A study by the Spanish Group for Bone Marrow Transplantation in Children (GETMON)]. / Aplasia medular grave adquirida: evolución histórica de los resultados obtenidos con trasplante de progenitores hematopoyéticos de donante familiar. Estudio del Grupo Español para el Trasplante de Médula Osea en Niños (GETMON).

INTRODUCTION: Allogeneic haematopoietic stem-cell transplantation is the treatment of choice for acquired aplastic anaemia in children. Experience with this approach from Spanish Working Party for Bone Marrow Transplantation in Children in two sequential time periods (1982-1990 and 1991-2004) is reported. PATIENTS AND METHODS: Sixty two consecutive patients with a median age of 10 years were transplanted; 18 in the 1982-1990 period and 44 in the 1991-2004 period. Conditioning regimen consisted mainly of irradiation and cyclophosphamide in the first period (72 % of patients) and cyclophosphamide +/- anti-thymocyte globulin (62 %) in the second. Graft versus host disease prophylaxis consisted of cyclosporine in most patients (57/62). RESULTS: Fifty one patients are alive and disease-free at a median follow-up of 127 months. Five years probability of event-free survival is 82 %. The survival increased from 61 % to 91 % during the two time periods. Eleven patients died from graft failure or rejection (3), acute or chronic graft versus host disease and infection (4) or multi-organ failure (4). Univariate analysis identified two significant prognostic factors: interval diagnostic/transplant and time period of transplant (for both p = 0.03). CONCLUSIONS: This experience corroborates that allogeneic haematopoietic stem-cell transplantation is the best treatment for severe acquired aplastic anaemia, with a current disease-free survival of 90 % of patients.

Aplasia medular grave adquirida: evolución histórica de los resultados obtenidos con trasplante de progenitores hematopoyéticos de donante familiar. Estudio del Grupo Español para el Trasplante de Médula Ósea en Niños (GETMON) / Severe acquired aplastic anemia: historical outcome of patients treated by allogeneic bone marrow transplantation from matched sibling donors. A study by the Spanish Group for Bone Marrow Transplantation in Children (GETMON)

Introducción: El trasplante de progenitores hematopoyéticos (TPH) de donante familiar compatible es el tratamiento de elección en la aplasia medular adquirida (AMA) grave en la infancia. Se presenta la experiencia de Grupo Español para el Trasplante de Médula Ósea en Niños en esta enfermedad a lo largo del período cronológico 1982-2004. Pacientes y métodos: Recibieron un trasplante 62 pacientes con una mediana de edad de 10 años. En el período 1982-1990 lo recibieron 18 pacientes y en el período 1991-2004, 44. El régimen de acondicionamiento varió según el período cronológico; en el primero se utilizó preferentemente la asociación de radioterapia y ciclofosfamida (72 % de los casos) y en el segundo ciclofosfamida con o sin globulina antitimocitaria (62 %). La profilaxis de enfermedad injerto contra huésped más utilizada fue la ciclosporina (57/62 pacientes). Resultados: Un total de 51 pacientes están vivos y en remisión completa de su aplasia con períodos de observación de entre 24 y 289 meses (mediana de 127 meses). La probabilidad de supervivencia actuarial libre de eventos a 5 años es del 82 %. Dicha supervivencia se incrementó del 61 al 90 % entre los dos períodos analizados. Un total de 11 pacientes fallecieron por fracaso o pérdida del injerto (3), enfermedad injerto contra huésped aguda o crónica asociada a infecciones (4) o fallo multiorgánico (4). El análisis univariante evidenció dos factores con valor predictivo para la supervivencia: el intervalo diagnóstico/trasplante y el período cronológico en que se efectuó (en ambos, p = 0,03). Conclusiones: Esta experiencia confirma que el trasplante de progenitores hematopoyéticos de donante familiar compatible es el tratamiento de elección para la aplasia medular grave adquirida, con un porcentaje de supervivencia libre de episodios del 90 % en la actualidad (AU)

Allogeneic haematopoietic stem-cell transplantation is the treatment of choice for acquired aplastic anaemia in children. Experience with this approach from Spanish Working Party for Bone Marrow Transplantation in Children in two sequential time periods (1982-1990 and 1991-2004) is reported. Patients and methods: Sixty two consecutive patients with a median age of 10 years were transplanted; 18 in the 1982-1990 period and 44 in the 1991-2004 period. Conditioning regimen consisted mainly of irradiation and cyclophosphamide in the first period (72 % of patients) and cyclophosphamide ± anti-thymocyte globulin (62 %) in the second. Graft versus host disease prophylaxis consisted of cyclosporine in most patients (57/62). Results: Fifty one patients are alive and disease-free at a median follow-up of 127 months. Five years probability of event-free survival is 82 %. The survival increased from 61 % to 91 % during the two time periods. Eleven patients died from graft failure or rejection (3), acute or chronic graft versus host disease and infection (4) or multi-organ failure (4). Univariate analysis identified two significant prognostic factors: interval diagnostic/transplant and time period of transplant (for both p = 0.03). Conclusions: This experience corroborates that allogeneic haematopoietic stem-cell transplantation is the best treatment for severe acquired aplastic anaemia, with a current disease - free survival of 90 % of patients (AU)

Resultados terapéuticos en la leucemia llinfoblástica aguda infantil con los protocolos SHOP de la Sociedad Española de hematología Pediátrica (SEHP) y la Sociedad Española de Oncología Pediátrica (SEOP) 1989-2005 / No disponible

Se presentan los resultados obtenidos por los protocolos los SHOP-89, SHOP-94 y SHOP-99 de las Sociedades Españolas de Hematología y Oncología Pediátricas en el tratamiento de Hematología y Oncología Pediátricas en el tratamiento de la leucemia aguda linfoblástica infantil. Se trata de los primeros protocolos exclusivamente pediátricos puestos en marcha en España, con los objetivos de mejorar los resultados y unificar los criterios diagnóstico-terapéuticos. Se excluyeron de su aplicación los niños menores de 1 año y los inmunofenotípicamente B. entre enero de 1989 y mayo de 2005 se incluyeron en estos protocolos 1.168 pacientes evaluables: 250 en el SHOP-89, 423 en el SHOP-94 y 495 en el SHOP-99. La supervivencia libre de eventos se incrementó desde el 57% en el SHOP-89 AL 69% en el SHOP-94 y al 79% en el SHOP-99 (p=0,002). En los pacientes de riesgo estándar, la SLE pasó del 62 al 80 y al 88%, respectivamente (p=0,024). La SLE acumulada en los pacientes de algo y muy algo riesgo pasó del 51 al 61 y al 75% (p=0,001) (AU)

The results obtained by the SHOP-89, SHOP-94 and SHOP-99 protocols of the Spanish Scoieties of Hematology and Pediatric Oncology in the treatment of infant acute lymphoblastic leukemia are presented. These are the first exclusively pediatric protocols initiated in Spain in order to improve results and unify the diagnostic-therapeutic criteria. Infants under 1 year and those who were immunophentypically B were excluded from their application. A total of 1.168 evaluable patients were excluded in these protocols between January 1989 and May 2005; 250 in SHOP-89, 423 in SHOP-94 and 495 in SHOP-99. Event free survival increased from 58% in SHOP-89 to 69% in SHOP-94 and to 79% in SHOP-99 (p=0.002). In patients with standard risk, systemic lupus erythematosus (SLE) went from 62% to 80% and 88% respectively (p=0.024). Acumulated SLE inpatients with high and very high risk went from 51% to 61% and 75% (p=0.001) (AU)

Trombosis venosa renal en recién nacida portadora de la mutación G20210A del gen de la protombina / Renal venous thrombosis in a neonate carrying the G20210a mutation of the prothrombin gene

No disponible

Deficiencia de zinc sintomática en prematuros alimentados con lactancia materna / Symptomatic zinc deficiency in breast-fed infants

La deficiencia sintomática de zinc en prematuros alimentados con lactancia materna exclusiva es un trastorno adquirido cuyas manifestaciones clínicas pueden ser similares a las de la acrodermatitis enteropática (AE) hereditaria. Los síntomas remiten tras la administración de suplementos orales de zinc. Caso clínico: lactante, varón, de 4 meses de edad, con antecedentes de prematuridad, que fue alimentado durante 8 días con nutrición parenteral en el periodo neonatal y posteriormente con lactancia materna exclusiva. A los 2 meses de vida presentó diarrea persistente, vómitos y lesiones cutáneas eczematosas, de predominio acro y periorificial. Los exámenes complementarios revelaron bajos niveles de zinc en el suero del lactante (3µmol/l) y en leche materna (8µmol/l), con niveles normales de zinc en suero materno (17µmol/l). Se efectuó tratamiento con sulfato de zinc oral (2mg/Kg), remitiendo los síntomas sin recidivas posteriores. Conclusión: El reconocimiento de la deficiencia sintomática de zinc en prematuros hijos de madre con leche deficitaria en zinc es importante, ya que el tratamiento es eficaz y definitivo. La nutrición parenteral sin suplementos de zinc puede agravar el déficit. En los lactantes de riesgo es recomendable determinar niveles séricos de zinc

Symptomatic zinc deficiency in breast-fed infants is a severe disorder, caused by a low level of zinc in mother’s milk. Premature infants are more vulnerable to develop zinc deficiency than full-term infants. The clinical symptoms resemble those of hereditary acrodermatitis enterophatica (AE). In acquired zinc deficiencies the disorder is transient and patients respond well to oral zinc supplements. Clinical case: A 4 month-old exclusively breast-fed premature infant presented with persistent diarrhea, vomiting and eczematoid skin lesions, with acral and peri-orificial dermatitis resembling AE. The symptoms began at 2 months of age. She received parenteral nutrition for the first eight days followed by mother’s milk exclusively. Laboratory investigations revealed lowered zinc levels in the infant’s serum (3µmol/l) and in her mother’s milk (8µmol/l), with normal level of zinc in the mother’s serum (17µmol/l). Healing was rapid after oral zinc supplementation (zinc sulphate 2mg/Kg), with complete remission of the symptoms. Conclusions: Recognition of zinc deficiency in premature newborns to mothers who seem to secrete milk that is zinc- deficiency is essential because its treatment is effective. This may lead to severe symptomatic zinc deficiency in premature infants, requiring treatment with oral zinc supplement. Parenteral nutrition without zinc supplements may be a contributory factor to zinc deficiency in preterm infants. Serum zinc levels should be checked in at-risk babies

[Long and medium-term neuropsychological sequelae of bone marrow transplantation in pediatric patients with hematological disease]. / Secuelas neuropsicológicas a medio y largo plazo del trasplante de medula ósea en pacientes con enfermedades hematológicas.

BACKGROUND: Few studies exist on the neuropsychological sequelae of bone marrow transplantation (BMT) in pediatric patients. Published results show considerable discrepancies although studies of children with acute lymphoblastic leukemia undergoing high doses of cranial radiotherapy report short- and long-term loss of cognitive ability. OBJECTIVES: To determine the effects of BMT and the effect of anxiety on the pre-BMT assessment in a group of children with severe hematological disease treated in our center. METHODS: We performed a descriptive, prospective, longitudinal study of 54 children, aged 4-15 years, who were treated between 1987 and 1995. Twenty-two children were evaluated before and after BMT by means of the Weschler Intelligence Scale. To control for the effect of anxiety on the pre-BMT scores, the patients were divided into two groups according to the scores obtained in this test (group 1: IQ score 100; group 1: IQ100). RESULTS: Comparison of pre- and post-BMT scores for both groups revealed no significant differences. However, comparison of the results between groups revealed that group I scored lower in the post-BMT test than in the pre-BMT test while group I scored higher in the post-BMT test than in the pre-BMT test. CONCLUSIONS: Although comparison between the pre- and post-BMT results obtained from the whole sample showed no differences that indicated post-treatment sequelae, treatment-induced anxiety may have influenced the pre-BMT score.

Secuelas neuropsicológicas a medio y largo plazo del trasplante de medula ósea en pacientes con enfermedades hematológicas / Long and medium-term neuropsychological sequelae of bone marrow transplantation in pediatric patients with hematological disease

Antecedentes: Existen pocos estudios sobre las secuelas neurocognitivas del trasplante de medula ósea (TMO) en pacientes pediátricos, y sus resultados a menudo son divergentes, aunque los estudios con niños enfermos de leucemia sometidos a altas dosis de radioterapia craneal muestran pérdida de capacidad cognitiva a medio y largo plazo. Objetivos: Conocer los efectos del TMO en un grupo de niños con graves enfermedades hematológicas tratados en nuestro centro, y el impacto de la ansiedad en la evaluación previa al TMO. Métodos: Se realizó un estudio descriptivo prospectivo y longitudinal, desde 1987 hasta 1995 con un grupo 54 niños, de entre 4 y 15 años. De este grupo 22 niños se evaluaron antes y después del TMO mediante la Escala de Inteligencia de Wechsler para niños (Wechsler Intelligence Scale, WIS). Con el fin de controlar el impacto de la ansiedad sobre el rendimiento de la evaluación previa al TMO se dividieron los pacientes en 2 grupos según la puntuación obtenida en dicha evaluación: grupo 1, cociente de inteligencia total (CIT) menor o igual a 100; grupo 2, CIT mayor de 100. Resultados: En la comparación entre los resultados de los 2 grupos pretrasplante y postrasplante del grupo inicial no se observaron diferencias significativas, pero al comparar los resultados por grupos, se observó un descenso significativo en el grupo 2, el que había puntuado más alto en la evaluación previa al TMO, mientras que el grupo 1 aumentaba su rendimiento. Conclusiones: Si bien en una primera comparación entre los resultados pretrasplante y postrasplante de la muestra no parece existir diferencias que muestren secuelas postratamiento, la ansiedad producida por el mismo pudo haber influido en la evaluación pretrasplante, de tal forma que enmascarase los efectos de éste (AU)

Trasplante de progenitores hematopoyéticos de sangre de cordón umbilical en niños / Transplantation of umbilical cord blood hematopoietic progenitor cells in children

OBJETIVO: Estudio retrospectivo de los resultados del trasplante de progenitores hematopoyéticos de sangre de cordón umbilical en España. MÉTODOS: Veintiocho niños con edad media de 6,5 años y peso medio de 25 kg recibieron un trasplante de sangre de cordón umbilical entre julio de 1994 y mayo de 1998 en distintos centros pertenecientes al Grupo Español para el Trasplante de Medula ósea en niños (GETMON). El donante fue en 2 pacientes un hermano HLA idéntico, en otros 2 pacientes un familiar no idéntico y en los 24 restantes un donante no emparentado. Entre éstos, la identidad antigénica HLA (A, B y DR) 6/6 sólo se observaba en 3 pacientes. Los trasplantes se realizaron en su mayoría por leucemia (21pacientes, 75) y en fase avanzada. Los restantes 7 pacientes se trasplantaron por una enfermedad genética, en su mayoría inmunodeficiencia congénita. El tratamiento de acondicionamiento incluyó irradiación corporal total en 10 pacientes y poliquimioterapia en los restantes. La profilaxis de la enfermedad del injerto contra huésped aguda se realizó con ciclosporina en todos los casos añadiendo corticoides o metotrexato en los trasplantes sin identidad HLA. La media de células perfundidas fue de 53,4x106/kg. RESULTADOS: El fallo de implante de la sangre de cordón umbilical se observó en 9 pacientes. Presentaron enfermedad del injerto contra huésped aguda superior al grado II 18 pacientes (64,3 por ciento). Ocho (28,6 por ciento) presentaron EICH grave. La supervivencia actuarial libre de enfermedad (SLE) de la serie global fue del 34,4>=9 por ciento a 3años, con una media de seguimiento de 16,6 meses. Se observó una mejor SLE en las enfermedades congénitas, con una SLE del 71>=17 por ciento y también en los pacientes que recibieron trasplante de sangre de cordón umbilical con una identidad HLA A, B y DR 6/6, en los que la SLE fue del 66>=19 por ciento. CONCLUSIÓN: Los mejores resultados se obtuvieron en las enfermedades genéticas. Se ha observado una correlación inversa entre la SLE y la disparidad antigénica HLA. La incidencia relativamente alta de la enfermedad injerto contra huésped aguda en esta serie, podría relacionarse con la escasa precisión de la tipificación HLA efectuada en algunos pacientes (AU)

[Transplantation of umbilical cord blood hematopoietic progenitor cells in children]. / Trasplante de progenitores hematopoyéticos de sangre de cordón umbilical en niños.

AIM: Retrospective study of the outcome of cord blood transplantation (CBT) in children in Spain. METHODS: Twenty-eight patients (mean age 6.5 years; mean weight 25 kg) received a CBT between July 1994 and May 1998 in several centres of the Spanish Pediatric Bone Marrow Transplant Group. In 2 patients the donor was an identical human leukocyte antigen (HLA)-sibling and in two the donor was a mismatched family donor. In 24 patients the donor was unrelated, and 21 of these received an HLA-mismatched CBT. Twenty-one patients (75 %) received a CBT for leukemia mainly in advanced phase. Seven patients were transplanted for genetic disease. Of these, five had congenital immunodeficiency. The conditioning treatment included total body irradiation in ten patients and combined chemotherapy in the remaining patients. In all patients graft-versus-host disease (GVHD) prophylaxis was performed with cyclosporine, and corticosteroids or methotrexate were added in patients with HLA-mismatched donors. The mean number of nucleated cells infused was 53.4 x 106/kg. RESULTS: Graft failure was observed in nine patients. Eighteen patients (64.3%) developed grade IIIV acute GVHD. Eight patients (28.6%) developed severe GVHD. Actuarial event free survival (EFS) of all the patients was 34.4 +/- 9% at 3 years, with a mean followup of 16.6 months. EFS was more favorable in patients with genetic disease (71>=6 17%) and in those with an HLA (A, B and DR) identical donor (6/6) (66>=6 19%). CONCLUSIONS: The most favorable results were obtained in patients with genetic diseases. We observed an inverse correlation between EFS and patients with HLA identical donors. The high incidence of severe acute GVHD could have been related to a lack of accuracy in the HLA typography of some patients.

Factors associated with outcome after cord blood transplantation in children with acute leukemia. Eurocord-Cord Blood Transplant Group.

We have analyzed factors influencing the outcome of 102 children with acute leukemia given a cord blood transplantation (CBT) and reported to the Eurocord Registry. Seventy patients with acute lymphoblastic and 32 with acute myeloid leukemia were given either a related (n = 42) or an unrelated (n = 60) CBT. Children given CBT during first or second complete remission were considered as belonging to the good-risk group (n = 66), whereas those who received a transplant in a more advanced stage of disease were assigned to the poor-risk group (n = 36). In the related group (RCBT), 12 of 42 patients received transplantation from an HLA-disparate donor, whereas in the unrelated group (UCBT) 54 of 60 received an HLA mismatched CBT. Kaplan-Meier estimates for neutrophil recovery at day 60 were 84% +/- 7% in RCBT and 79 +/- 6% in UCBT (P =.16). In multivariate analysis, the most important factor influencing neutrophil engraftment in UCBT was a nucleated cell dose infused greater than 3.7 x 10(7)/kg (P =.05, relative risk [RR] of 1.85, 95% confidence interval [CI]: 0.98-3.4). The incidence of grade II through IV acute graft-versus-host disease was 41% +/- 8% in the RCBT group and 37% +/- 6% in the UCBT group (P =.59). Kaplan-Meier estimates of 2-year event-free survival (EFS) after RCBT or UCBT were 39% +/- 8% and 30% +/- 7%, respectively (P =.19). In multivariate analysis, the most important factor influencing EFS was disease status at time of transplantation: good-risk patients had a 2-year EFS of 49% +/- 7% as compared to 8% +/- 5% in patients with more advanced disease (P =.0003, RR: 0.40, 95% CI: 0.24 to 0. 65). This was a consequence of both an increased 1-year transplant related mortality and a higher 2-year relapse rate in the poor-risk group (65% +/- 9% and 77% +/- 14%, respectively), as compared with good risk patients (34% +/- 6% and 31% +/- 9%, respectively). These data confirm that allogeneic CBT from either a related or an unrelated donor is a feasible procedure able to cure a significant proportion of children with acute leukemia, especially if transplanted in a favorable phase of disease.

[Allogeneic bone marrow transplantation in children with severe acquired aplastic anemia. The long-term results. The Spanish Group for Bone Marrow Transplantation in Children (GETMON)]. / Transplante alogénico de médula ósea en niños con aplasia medular grave adquirida. Resultados a largo plazo. Grupo Español para el Trasplante de Médula Osea en Niños (GETMON).

OBJECTIVE: The objective of this study was to evaluate retrospectively the efficacy of allogeneic BMT in the treatment of childhood severe acquired aplastic anemia (SAAA). PATIENTS AND METHODS: Twenty-seven children aged 2 to 16 years (median 11 years) received a BMT from an HLA identical sibling. Conditioning consisted in irradiation (total, nodal or thoraco-abdominal) plus cyclophosphamide (120-200 mg/kg) in 15 patients and cyclophosphamide alone (200 mg/kg) in the rest. Prophylaxis for graft-versus-host disease (GVHD) was cyclosporine and methotrexate in most patients. RESULTS: Twenty-four children achieved the bone marrow graft at a median of 18 days (neutrophils) and 21 days (platelets). Two patients failed engraftment and 1 had a late graft rejection. Three patients developed acute GVHD grades 3-4 and six chronic GVHD, which was extensive in 4 of them. Twenty patients/71%) are alive and disease-free at a median follow-up of 110 months and the estimated disease free survival at 6 years is 67%. CONCLUSIONS: Our results confirm that allogeneic bone marrow transplantation from an HLA identical sibling is the best treatment modality for children with SAAA. Acute GVHD associated with infections and graft rejection were responsible for treatment failures.