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1.
Pediatr Transplant ; : e13584, 2019 Sep 26.
Artigo em Inglês | MEDLINE | ID: mdl-31556188

RESUMO

Cytomegalovirus encephalitis is a challenging life-threatening complication following hematopoietic stem cell transplantation for which medical treatment is usually ineffective or toxic. However, in recent years, adoptive T-cell therapy has been reported to provide a significant chance of cure for patients with viral infections. Herein, two cases of pediatric patients successfully treated with third-party donor-derived virus-specific T cells for CMV meningoencephalitis are reported.

2.
Nat Med ; 25(9): 1396-1401, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31501599

RESUMO

Fanconi anemia (FA) is a DNA repair syndrome generated by mutations in any of the 22 FA genes discovered to date1,2. Mutations in FANCA account for more than 60% of FA cases worldwide3,4. Clinically, FA is associated with congenital abnormalities and cancer predisposition. However, bone marrow failure is the primary pathological feature of FA that becomes evident in 70-80% of patients with FA during the first decade of life5,6. In this clinical study (ClinicalTrials.gov, NCT03157804 ; European Clinical Trials Database, 2011-006100-12), we demonstrate that lentiviral-mediated hematopoietic gene therapy reproducibly confers engraftment and proliferation advantages of gene-corrected hematopoietic stem cells (HSCs) in non-conditioned patients with FA subtype A. Insertion-site analyses revealed the multipotent nature of corrected HSCs and showed that the repopulation advantage of these cells was not due to genotoxic integrations of the therapeutic provirus. Phenotypic correction of blood and bone marrow cells was shown by the acquired resistance of hematopoietic progenitors and T lymphocytes to DNA cross-linking agents. Additionally, an arrest of bone marrow failure progression was observed in patients with the highest levels of gene marking. The progressive engraftment of corrected HSCs in non-conditioned patients with FA supports that gene therapy should constitute an innovative low-toxicity therapeutic option for this life-threatening disorder.

3.
Euro Surveill ; 24(7)2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30782268

RESUMO

INTRODUCTION: Although human papillomavirus (HPV) routine vaccination programmes have been implemented around the world and recommendations have been expanded to include other high-risk individuals, current recommendations often differ between countries in Europe, as well as worldwide. AIM: To find and summarise the best available evidence of HPV vaccination in high-risk patients aiding clinicians and public health workers in the day-to-day vaccine decisions relating to HPV in Spain. METHODS: We conducted a systematic review of the immunogenicity, safety and efficacy/effectiveness of HPV vaccination in high-risk populations between January 2006 and June 2016. HPV vaccination recommendations were established with levels of evidence according to the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system. RESULTS: A strong recommendation about HPV vaccination was made in the following groups: HIV infected patients aged 9-26 years; men who have sex with men aged 9-26 years; women with precancerous cervical lesions; patients with congenital bone marrow failure syndrome; women who have received a solid organ transplant or hematopoietic stem cell transplantation aged 9-26 years; and patients diagnosed with recurrent respiratory papillomatosis. CONCLUSIONS: Data concerning non-routine HPV vaccination in populations with a high risk of HPV infection and associated lesions were scarce. We have developed a document to evaluate and establish evidence-based guidelines on HPV vaccination in high-risk populations in Spain, based on best available scientific evidence.

4.
Med. clín (Ed. impr.) ; 152(4): 135-145, feb. 2019. graf, tab
Artigo em Espanhol | IBECS | ID: ibc-181880

RESUMO

Antecedentes y objetivos: El incremento descrito en la prevalencia de hemoglobinopatías, de ß-talasemia mayor (TM) y de enfermedad drepanocítica (ED) que ha ocurrido en las últimas dos décadas en nuestro país ha generado nuevas necesidades en cuanto a recursos médicos tanto para la prevención como para el tratamiento de estos pacientes. El trasplante alogénico de progenitores hematopoyéticos (alo-TPH) es el tratamiento curativo disponible en nuestro medio para pacientes con hemoglobinopatías graves. El objetivo principal de este estudio fue conocer los resultados del alo-TPH en pacientes pediátricos con TM o ED realizados en unidades de trasplante hematopoyético pediátrico incluidas dentro del Grupo Español de Trasplante de Médula Ósea en Niños (GETMON). Material y métodos: Revisión retrospectiva de los pacientes sometidos a TPH en unidades de TPH del GETMON hasta el año 2015. Resultados: Se analizaron un total de 65 pacientes (43 pacientes afectados de TM y 22 de ED) que recibieron el alo-TPH en 6 unidades GETMON entre noviembre de 1989 y diciembre de 2014. La supervivencia libre de eventos 3años postrasplante fue del 81% y la supervivencia global del 92% en pacientes con TM. La supervivencia libre de eventos 3años postrasplante fue del 79% y la supervivencia global del 85% en pacientes con ED. Conclusiones: Los resultados de esta serie son comparables a los resultados de otras series internacionales y ofrecen un punto de partida para continuar intentando mejorar la evolución de estos pacientes


Background and objectives: A recently occurring increase of the prevalence of haemoglobinopathies, ß-thalassaemia major (TM) and sickle cell disease (SCD) over the last two decades in our country has generated new needs in terms of medical resources for both prevention and treatment of these patients. Allogeneic haematopoietic stem cell transplant (allo-HSCT) is a curative treatment available for patients who have severe haemoglobinopathies. The main objective of this study was to evaluate the results of allo-HSCT in paediatric patients with TM or SCD performed in paediatric hematopoietic transplant units within the Spanish Group of Bone Marrow Transplantation in Children (GETMON). Material and methods: Retrospective review of patients undergoing HSCT in the GETMON units until 2015. Results: A total of 65 patients were analysed (43 patients were affected with TM and 22 with SCD), who received allo-HSCT in 6 GETMON units between November 1989 and December 2014. Event-free survival three years post-transplant was 81% and overall survival 92% in patients with TM. Event-free survival three years post-transplant was 79% and overall survival 85% in patients with SCD. Conclusions: The results of this series are comparable to the results of other international series and offer a platform from which to continue trying to improve the evolution of these patients


Assuntos
Humanos , Transplante de Células-Tronco Hematopoéticas , Talassemia/epidemiologia , Hemoglobinopatias/epidemiologia , Transplante Homólogo/métodos , Neutrófilos/transplante , Hemoglobinopatias/prevenção & controle , Hemoglobinopatias/terapia , Estudos Retrospectivos , Sociedades Médicas/normas , Doença Enxerto-Hospedeiro , Sobrevivência
5.
Am J Transplant ; 19(6): 1798-1805, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30586230

RESUMO

We report data obtained from a retrospective multicenter pediatric survey on behalf of the European Society for Blood and Marrow Transplantation (EBMT). Information on solid organ transplantation (SOT) performed in pediatric recipients of either autologous or allogeneic hematopoietic stem cell transplantation (HSCT) between 1984 and 2016 was collected in 20 pediatric EBMT Centers (25.6%). Overall, we evaluated data on 44 SOTs following HSCT including 20 liver (LTx), 12 lung (LuTx), 6 heart (HTx), and 6 kidney (KTx) transplantations. The indication for SOT was organ failure related to intractable graft-vs-host disease in 16 children (36.3%), acute or chronic HSCT-related toxicity in 18 (40.9%), and organ dysfunction related to the underlying disease in 10 (22.8%). The median follow-up was 10.9 years (95% confidence interval: 1.7-29.5). The overall survival rate at 1 and 5 years after SOT was 85.7% and 80.4%, respectively: it was 74% and 63.2% after LTx, 83.2% after HTx, and 100% equally after LuTx and KTx. This multicenter survey confirms that SOT represents a promising option in children with severe organ failure occurring after HSCT. Additional studies are needed to further establish the effectiveness of SOT after HSCT and to better understand the mechanism underlying this encouraging success.

6.
Biol Blood Marrow Transplant ; 24(11): 2316-2323, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30031939

RESUMO

The CD45RA T cell depletion (TCD) method has been used to deplete naive T cells, preventing graft-versus-host disease (GVHD) but preserving memory cells, providing immediate functional T cells with anti-infection, antileukemia, and antirejection effects. We describe a series of 25 consecutive high-risk patients with leukemia who received haploidentical hematopoietic stem cell transplantation (haplo-HSCT) with CD45RA TCD. Each patient received 2 cell products: 1 created by CD34 positive selection and the other through CD45RA depletion from the CD34 negative fraction by a CliniMACS device. CD45RA-depleted haplo-HSCT was well tolerated, with rapid engraftment and low risk of severe acute GVHD and chronic GVHD. Although this treatment achieved a good control of viral reactivations, such as cytomegalovirus and adenovirus, we observed an unexpectedly high rate of limbic encephalitis due to human herpesvirus-6 (HHV-6; 8 cases). Characteristically, the infection appeared early in almost all patients, just after the engraftment. Although no patient died from encephalitis, 1 patient showed neuropsychological sequelae, and another experienced secondary graft failure just after the HHV-6 reactivation.

7.
Med Clin (Barc) ; 2018 Jul 09.
Artigo em Inglês, Espanhol | MEDLINE | ID: mdl-30001893

RESUMO

BACKGROUND AND OBJECTIVES: A recently occurring increase of the prevalence of haemoglobinopathies, ß-thalassaemia major (TM) and sickle cell disease (SCD) over the last two decades in our country has generated new needs in terms of medical resources for both prevention and treatment of these patients. Allogeneic haematopoietic stem cell transplant (allo-HSCT) is a curative treatment available for patients who have severe haemoglobinopathies. The main objective of this study was to evaluate the results of allo-HSCT in paediatric patients with TM or SCD performed in paediatric hematopoietic transplant units within the Spanish Group of Bone Marrow Transplantation in Children (GETMON). MATERIAL AND METHODS: Retrospective review of patients undergoing HSCT in the GETMON units until 2015. RESULTS: A total of 65 patients were analysed (43 patients were affected with TM and 22 with SCD), who received allo-HSCT in 6 GETMON units between November 1989 and December 2014. Event-free survival three years post-transplant was 81% and overall survival 92% in patients with TM. Event-free survival three years post-transplant was 79% and overall survival 85% in patients with SCD. CONCLUSIONS: The results of this series are comparable to the results of other international series and offer a platform from which to continue trying to improve the evolution of these patients.

8.
Br J Haematol ; 183(1): 110-118, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29984823

RESUMO

Dyskeratosis congenita (DC) is a genetic multisystem disorder with frequent involvement of the bone marrow. Haematopoietic stem cell transplantation (HSCT) is the only definitive cure to restore haematopoiesis, even though it cannot correct other organ dysfunctions. We collected data on the outcome of HSCT in the largest cohort of DC (n = 94) patients ever studied. Overall survival (OS) and event-free survival (EFS) at 3 years after HSCT were 66% and 62%, respectively. Multivariate analysis showed better outcomes in patients aged less than 20 years and in patients transplanted from a matched, rather than a mismatched, donor. OS and EFS curves tended to decline over time. Early lethal events were infections, whereas organ damage and secondary malignancies appeared afterwards, even a decade after HSCT. A non-myeloablative conditioning regimen appeared to be most advisable. Organ impairment present before HSCT seemed to favour the development of chronic graft-versus-host disease and T-B immune deficiency appeared to enhance pulmonary fibrosis. According to the present data, HSCT in DC is indicated in cases of progressive marrow failure, whereas in patients with pre-existing organ damage, this should be carefully evaluated. Further efforts to investigate treatment alternatives to HSCT should be encouraged.

9.
J Pediatr Urol ; 14(5): 366-373, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29776868

RESUMO

OBJECTIVE: Hemorrhagic cystitis (HC) is a serious event that can occur after hematopoietic stem cell transplantation (HSCT). Treatment goals are primarily to preserve life, and then the functionality of the bladder. There is no standard therapeutic approach for HC. Described treatment options provide low success rates and are related to potential life-threatening side effects. The aim of this study was to describe our experience in treatment of HC following HSCT. PATIENTS AND METHODS: This was a retrospective study of patients with HC treated at our institution between January 2010 and October 2016. We analyzed demographics, underlying diagnosis, and treatment modalities. RESULTS: We treated 39 patients with HC. Mean age was 9.4 years (SD 4.20) and 64% were males. Acute leukemia was the most common underlying diagnosis in 27 (69%). Mean time from HSCT to HC onset was 55.46 days (SD 112.35). HC grades were: I (3), II (21), III (8), and IV (7). BK-viuria was present in 34 patients (87.2%). Non-invasive treatment was performed in 28 patients (71.8%). The remaining 11 (28.2%) required urological intervention (all high-grade), consisting of bladder irrigation in all of these. Additional treatments consisted of: intravesical cidofovir (4), intravesical sodium hyaluronate (5), cystoscopy and clot evacuation (4), selective angioembolization (2), percutaneous nephrostomy (1), and open extraction of bladder clots and cutaneous cystotomy (1). Overall, eight patients (20.5%) died as a result of the malignancy (3 in the urological intervention group), and of these four had active HC at death. Mean follow-up was 36.2 months (SD 24.9). CONCLUSION: HC is associated with high morbidity and mortality. Treatment should be individualized and designed to prioritize survival. However, bladder function should be preserved for the future.

10.
An. pediatr. (2003. Ed. impr.) ; 88(4): 196-203, abr. 2018. tab
Artigo em Espanhol | IBECS | ID: ibc-172989

RESUMO

Introducción: El trasplante de progenitores hematopoyéticos (TPH) consiste en implantar elementos celulares capaces de generar un sistema hematopoyético nuevo y sano. El régimen de intensidad reducida (RIR) consiste en un tratamiento predominantemente inmunosupresor, para facilitar un implante progresivo con menor morbilidad. Este tipo de acondicionamiento puede también provocar mielosupresión, aunque potencialmente reversible en el tiempo. El acondicionamiento RIR permite aplicar TPH a pacientes con enfermedad genética en los que no es deseable añadir comorbilidad por las altas dosis de quimioterapia que conlleva el régimen mieloablativo convencional. Pacientes y métodos: Se analiza la evolución de 68 pacientes pediátricos con enfermedades genéticas que entre los años 2005-2013 se han sometido a un TPH con RIR en las Unidades pediátricas de Trasplante Hematopoyético de los hospitales españoles integrantes del Grupo Español para Trasplante de Médula Ósea en niños. Se trata de un estudio multicéntrico que incluye a 68 pacientes, de los cuales 43 presentan inmunodeficiencia primaria, 21 presentan hemopatía congénita y 4 están afectados de metabolopatía. Resultados: Cincuenta de los 68 pacientes se encuentran vivos (73,5%). La supervivencia global (SG) a 9 años es de 0,74. Veintitrés (33,8%) han presentado en el transcurso del TPH algún evento. Supervivencia libre de evento de 0,66. La SG en los pacientes con hemopatía es de 0,81; en las inmunodeficiencias primarias es de 0,70 y en las metabolopatías es de 0,4. No se observa diferencia significativa entre los 3 grupos de enfermedades. Respecto a la fuente de progenitores hematopoyéticos, la SG en los pacientes trasplantados con sangre periférica es de 0,74; con médula ósea es de 0,70 y con la sangre de cordón umbilical es de 0,70. No se observa tampoco diferencia estadística significativa. Conclusiones: En nuestro trabajo, de ámbito nacional, hemos evidenciado unos resultados favorables en TPH con régimen de intensidad reducida en las enfermedades genéticas. Cabe destacar que las metabolopatías requieren una consideración individualizada para sopesar en cada paciente los riesgos y beneficios que comporta el RIR


Introduction: Haematopoietic stem cell transplantation (HSCT) involves implanting cellular elements capable of generating a new and healthy haematopoietic system. Reduced intensity conditioning (RIC) consists of an immunosuppressive treatment to facilitate a progressive implant with lower morbidity. This type of conditioning can also lead to myelosuppression, which is potentially reversible over time. Reduced intensity conditioning enables HSCT to be performed on patients with genetic diseases for whom added comorbidity is undesirable due to the high doses of chemotherapy that accompanies conventional myeloablative regimens. Patients and methods: An analysis was performed on the outcomes of 68 paediatric patients with genetic diseases who underwent HSCT with RIC between 2005 and 2013 in the of Paediatric Haematopoietic Stem Cell Transplantation Units that are part of the Spanish Working Group for Bone Marrow Transplantation in Children. A multicentre study was conducted including 68 patients, of whom 43 had Primary Immunodeficiency, 21 with congenital haematological diseases, and 4 with metabolic diseases. Results: Fifty (73.5%) of the 68 patients were still alive. The Overall Survival (OS) at nine years was 0.74. Twenty-three (33.8%) had some event during the course of the HSCT, with an event-free survival rate of 0.66. The OS in patients with haematological diseases was 0.81, being 0.7 in primary immunodeficiencies, and 0.4 in metabolic diseases. No significant difference was observed between the 3 groups of diseases. As regards the source of haematopoietic progenitors, there was an OS rate of 0.74 in patients transplanted with peripheral blood, 0.70 with bone marrow, and 0.70 and with cord blood, with no statistically significant differences. Conclusions: Favourable results have been obtained in HSCT with reduced intensity conditioning in genetic diseases. It should be noted that the risks and benefits of the RIC in patients with metabolic diseases need to be assessed on an individual basis


Assuntos
Humanos , Masculino , Feminino , Criança , Transplante de Medula Óssea/métodos , Transplante de Células-Tronco Hematopoéticas/métodos , Doenças Genéticas Inatas/complicações , Condicionamento Pré-Transplante/métodos , Comorbidade , Estudos Retrospectivos , Estudos Prospectivos
11.
J Allergy Clin Immunol ; 141(3): 1036-1049.e5, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29241729

RESUMO

BACKGROUND: Immunodysregulation polyendocrinopathy enteropathy x-linked (IPEX) syndrome is a monogenic autoimmune disease caused by FOXP3 mutations. Because it is a rare disease, the natural history and response to treatments, including allogeneic hematopoietic stem cell transplantation (HSCT) and immunosuppression (IS), have not been thoroughly examined. OBJECTIVE: This analysis sought to evaluate disease onset, progression, and long-term outcome of the 2 main treatments in long-term IPEX survivors. METHODS: Clinical histories of 96 patients with a genetically proven IPEX syndrome were collected from 38 institutions worldwide and retrospectively analyzed. To investigate possible factors suitable to predict the outcome, an organ involvement (OI) scoring system was developed. RESULTS: We confirm neonatal onset with enteropathy, type 1 diabetes, and eczema. In addition, we found less common manifestations in delayed onset patients or during disease evolution. There is no correlation between the site of mutation and the disease course or outcome, and the same genotype can present with variable phenotypes. HSCT patients (n = 58) had a median follow-up of 2.7 years (range, 1 week-15 years). Patients receiving chronic IS (n = 34) had a median follow-up of 4 years (range, 2 months-25 years). The overall survival after HSCT was 73.2% (95% CI, 59.4-83.0) and after IS was 65.1% (95% CI, 62.8-95.8). The pretreatment OI score was the only significant predictor of overall survival after transplant (P = .035) but not under IS. CONCLUSIONS: Patients receiving chronic IS were hampered by disease recurrence or complications, impacting long-term disease-free survival. When performed in patients with a low OI score, HSCT resulted in disease resolution with better quality of life, independent of age, donor source, or conditioning regimen.

12.
An Pediatr (Barc) ; 88(4): 196-203, 2018 Apr.
Artigo em Espanhol | MEDLINE | ID: mdl-28694008

RESUMO

INTRODUCTION: Haematopoietic stem cell transplantation (HSCT) involves implanting cellular elements capable of generating a new and healthy haematopoietic system. Reduced intensity conditioning (RIC) consists of an immunosuppressive treatment to facilitate a progressive implant with lower morbidity. This type of conditioning can also lead to myelosuppression, which is potentially reversible over time. Reduced intensity conditioning enables HSCT to be performed on patients with genetic diseases for whom added comorbidity is undesirable due to the high doses of chemotherapy that accompanies conventional myeloablative regimens. PATIENTS AND METHODS: An analysis was performed on the outcomes of 68 paediatric patients with genetic diseases who underwent HSCT with RIC between 2005 and 2013 in the of Paediatric Haematopoietic Stem Cell Transplantation Units that are part of the Spanish Working Group for Bone Marrow Transplantation in Children. A multicentre study was conducted including 68 patients, of whom 43 had Primary Immunodeficiency, 21 with congenital haematological diseases, and 4 with metabolic diseases. RESULTS: Fifty (73.5%) of the 68 patients were still alive. The Overall Survival (OS) at nine years was 0.74. Twenty-three (33.8%) had some event during the course of the HSCT, with an event-free survival rate of 0.66. The OS in patients with haematological diseases was 0.81, being 0.7 in primary immunodeficiencies, and 0.4 in metabolic diseases. No significant difference was observed between the 3 groups of diseases. As regards the source of haematopoietic progenitors, there was an OS rate of 0.74 in patients transplanted with peripheral blood, 0.70 with bone marrow, and 0.70 and with cord blood, with no statistically significant differences. CONCLUSIONS: Favourable results have been obtained in HSCT with reduced intensity conditioning in genetic diseases. It should be noted that the risks and benefits of the RIC in patients with metabolic diseases need to be assessed on an individual basis.

13.
EMBO Mol Med ; 9(11): 1574-1588, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-28899930

RESUMO

Gene targeting constitutes a new step in the development of gene therapy for inherited diseases. Although previous studies have shown the feasibility of editing fibroblasts from Fanconi anemia (FA) patients, here we aimed at conducting therapeutic gene editing in clinically relevant cells, such as hematopoietic stem cells (HSCs). In our first experiments, we showed that zinc finger nuclease (ZFN)-mediated insertion of a non-therapeutic EGFP-reporter donor in the AAVS1 "safe harbor" locus of FA-A lymphoblastic cell lines (LCLs), indicating that FANCA is not essential for the editing of human cells. When the same approach was conducted with therapeutic FANCA donors, an efficient phenotypic correction of FA-A LCLs was obtained. Using primary cord blood CD34+ cells from healthy donors, gene targeting was confirmed not only in in vitro cultured cells, but also in hematopoietic precursors responsible for the repopulation of primary and secondary immunodeficient mice. Moreover, when similar experiments were conducted with mobilized peripheral blood CD34+ cells from FA-A patients, we could demonstrate for the first time that gene targeting in primary hematopoietic precursors from FA patients is feasible and compatible with the phenotypic correction of these clinically relevant cells.


Assuntos
Antígenos CD34/metabolismo , Proteína do Grupo de Complementação A da Anemia de Fanconi/genética , Anemia de Fanconi/patologia , Edição de Genes/métodos , Células-Tronco Hematopoéticas/metabolismo , Animais , Sequência de Bases , Células Cultivadas , Dependovirus/genética , Anemia de Fanconi/metabolismo , Proteína do Grupo de Complementação A da Anemia de Fanconi/metabolismo , Sangue Fetal/citologia , Vetores Genéticos/genética , Vetores Genéticos/metabolismo , Transplante de Células-Tronco Hematopoéticas , Células-Tronco Hematopoéticas/citologia , Humanos , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Camundongos Transgênicos , Espécies Reativas de Oxigênio/metabolismo , Nucleases de Dedos de Zinco/genética , Nucleases de Dedos de Zinco/metabolismo
14.
An. pediatr. (2003. Ed. impr.) ; 87(3): 155-163, sept. 2017. tab
Artigo em Espanhol | IBECS | ID: ibc-166299

RESUMO

Introducción: El cáncer es la primera causa de muerte por enfermedad entre el primer año de vida y la adolescencia. Algunos tipos de enfermedad siguen constituyendo un reto en términos de curación. Existe por tanto una necesidad imperiosa de nuevos fármacos. Algunos descubrimientos recientes en la biología del cáncer abren la puerta al desarrollo de terapias dirigidas contra alteraciones moleculares concretas e inmunoterapia. Esto se ha traducido en resultados prometedores sobre todo en oncología de adultos, y en menor medida todavía en niños. Presentamos la actividad en ensayos clínicos precoces (fase i-ii) en oncología pediátrica en España. Material y métodos: A través de la Sociedad Española de Oncología y Hematología Pediátrica (SEHOP) contactamos a sus miembros para identificar los ensayos fase i-ii en cáncer pediátrico abiertos entre 2005 y 2015. Resultados: En este periodo se abrieron 30 ensayos: 21 (70%) en tumores sólidos y 9 (30%) en hemopatías malignas y se incluyó a 212 pacientes. La mayoría están promovidos por la industria farmacéutica (53%). Desde 2010, 4 centros se han integrado en el consorcio internacional ITCC cuyo objetivo es desarrollar nuevas terapias en cáncer infantil. Esto ha permitido ampliar el abanico de posibilidades terapéuticas. Los resultados de ensayos clínicos terminados muestran la contribución de los investigadores españoles, la introducción de terapias dirigidas y sus beneficios. Conclusiones: La actividad en ensayos clínicos precoces ha aumentado en estos años. La SEHOP está comprometida a desarrollar y participar en ensayos clínicos académicos colaborativos, que favorezcan el avance en las terapias frente al cáncer infantil (AU)


Introduction: Cancer is the leading cause of death between the first year of life and adolescence, and some types of diseases are still a major challenge in terms of cure. There is, therefore, a major need for new drugs. Recent findings in cancer biology open the door to the development of targeted therapies against individual molecular changes, as well as immunotherapy. Promising results in adult anti-cancer drug development have not yet been translated into paediatric clinical practice. A report is presented on the activity in early paediatric oncology trials (phase I-II) in Spain. Material and methods: All members of the Spanish Society of Paediatric Haematology Oncology (SEHOP) were contacted in order to identify early clinical trials in paediatric cancer opened between 2005 and 2015. Results: A total of 30 trials had been opened in this period: 21 (70%) in solid tumours, and 9 (30%) in malignant haemopathies. A total of 212 patients have been enrolled. The majority was industry sponsored (53%). Since 2010, four centres have joined the international consortium of Innovative Therapies for Children with Cancer (ITCC), which has as its aim to develop novel therapies for paediatric tumours. A significant number of new studies have opened since 2010, improving the treatment opportunities for our children. Results of recently closed trials show the contribution of Spanish investigators, the introduction of molecularly targeted agents, and their benefits. Conclusions: The activity in clinical trials has increased in the years analysed. The SEHOP is committed to develop and participate in collaborative academic trials, in order to help in the advancement and optimisation of existing therapies in paediatric cancer (AU)


Assuntos
Humanos , Criança , Drogas em Investigação , Avaliação de Medicamentos/tendências , Antineoplásicos/farmacologia , Neoplasias/tratamento farmacológico , Ensaios Clínicos como Assunto/estatística & dados numéricos , Medicina de Precisão/tendências
15.
Blood ; 130(13): 1535-1542, 2017 09 28.
Artigo em Inglês | MEDLINE | ID: mdl-28801449

RESUMO

Previous Fanconi anemia (FA) gene therapy studies have failed to demonstrate engraftment of gene-corrected hematopoietic stem and progenitor cells (HSPCs) from FA patients, either after autologous transplantation or infusion into immunodeficient mice. In this study, we demonstrate that a validated short transduction protocol of G-CSF plus plerixafor-mobilized CD34+ cells from FA-A patients with a therapeutic FANCA-lentiviral vector corrects the phenotype of in vitro cultured hematopoietic progenitor cells. Transplantation of transduced FA CD34+ cells into immunodeficient mice resulted in reproducible engraftment of myeloid, lymphoid, and CD34+ cells. Importantly, a marked increase in the proportion of phenotypically corrected, patient-derived hematopoietic cells was observed after transplantation with respect to the infused CD34+ graft, indicating the proliferative advantage of corrected FA-A hematopoietic repopulating cells. Our data demonstrate for the first time that optimized protocols of hematopoietic stem cell collection from FA patients, followed by the short and clinically validated transduction of these cells with a therapeutic lentiviral vector, results in the generation of phenotypically corrected HSPCs capable of repopulating and developing proliferation advantage in immunodeficient mice. Our results suggest that clinical approaches for FA gene therapy similar to those used in this study will facilitate hematopoietic repopulation in FA patients with gene corrected HSPCs, opening new prospects for gene therapy of FA patients.


Assuntos
Proteína do Grupo de Complementação C da Anemia de Fanconi/genética , Anemia de Fanconi/terapia , Terapia Genética/métodos , Vetores Genéticos , Transplante de Células-Tronco Hematopoéticas/métodos , Transdução Genética/métodos , Animais , Antígenos CD34/imunologia , Criança , Pré-Escolar , Anemia de Fanconi/patologia , Sobrevivência de Enxerto , Mobilização de Células-Tronco Hematopoéticas , Células-Tronco Hematopoéticas/patologia , Xenoenxertos , Humanos , Lentivirus/genética , Camundongos
16.
Biol Blood Marrow Transplant ; 23(11): 1939-1948, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28797779

RESUMO

Cord blood transplantation (CBT) from HLA-identical siblings is an attractive option for patients with bone marrow failure (BMF) syndrome because of the low risk of graft-versus-host disease (GVHD) and the absence of risk to the donor. We analyzed outcomes of 117 patients with inherited or acquired BMF syndrome who received CBT from a related HLA-identical donor in European Society for Blood and Marrow Transplantation centers between 1988 and 2014. Ninety-seven patients had inherited and 20 patients acquired BMF syndrome. Eighty-two patients received a single cord blood (CB) unit, whereas 35 patients received a combination of CB and bone marrow cells from the same donor. Median age at CBT was 6.7 years, and median follow-up was 86.7 months. The cumulative incidence function (CIF) of neutrophil recovery was 88.8% (95% CI, 83.1% to 94.9%), 100-day CIF of grades II to IV acute GVHD was 15.2%, and 7-year CIF of chronic GVHD was 14.5%. Overall survival at 7 years was 87.9% (95% CI, 80.8% to 92.6%), 89% for inherited and 81% for acquired BMF syndromes (P = .66). Results of this study are consistent with outcomes of bone marrow transplantation shown by previous series in the same setting and indicate that in pediatric patients with BMF syndrome, CBT from an HLA-identical sibling donor is associated with excellent long-term outcomes and that collection of CB unit at birth of a new sibling is strongly recommended.


Assuntos
Anemia Aplástica/terapia , Doenças da Medula Óssea/terapia , Transplante de Células-Tronco de Sangue do Cordão Umbilical/métodos , Antígenos HLA/metabolismo , Hemoglobinúria Paroxística/terapia , Adolescente , Criança , Pré-Escolar , Europa (Continente) , Feminino , Humanos , Lactente , Masculino , Irmãos
17.
Biol Blood Marrow Transplant ; 23(8): 1350-1358, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28438676

RESUMO

For pediatric patients with acute lymphoblastic leukemia (ALL), relapse is an important cause of treatment failure after unrelated cord blood transplant (UCBT). Compared with other donor sources, relapse is similar or even reduced after UCBT despite less graft-versus-host disease (GVHD). We performed a retrospective analysis to identify risk factors associated with the 5-year cumulative incidence of relapse after UCBT. In this retrospective, registry-based study, we examined the outcomes of 640 children (<18 years) with ALL in first complete remission (CR1; n = 257, 40%) or second complete remission (CR2; n = 383, 60%) who received myeloablative conditioning followed by a single-unit UCBT from 2000 to 2012. Most received antithymocyte globulin (88%) or total body irradiation (TBI; 69%), and cord blood grafts were primarily mismatched at 1 (50%) or 2+ (34%) HLA loci. Considering patients in CR1, the rates of 5-year overall survival (OS), leukemia-free survival (LFS), and relapse were 59%, 52%, and 23%, respectively. In multivariate analysis (MVA), acute GVHD (grades II to IV) and TBI protected against relapse. In patients in CR2, rates of 5-year OS, LFS, and the cumulative incidence of relapse were 46%, 44%, and 28%, respectively. In MVA, longer duration from diagnosis to UCBT (≥30 months) and TBI were associated with decreased relapse risk. Importantly, receiving a fully HLA matched graft was a strong risk factor for increased relapse in MVA. An exploratory analysis of all 640 patients supported the important association between the presence of acute GVHD and less relapse but also demonstrated an increased risk of nonrelapse mortality. In conclusion, the impact of GVHD as a graft-versus-leukemia marker is evident in pediatric ALL after UCBT. Strategies that promote graft-versus-leukemia while harnessing GVHD should be further investigated.


Assuntos
Transplante de Células-Tronco de Sangue do Cordão Umbilical , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidade , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Condicionamento Pré-Transplante , Doadores não Relacionados , Adolescente , Aloenxertos , Criança , Pré-Escolar , Intervalo Livre de Doença , Feminino , Humanos , Lactente , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Recidiva , Fatores de Risco , Taxa de Sobrevida , Fatores de Tempo
18.
An Pediatr (Barc) ; 87(3): 155-163, 2017 Sep.
Artigo em Espanhol | MEDLINE | ID: mdl-28279690

RESUMO

INTRODUCTION: Cancer is the leading cause of death between the first year of life and adolescence, and some types of diseases are still a major challenge in terms of cure. There is, therefore, a major need for new drugs. Recent findings in cancer biology open the door to the development of targeted therapies against individual molecular changes, as well as immunotherapy. Promising results in adult anti-cancer drug development have not yet been translated into paediatric clinical practice. A report is presented on the activity in early paediatric oncology trials (phase I-II) in Spain. MATERIAL AND METHODS: All members of the Spanish Society of Paediatric Haematology Oncology (SEHOP) were contacted in order to identify early clinical trials in paediatric cancer opened between 2005 and 2015. RESULTS: A total of 30 trials had been opened in this period: 21 (70%) in solid tumours, and 9 (30%) in malignant haemopathies. A total of 212 patients have been enrolled. The majority was industry sponsored (53%). Since 2010, four centres have joined the international consortium of Innovative Therapies for Children with Cancer (ITCC), which has as its aim to develop novel therapies for paediatric tumours. A significant number of new studies have opened since 2010, improving the treatment opportunities for our children. Results of recently closed trials show the contribution of Spanish investigators, the introduction of molecularly targeted agents, and their benefits. CONCLUSIONS: The activity in clinical trials has increased in the years analysed. The SEHOP is committed to develop and participate in collaborative academic trials, in order to help in the advancement and optimisation of existing therapies in paediatric cancer.

19.
Biol Blood Marrow Transplant ; 23(1): 96-102, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-27777140

RESUMO

Infant acute leukemia still has a poor prognosis, and allogeneic hematopoietic stem cell transplantation is indicated in selected patients. Umbilical cord blood (UCB) is an attractive cell source for this population because of the low risk of chronic graft-versus-host disease (GVHD), the strong graft-versus-leukemia effect, and prompt donor availability. This retrospective, registry-based study reported UCB transplantation (UCBT) outcomes in 252 children with acute lymphoblastic leukemia (ALL; n = 157) or acute myelogenous leukemia (AML; n = 95) diagnosed before 1 year of age who received a single-unit UCBT after myeloablative conditioning between 1996 and 2012 in European Society for Blood and Marrow Transplantation centers. Median age at UCBT was 1.1 years, and median follow-up was 42 months. Most patients (57%) received a graft with 1 HLA disparity and were transplanted in first complete remission (CR; 55%). Cumulative incidence function (CIF) of day 100 acute GVHD (grades II to IV) was 40% ± 3% and of 4-year chronic GVHD was 13% ± 2%. CIF of 1-year transplant-related mortality was 23% ± 3% and of 4-year relapse was 27% ± 3%. Leukemia-free-survival (LFS) at 4 years was 50% ± 3%; it was 40% and 66% for those transplanted for ALL and AML, respectively (P = .001). LFS was better for patients transplanted in first CR, regardless of diagnosis. In multivariate model, diagnosis of ALL (P = .001), advanced disease status at UCBT (<.001), age at diagnosis younger than 3 months (P = .012), and date of transplant before 2004 were independently associated with worse LFS. UCBT is a suitable option for patients diagnosed with infant acute leukemia who achieve CR. In this cohort, patients with AML had better survival than those with ALL.


Assuntos
Transplante de Células-Tronco de Sangue do Cordão Umbilical/métodos , Leucemia/terapia , Doença Aguda , Transplante de Células-Tronco de Sangue do Cordão Umbilical/efeitos adversos , Transplante de Células-Tronco de Sangue do Cordão Umbilical/mortalidade , Doença Enxerto-Hospedeiro/etiologia , Humanos , Lactente , Recém-Nascido , Leucemia/complicações , Leucemia/mortalidade , Leucemia Mieloide Aguda/complicações , Leucemia Mieloide Aguda/mortalidade , Leucemia Mieloide Aguda/terapia , Agonistas Mieloablativos/uso terapêutico , Leucemia-Linfoma Linfoblástico de Células Precursoras/complicações , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidade , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Sistema de Registros , Indução de Remissão , Estudos Retrospectivos , Fatores de Risco , Condicionamento Pré-Transplante/métodos , Resultado do Tratamento , Doadores não Relacionados
20.
Blood ; 129(4): 525-532, 2017 01 26.
Artigo em Inglês | MEDLINE | ID: mdl-27811020

RESUMO

We evaluated the impact of recipient and cord blood unit (CBU) genetic polymorphisms related to immune response on outcomes after unrelated cord blood transplantations (CBTs). Pretransplant DNA samples from 696 CBUs with malignant diseases were genotyped for NLRP1, NLRP2, NLRP3, TIRAP/Mal, IL10, REL, TNFRSF1B, and CTLA4. HLA compatibility was 6 of 6 in 10%, 5 of 6 in 39%, and ≥4 of 6 in 51% of transplants. Myeloablative conditioning was used in 80%, and in vivo T-cell depletion in 81%, of cases. The median number of total nucleated cells infused was 3.4 × 107/kg. In multivariable analysis, patients receiving CBUs with GG-CTLA4 genotype had poorer neutrophil recovery (hazard ratio [HR], 1.33; P = .02), increased nonrelapse mortality (NRM) (HR, 1.50; P < .01), and inferior disease-free survival (HR, 1.41; P = .02). We performed the same analysis in a more homogeneous subset of cohort 1 (cohort 2, n = 305) of patients who received transplants for acute leukemia, all given a myeloablative conditioning regimen, and with available allele HLA typing (HLA-A, -B, -C, and -DRB1). In this more homogeneous but smaller cohort, we were able to demonstrate that GG-CTLA4-CBU was associated with increased NRM (HR, 1.85; P = .01). Use of GG-CTLA4-CBU was associated with higher mortality after CBT, which may be a useful criterion for CBU selection, when multiple CBUs are available.


Assuntos
Antígeno CTLA-4/imunologia , Transplante de Células-Tronco de Sangue do Cordão Umbilical , Antígenos HLA/imunologia , Neoplasias Hematológicas/genética , Polimorfismo Genético , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/imunologia , Adolescente , Adulto , Alelos , Proteínas Reguladoras de Apoptose/genética , Proteínas Reguladoras de Apoptose/imunologia , Antígeno CTLA-4/genética , Criança , Pré-Escolar , Intervalo Livre de Doença , Feminino , Sangue Fetal/citologia , Sangue Fetal/imunologia , Sangue Fetal/transplante , Expressão Gênica , Genótipo , Antígenos HLA/genética , Neoplasias Hematológicas/imunologia , Neoplasias Hematológicas/patologia , Neoplasias Hematológicas/terapia , Teste de Histocompatibilidade , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Agonistas Mieloablativos/uso terapêutico , Modelos de Riscos Proporcionais , Isoformas de Proteínas/genética , Isoformas de Proteínas/imunologia , Estudos Retrospectivos , Condicionamento Pré-Transplante , Doadores não Relacionados
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