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1.
Bone Marrow Transplant ; 54(7): 1176, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30733543

RESUMO

In the original version of this article, author 'Lucia López-Corral' was incorrectly listed as 'Lucia López'. This has now been corrected in both the PDF and HTML versions of the article to 'Lucia López-Corral'.

5.
Transfus Med Rev ; 2018 Mar 03.
Artigo em Inglês | MEDLINE | ID: mdl-29573905

RESUMO

Autoimmune hemolytic anemia (AIHA) is a complication of allogeneic hematopoietic stem cell transplantation (HSCT) associated with poor outcome. However, an optimal therapeutic approach is lacking. Between 2000 and 2015, 4099 allogeneic HSCT were performed in eight pediatric centers of the Grupo Español De Trasplante de Medula Osea en Niños (GETMON) and six adult centers of the Grupo Español de Trasplante Hematopoyetico (GETH). Sixty cases of AIHA were registered with a cumulative incidence of 1.5% occurring at a median of 6 months after HSCT. Patients aged less than 15 years (P=.005), and patients using cord blood (P=.005) or an HLA mismatch donor (P=.005) were more likely to develop AIHA. Most patients were lymphopenic at the time of diagnosis of AIHA, including a low number of regulatory T lymphocytes (median 3/µL). Median lines of treatment received for AIHA was 3 (range, 1-7). Almost all patients received corticosteroids (88%) and more than half received immunoglobulins or rituximab (63% and 67%, respectively). Complete resolution of AIHA was achieved in 33 of 60 cases (55%). Cumulative incidence of AIHA-related mortality was 17±6%. We found a correlation of AIHA outcome with age (better outcome in younger than 15 years, RR=1.87, P=.01) and rituximab response (higher rate of complete remission in patients responding to rituximab, RR=1.72, P=.025). We analyzed the factors involved in the response to rituximab and found a better response when there was ABO donor/receptor disparity (P=.014) and in those patients with B lymphocytes count above the median (38/µL) (P=.05).Thirty-six of 60 patients survived yielding a disease free survival of 52±8% at 40 months. In Cox analysis, age (children vs adults, HR: 8.19, CI 95%: 2.39-28.12, P=.001) and AIHA outcome (complete remission vs partial remission/non-response, HR: 4.18, CI 95%: 1.55-11.22, P=.005) were associated with a better survival. Our data suggest that patients who developed AIHA after HSCT are severely lymphopenic and have a high risk of mortality. Outcome is better in children and in patients treated with rituximab. We also propose an algorithm for treatment of AIHA after HSCT.

6.
Exp Hematol ; 62: 24-32, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29526774

RESUMO

Relapse of acute leukemia (AL) after allogeneic hematopoietic cell transplantation (Allo-HCT) entails a dismal prognosis. In this scenario, donor lymphocyte infusions (DLIs) and second Allo-HCT are two major approaches. We compared outcomes of AL patients treated for relapse with DLI or second Allo-HCT after receiving debulking therapy. In total, 46 patients were included in the study; 30 (65%) had acute myeloid leukemia and 16 (35%) had acute lymphoblastic leukemia. The median age was 38 years (range 4-66). Twenty-seven patients received a second Allo-HCT and 19 patients received DLI. The median follow-up of the cohort was 273 days (range 9-7013). Overall survival (OS), disease-free survival (DFS), nonrelapse mortality, and cumulative incidence (CI) of relapse were calculated from DLI or second Allo-HCT date. In univariate analysis, second Allo-HCT was associated with higher OS (p = 0.021) and a trend to higher DFS (p = 0.097) and CI of relapse (p = 0.094) on univariate analysis. However, multivariate analysis showed comparable outcomes between DLI and second Allo-HCT, with the time interval to relapse before DLI or second Allo-HCT the only statistically significant factor with an impact on OS and DFS. Within the DLI cohort, T-cell-depleted Allo-HCT was associated with higher OS (p = 0.003) and DFS (p < 0.001) and lower CI of relapse (p = 0.002) than T-cell-replete Allo-HCT. Overall, in this cohort of AL patients, second Allo-HCT and DLI associated similar outcomes. As in other relapse studies, the length of remission (time to relapse) was identified as a factor with statistical impact on survival. Further studies are warranted.

7.
Clin Cancer Res ; 23(21): 6478-6486, 2017 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-28754820

RESUMO

Purpose: Survival of acute leukemia (AL) patients following umbilical cord blood transplantation (UCBT) is dependent on an array of individual features. Integrative models for risk assessment are lacking. We sought to develop a scoring system for prediction of overall survival (OS) and leukemia-free survival (LFS) at 2 years following UCBT in AL patients.Experimental Design: The study cohort included 3,140 pediatric and adult AL UCBT patients from the European Society of Blood and Marrow Transplantation and Eurocord registries. Patients received single or double cord blood units. The dataset was geographically split into a derivation (n = 2,362, 65%) and validation set (n = 778, 35%). Top predictors of OS were identified using the Random Survival Forest algorithm and introduced into a Cox regression model, which served for the construction of the UCBT risk score.Results: The score includes nine variables: disease status, diagnosis, cell dose, age, center experience, cytomegalovirus serostatus, degree of HLA mismatch, previous autograft, and anti-thymocyte globulin administration. Over the validation set an increasing score was associated with decreasing probabilities for 2 years OS and LFS, ranging from 70.21% [68.89-70.71, 95% confidence interval (CI)] and 64.76% (64.33-65.86, 95% CI) to 14.78% (10.91-17.41) and 18.11% (14.40-22.30), respectively. It stratified patients into six distinct risk groups. The score's discrimination (AUC) over multiple imputations of the validation set was 68.76 (68.19-69.04, range) and 65.78 (65.20-66.28) for 2 years OS and LFS, respectively.Conclusions: The UCBT score is a simple tool for risk stratification of AL patients undergoing UCBT. Widespread application of the score will require further independent validation. Clin Cancer Res; 23(21); 6478-86. ©2017 AACR.


Assuntos
Transplante de Células-Tronco de Sangue do Cordão Umbilical , Leucemia Mieloide Aguda/patologia , Leucemia Mieloide Aguda/terapia , Prognóstico , Adolescente , Adulto , Criança , Intervalo Livre de Doença , Feminino , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/patologia , Humanos , Leucemia Mieloide Aguda/classificação , Leucemia Mieloide Aguda/complicações , Masculino , Medicina de Precisão , Modelos de Riscos Proporcionais , Adulto Jovem
8.
Br J Haematol ; 169(1): 103-10, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25521756

RESUMO

Umbilical cord blood (UCB) from an human leucocyte antigen (HLA)-identical sibling can be used for transplantation of patients with malignant and non-malignant diseases. However, the low cellular content of most UCB units represents a limitation to this approach. An option to increase cell dose is to harvest bone marrow (BM) cells from the same donor and infuse them along with the UCB. We studied 156 children who received such a combined graft between 1992 and 2011. Median age was 7 years and 78% of patients (n = 122) were transplanted for non-malignant diseases, mainly haemoglobinopathies. Acute leukaemia (n = 26) was the most frequent malignant diagnosis. Most patients (91%) received myeloablative conditioning. Median donor age was 1·7 years, median infused nucleated cell dose was 24·4 × 10(7) /kg and median follow-up was 41 months. Sixty-days neutrophil recovery occurred in 96% of patients at a median of 17 d. The probabilities of grade-II-IV acute and chronic graft-versus-host disease (GVHD) were 19% and 10%, respectively. Four-year overall survival was 90% (68% malignant; 97% non-malignant diseases) with 3% probability of death. In conclusion, combined UCB and BM transplantation from an HLA-identical sibling donor is an effective treatment for children with malignant and non-malignant disorders with high overall survival and low incidence of GVHD.


Assuntos
Transplante de Medula Óssea , Transplante de Células-Tronco de Sangue do Cordão Umbilical , Doença Enxerto-Hospedeiro/mortalidade , Doença Enxerto-Hospedeiro/terapia , Leucemia/mortalidade , Leucemia/terapia , Condicionamento Pré-Transplante , Doença Aguda , Adolescente , Adulto , Aloenxertos , Criança , Pré-Escolar , Doença Crônica , Intervalo Livre de Doença , Feminino , Seguimentos , Doença Enxerto-Hospedeiro/etiologia , Humanos , Lactente , Doadores Vivos , Masculino , Taxa de Sobrevida
9.
Haematologica ; 99(5): 811-20, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-24790059

RESUMO

Thalassemia major and sickle cell disease are the two most widely disseminated hereditary hemoglobinopathies in the world. The outlook for affected individuals has improved in recent years due to advances in medical management in the prevention and treatment of complications. However, hematopoietic stem cell transplantation is still the only available curative option. The use of hematopoietic stem cell transplantation has been increasing, and outcomes today have substantially improved compared with the past three decades. Current experience world-wide is that more than 90% of patients now survive hematopoietic stem cell transplantation and disease-free survival is around 80%. However, only a few controlled trials have been reported, and decisions on patient selection for hematopoietic stem cell transplantation and transplant management remain principally dependent on data from retrospective analyses and on the clinical experience of the transplant centers. This consensus document from the European Blood and Marrow Transplantation Inborn Error Working Party and the Paediatric Diseases Working Party aims to report new data and provide consensus-based recommendations on indications for hematopoietic stem cell transplantation and transplant management.


Assuntos
Anemia Falciforme/terapia , Transplante de Células-Tronco Hematopoéticas , Talassemia beta/terapia , Anemia Falciforme/diagnóstico , Criança , Humanos , Talassemia beta/diagnóstico
10.
Haematologica ; 99(2): 378-84, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24097633

RESUMO

There are very few disease-specific studies focusing on outcomes of umbilical cord blood transplantation for Philadelphia chromosome-positive acute lymphoblastic leukemia. We report the outcome of 45 patients with Philadelphia chromosome-positive acute lymphoblastic leukemia who underwent myeloablative single unit cord blood transplantation from unrelated donors within the GETH/GITMO cooperative group. Conditioning regimens were based on combinations of thiotepa, busulfan, cyclophospamide or fludarabine, and antithymocyte globulin. At the time of transplantation, 35 patients (78%) were in first complete remission, four (8%) in second complete remission and six (14%) in third or subsequent response. The cumulative incidence of myeloid engraftment was 96% at a median time of 20 days and significantly better for patients receiving higher doses of CD34(+) cells. The incidence of acute grade II-IV graft-versus-host disease was 31%, while that of overall chronic graft-versus-host disease was 53%. Treatment-related mortality was 17% at day +100 and 31% at 5 years. The 5-year relapse, event-free survival and overall survival rates were 31%, 36% and 44%, respectively. Although the event-free and overall survival rates in patients without BCR/ABL transcripts detectable at time of transplant were better than those in whom BCR/ABL transcripts were detected (46% versus 24% and 60% versus 30%, respectively) these differences were not statistically significant in the univariate analysis (P=0.07). These results demonstrate that umbilical cord blood transplantation from unrelated donors can be a curative treatment for a substantial number of patients with Philadelphia chromosome-positive acute lymphoblastic leukemia.


Assuntos
Transplante de Células-Tronco de Sangue do Cordão Umbilical , Agonistas Mieloablativos/administração & dosagem , Cromossomo Filadélfia , Leucemia-Linfoma Linfoblástico de Células Precursoras , Condicionamento Pré-Transplante , Adolescente , Adulto , Aloenxertos , Criança , Pré-Escolar , Doença Crônica , Intervalo Livre de Doença , Feminino , Seguimentos , Doença Enxerto-Hospedeiro/mortalidade , Doença Enxerto-Hospedeiro/patologia , Doença Enxerto-Hospedeiro/prevenção & controle , Humanos , Masculino , Pessoa de Meia-Idade , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidade , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Estudos Retrospectivos , Taxa de Sobrevida
11.
Biol Blood Marrow Transplant ; 19(9): 1387-92, 2013 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-23850652

RESUMO

Myeloablative single-unit umbilical cord blood transplantation (sUCBT) using busulfan, thiotepa, fludarabine, and antithymocyte globulin (Grupo Español de Trasplante Hematopoyético [GETH]-2005 protocol) resulted in high rates of engraftment and high antitumor activity. We designed a new graft-versus-host disease prophylaxis, substituting long-term steroids with mycophenolate mofetil together with a slight reduction of antithymocyte globulin (GETH/Gruppo Italiano Trapianto Midollo Osseo [GITMO]-2008 protocol). The results in 145 consecutive patients were compared with those obtained in 88 patients from the previous GETH-2005 trial. The cumulative incidence (CI) of myeloid engraftment at 60 days for patients in the GETH-2005 and GETH/GITMO-2008 trials was 94% and 88%, respectively, at a median time to neutrophil recovery of 19 and 23 days, respectively (P < .0001). In the multivariable analyses, platelet engraftment, acute and chronic graft-versus-host disease, nonrelapse mortality, relapse, and event-free survival were not significantly different. The 3-year event-free survival rate in the GETH/GITMO-2008 trial was 66%, 31%, and 25% for patients transplanted in early, intermediate, and advanced stages of the disease, respectively (P < .0001). This study confirms that myeloablative sUCBT using busulfan-based conditioning is a valuable strategy for patients with hematological malignancies. The use of mycophenolate mofetil apparently had an adverse effect on myeloid engraftment, and therefore a cautious use of this agent is warranted in the UCBT setting.


Assuntos
Transplante de Células-Tronco de Sangue do Cordão Umbilical/métodos , Doença Enxerto-Hospedeiro/prevenção & controle , Condicionamento Pré-Transplante/métodos , Adulto , Transplante de Células-Tronco de Sangue do Cordão Umbilical/efeitos adversos , Intervalo Livre de Doença , Feminino , Sobrevivência de Enxerto , Doença Enxerto-Hospedeiro/etiologia , Humanos , Masculino , Fatores de Risco , Análise de Sobrevida , Condicionamento Pré-Transplante/efeitos adversos , Adulto Jovem
14.
J Antimicrob Chemother ; 67(3): 700-6, 2012 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-22190607

RESUMO

OBJECTIVES: To evaluate voriconazole plasma level monitoring in immunocompromised children and determine the relationship of plasma levels with dose, safety and efficacy. METHODS: We used a prospective study including all consecutive children with invasive fungal infection (IFI) treated with voriconazole between August 2008 and May 2010. IFI diagnosis and clinical outcome evaluation were based on European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group ('EORTC/MSG') definitions. RESULTS: A total of 196 voriconazole plasma trough measurements from 30 patients (median age 10 years) obtained during 2135 days of voriconazole therapy were analysed. Nineteen patients (63%) presented with proven or probable IFI. Voriconazole plasma levels varied widely and 73% of patients required dose adjustment. The median voriconazole dose was 20 mg/kg/day and the median duration of therapy was 6 weeks. Age 5 was the smallest value defining two groups on which the correlation between dose and plasma levels had a different behaviour, and this relationship was especially significant for patients <5 years old (Spearman's rank correlation coefficient=0.38213, P=0.008). For patients <5 years old the median dose to achieve therapeutic levels was 38.0 mg/kg/day (12-40.0) and for those ≥5 years old it was 15 mg/kg (4-52). Voriconazole plasma levels showed a significant relationship with early outcome (P=0.0268), but not late outcome (P=0.2015). Overall mortality was 42% and a significant relationship with voriconazole therapeutic plasma levels was not demonstrated. A significant relationship was established between plasma levels above normal range and skin and neurological toxicity (P=0.0001), but this could not be demonstrated for liver toxicity. CONCLUSIONS: Our study confirms the large variability in voriconazole trough plasma levels in children and a trend to non-linear pharmacokinetics in older patients. In addition, doses significantly higher than those recommended in younger children seem warranted and a significant relationship between plasma voriconazole above the normal range and some adverse events is confirmed.


Assuntos
Antifúngicos/administração & dosagem , Monitoramento de Medicamentos/métodos , Micoses/tratamento farmacológico , Pirimidinas/administração & dosagem , Triazóis/administração & dosagem , Adolescente , Antifúngicos/efeitos adversos , Antifúngicos/farmacocinética , Criança , Pré-Escolar , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Feminino , Humanos , Hospedeiro Imunocomprometido , Incidência , Lactente , Masculino , Plasma/química , Estudos Prospectivos , Pirimidinas/efeitos adversos , Pirimidinas/farmacocinética , Resultado do Tratamento , Triazóis/efeitos adversos , Triazóis/farmacocinética , Voriconazol
15.
Nat Immunol ; 13(2): 170-80, 2011 Dec 25.
Artigo em Inglês | MEDLINE | ID: mdl-22197976

RESUMO

Neutrophils use immunoglobulins to clear antigen, but their role in immunoglobulin production is unknown. Here we identified neutrophils around the marginal zone (MZ) of the spleen, a B cell area specialized in T cell-independent immunoglobulin responses to circulating antigen. Neutrophils colonized peri-MZ areas after postnatal mucosal colonization by microbes and enhanced their B cell-helper function after receiving reprogramming signals, including interleukin 10 (IL-10), from splenic sinusoidal endothelial cells. Splenic neutrophils induced immunoglobulin class switching, somatic hypermutation and antibody production by activating MZ B cells through a mechanism that involved the cytokines BAFF, APRIL and IL-21. Neutropenic patients had fewer and hypomutated MZ B cells and a lower abundance of preimmune immunoglobulins to T cell-independent antigens, which indicates that neutrophils generate an innate layer of antimicrobial immunoglobulin defense by interacting with MZ B cells.


Assuntos
Linfócitos B/imunologia , Imunoglobulinas/biossíntese , Imunoglobulinas/imunologia , Neutrófilos/imunologia , Baço/imunologia , Adolescente , Adulto , Animais , Anticorpos/imunologia , Anticorpos/metabolismo , Células Cultivadas , Criança , Doenças Transmissíveis/imunologia , Citocinas/imunologia , Feminino , Infecções por HIV/imunologia , Humanos , Switching de Imunoglobulina/imunologia , Interleucina-10/imunologia , Lúpus Eritematoso Sistêmico/imunologia , Macaca mulatta/imunologia , Masculino , Camundongos , Pessoa de Meia-Idade , Hipermutação Somática de Imunoglobulina/imunologia , Adulto Jovem
16.
Blood ; 117(14): 3759-69, 2011 Apr 07.
Artigo em Inglês | MEDLINE | ID: mdl-21273304

RESUMO

Fanconi anemia is characterized by congenital abnormalities, bone marrow failure, and cancer predisposition. To investigate the origin, functional role, and clinical impact of FANCA mutations, we determined a FANCA mutational spectrum with 130 pathogenic alleles. Some of these mutations were further characterized for their distribution in populations, mode of emergence, or functional consequences at cellular and clinical level. The world most frequent FANCA mutation is not the result of a mutational "hot-spot" but results from worldwide dissemination of an ancestral Indo-European mutation. We provide molecular evidence that total absence of FANCA in humans does not reduce embryonic viability, as the observed frequency of mutation carriers in the Gypsy population equals the expected by Hardy-Weinberg equilibrium. We also prove that long distance Alu-Alu recombination can cause Fanconi anemia by originating large interstitial deletions involving FANCA and 2 adjacent genes. Finally, we show that all missense mutations studied lead to an altered FANCA protein that is unable to relocate to the nucleus and activate the FA/BRCA pathway. This may explain the observed lack of correlation between type of FANCA mutation and cellular phenotype or clinical severity in terms of age of onset of hematologic disease or number of malformations.


Assuntos
Proteína do Grupo de Complementação A da Anemia de Fanconi/genética , Proteína do Grupo de Complementação A da Anemia de Fanconi/fisiologia , Anemia de Fanconi/genética , Anemia de Fanconi/patologia , Mutação , Adolescente , Idade de Início , Sequência de Bases , Técnicas de Cultura de Células , Células Cultivadas , Criança , Pré-Escolar , Aberrações Cromossômicas , Hibridização Genômica Comparativa , Análise Mutacional de DNA , Anemia de Fanconi/diagnóstico , Anemia de Fanconi/epidemiologia , Proteína do Grupo de Complementação A da Anemia de Fanconi/metabolismo , Frequência do Gene , Humanos , Lactente , Modelos Biológicos , Dados de Sequência Molecular , Mutação/fisiologia , Fenótipo , Espanha/epidemiologia
17.
J Med Genet ; 48(4): 242-50, 2011 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-21217111

RESUMO

BACKGROUND: Fanconi anaemia (FA) is a rare syndrome characterized by bone marrow failure, malformations and cancer predisposition. Chromosome fragility induced by DNA interstrand crosslink (ICL)-inducing agents such as diepoxybutane (DEB) or mitomycin C (MMC) is the 'gold standard' test for the diagnosis of FA. OBJECTIVE: To study the variability, the diagnostic implications and the clinical impact of chromosome fragility in FA. METHODS: Data are presented from 198 DEB-induced chromosome fragility tests in patients with and without FA where information on genetic subtype, cell sensitivity to MMC and clinical data were available. RESULTS: This large series allowed quantification of the variability and the level of overlap in ICL sensitivity among patients with FA and the normal population. A new chromosome fragility index is proposed that provides a cut-off diagnostic level to unambiguously distinguish patients with FA, including mosaics, from non-FA individuals. Spontaneous chromosome fragility and its correlation with DEB-induced fragility was also analysed, indicating that although both variables are correlated, 54% of patients with FA do not have spontaneous fragility. The data reveal a correlation between malformations and sensitivity to ICL-inducing agents. This correlation was also statistically significant when the analysis was restricted to patients from the FA-A complementation group. Finally, chromosome fragility does not correlate with the age of onset of haematological disease. CONCLUSIONS: This study proposes a new chromosome fragility index and suggests that genome instability during embryo development may be related to malformations in FA, while DEB-induced chromosome breaks in T cells have no prognostic value for the haematological disease.


Assuntos
Fragilidade Cromossômica , Anemia de Fanconi/genética , Reagentes para Ligações Cruzadas/farmacologia , Compostos de Epóxi/farmacologia , Anemia de Fanconi/diagnóstico , Humanos , Mitomicina/farmacologia , Mosaicismo , Fenótipo
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