RESUMEN
We report a case of mild cannabinoid poisoning in a preschool child, after 3-week ingestion of hemp seed oil prescribed by his pediatrician to strengthen his immune system. The patient presented neurological symptoms that disappeared after intravenous hydration. A possible mild withdrawal syndrome was reported after discharge. The main metabolite of Δ-tetrahydrocannabinol was detected in urine, and very low concentration of Δ-tetrahydrocannabinol was detected in the ingested product. This is, as far as we know, the first report of cannabinoid poisoning after medical prescription of hemp seed oil in a preschool child.
Asunto(s)
Cannabinoides/envenenamiento , Cannabis/efectos adversos , Dronabinol/orina , Aceites de Plantas/uso terapéutico , Intoxicación/diagnóstico , Semillas/efectos adversos , Síndrome de Abstinencia a Sustancias/diagnóstico , Preescolar , Citocromo P-450 CYP2C9/metabolismo , Citocromo P-450 CYP3A/metabolismo , Dronabinol/metabolismo , Humanos , Infusiones Intravenosas/métodos , Masculino , Aceites de Plantas/administración & dosificación , Aceites de Plantas/efectos adversos , Intoxicación/etiología , Intoxicación/terapia , Síndrome de Abstinencia a Sustancias/etiología , Resultado del TratamientoRESUMEN
We analyzed 97 Fanconi anemia patients from a clinic/biological database for genotype, somatic, and hematologic phenotype, adverse hematological events, solid tumors, and treatment. Seventy-two patients belonged to complementation group A. Eighty percent of patients presented with mild/moderate somatic phenotype and most with cytopenia. No correlation was seen between somatic/hematologic phenotype and number of missense mutations of FANCA alleles. Over follow-up, 33% of patients improved or maintained mild/moderate cytopenia or normal blood count, whereas remaining worsened cytopenia. Eleven patients developed a hematological adverse event (MDS, AML, pathological cytogenetics) and three developed solid tumors. 10 years cumulative risk of death of the whole cohort was 25.6% with median follow-up 5.8 years. In patients eligible to hematopoietic stem cell transplantation because of moderate cytopenia, mortality was significantly higher in subjects transplanted from matched unrelated donor over nontransplanted subjects, whereas there was no significant difference between matched sibling donor transplants and nontransplanted patients. In patients eligible to transplant because of severe cytopenia and clonal disease, mortality risk was not significantly different in transplanted from matched unrelated versus matched sibling donor versus nontransplanted subjects. The decision to transplant should rely on various elements including, type of donor, HLA matching, patient comorbidities, impairment, and clonal evolution of hematopoiesis. Am. J. Hematol. 91:666-671, 2016. © 2016 Wiley Periodicals, Inc.
Asunto(s)
Anemia de Fanconi/terapia , Trasplante de Células Madre Hematopoyéticas/métodos , Adolescente , Adulto , Niño , Preescolar , Toma de Decisiones , Anemia de Fanconi/mortalidad , Femenino , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Trasplante de Células Madre Hematopoyéticas/mortalidad , Prueba de Histocompatibilidad , Humanos , Lactante , Recién Nacido , Italia , Masculino , Pancitopenia/inducido químicamente , Fenotipo , Hermanos , Donantes de Tejidos , Resultado del Tratamiento , Adulto JovenRESUMEN
Acquired aplastic anemia (AA) is a rare heterogeneous disease characterized by pancytopenia and hypoplastic bone marrow. The incidence is 2-3/million inhabitants/year, in Europe, but higher in East Asia. Survival in severe aplastic anemia (SAA) has markedly improved in the past 2 decades because of advances in hematopoietic stem cell transplantation, immunosuppressive and biologic drugs, and supportive care. In SAA hematopoietic stem cell transplant (HSCT) from a matched sibling donor (MSD) is the treatment of choice. If a MSD is not available, the options include immunosuppressive therapy (IST) or unrelated donor HSCT. The objective of this guideline is to provide healthcare professionals with clear guidance on the diagnosis and management of pediatric patients with AA. A preliminary, evidence-based document issued by a group of pediatric hematologists was discussed, modified and approved during a series of "Consensus Conferences" according to procedures previously validated by the AIEOP Board. The guidelines highlight the importance of referring pediatric patients with AA to pediatric centers with long experience in diagnosis, differential diagnosis, management, supportive care and follow-up of AA.
Asunto(s)
Anemia Aplásica/diagnóstico , Anemia Aplásica/terapia , Trasplante de Células Madre Hematopoyéticas/métodos , Inmunosupresores/uso terapéutico , Pancitopenia/diagnóstico , Pancitopenia/terapia , Anemia Aplásica/inducido químicamente , Anemia Aplásica/inmunología , Antibacterianos/efectos adversos , Antiinflamatorios/efectos adversos , Suero Antilinfocítico/uso terapéutico , Antirreumáticos/efectos adversos , Médula Ósea/efectos de los fármacos , Médula Ósea/inmunología , Médula Ósea/patología , Niño , Ciclosporina/uso terapéutico , Manejo de la Enfermedad , Prueba de Histocompatibilidad , Humanos , Organofosfatos/toxicidad , Pancitopenia/inducido químicamente , Pancitopenia/inmunología , Hermanos , Donante no EmparentadoRESUMEN
We have analyzed 1448 patients with acquired aplastic anemia grafted between 2005 and 2009, and compared outcome of identical sibling (n=940) versus unrelated donor (n=508) transplants. When compared to the latter, sibling transplants were less likely to be performed beyond 180 days from diagnosis (39% vs. 85%), to have a cytomegalovirus negative donor/recipient status (15% vs. 23%), to receive antithymocyte globulin in the conditioning (52% vs. 61%), and more frequently received marrow as a stem cell source (60% vs. 52%). Unrelated donor grafts had significantly more acute grade II-IV (25% vs. 13%) and significantly more chronic graft-versus-host disease (26% vs. 14%). In multivariate analysis, the risk of death of unrelated donor grafts was higher, but not significantly higher, compared to a sibling donor (P=0.16). The strongest negative predictor of survival was the use of peripheral blood as a stem cell source (P<0.00001), followed by an interval of diagnosis to transplant of 180 days or more (P=0.0005), patient age 20 years or over (P=0.0005), no antithymocyte globulin in the conditioning (P=0.003), and donor/recipient cytomegalovirus sero-status, other than negative/negative (P=0.04). In conclusion, in multivariate analysis, the outcome of unrelated donor transplants for acquired aplastic anemia, is currently not statistically inferior when compared to sibling transplants, although patients are at greater risk of acute and chronic graft-versus-host disease. The use of peripheral blood grafts remains the strongest negative predictor of survival.
Asunto(s)
Anemia Aplásica/mortalidad , Anemia Aplásica/terapia , Trasplante de Células Madre Hematopoyéticas , Hermanos , Donante no Emparentado , Anemia Aplásica/epidemiología , Europa (Continente)/epidemiología , Femenino , Supervivencia de Injerto , Enfermedad Injerto contra Huésped/epidemiología , Enfermedad Injerto contra Huésped/etiología , Antígenos HLA/genética , Antígenos HLA/inmunología , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Humanos , Incidencia , Masculino , Factores de Riesgo , Análisis de Supervivencia , Acondicionamiento Pretrasplante/métodos , Trasplante Homólogo , Resultado del TratamientoRESUMEN
We describe the case of an 8-year-old girl with common precursor B-cell acute lymphoblastic leukemia who presented with severe pancytopenia during maintenance therapy with methotrexate and 6-mercaptopurine. The bone marrow smear showed moderate hypocellularity and trilinear dysplastic changes consistent with a diagnosis of drug toxicity, with no evidence of lymphoblasts. Flow cytometric immunophenotyping was negative for leukemic cells. Blood cell counts normalized after treatment with folinic acid. Maintenance therapy was gradually restarted and she remained well at follow-up visits. Myelotoxicity from methotrexate and 6-mercaptopurine may represent an unpredictable incident during an otherwise uneventful maintenance therapy, and may occur independently of other organ toxicities.
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Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Enfermedades de la Médula Ósea/inducido químicamente , Leucemia-Linfoma Linfoblástico de Células Precursoras B/tratamiento farmacológico , Niño , Manejo de la Enfermedad , Femenino , Estudios de Seguimiento , Humanos , Mercaptopurina/administración & dosificación , Metotrexato/administración & dosificación , PronósticoRESUMEN
This document updates and expands the recommendations on primary prophylaxis of invasive fungal diseases (IFD) in allogeneic hematopoietic stem cell transplantation (allo-HSCT) recipients, published in 2009 by the Gruppo Italiano Trapianto Midollo Osseo (GITMO). A consensus process was undertaken to describe and evaluate current information and practice regarding risk stratification and primary antifungal prophylaxis during the pre-engraftment and postengraftment phases after allo-HSCT. The revised recommendations were based on the evaluation of recent literature including a large, prospective, multicenter epidemiological study of allo-HSCT recipients conducted among the GITMO transplantation centers during the period of 2008 to 2010. It is intended as a guide for the identification of types and phases of transplantation at low, standard, and high risk for IFD, according to the underlying disease, transplantation, and post-transplantation factors. The risk stratification was the critical determinant of the primary antifungal approach for allo-HSCT recipients.
Asunto(s)
Antifúngicos/uso terapéutico , Trasplante de Células Madre Hematopoyéticas/métodos , Micosis/prevención & control , Acondicionamiento Pretrasplante/métodos , Trasplante Homólogo/métodos , Consenso , Humanos , ItaliaRESUMEN
One hundred and forty patients who had undergone hematopoietic stem cell transplantation (HSCT) for myelodysplastic syndrome (MDS) or acute myelogenous leukemia (AML) transformation after treatment of severe aplastic anemia (SAA) were identified in the European Group for Blood and Marrow Transplantation (EBMT) database. The median age at HSCT was 29 years (range, 1 to 66 years). The transplant donor was related in 49% cases and unrelated in 51% cases. The 5-year probability of relapse was 17%, and that of nonrelapse mortality was 41%. The 5-year overall survival was 45% ± 9%, better for patients untreated and patients in remission compared with patients with refractory disease. Our data indicate that allogeneic HSCT leads to prolonged survival in close to one-half of the patients transforming to MDS or AML from SAA.
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Anemia Aplásica/terapia , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Acondicionamiento Pretrasplante/efectos adversos , Trasplante Homólogo/efectos adversos , Adolescente , Adulto , Anciano , Niño , Preescolar , Europa (Continente) , Femenino , Humanos , Lactante , Leucemia , Masculino , Persona de Mediana Edad , Síndromes Mielodisplásicos , Recurrencia Local de Neoplasia , Resultado del Tratamiento , Adulto JovenRESUMEN
Epidemiologic investigation of invasive fungal diseases (IFDs) in allogeneic hematopoietic stem cell transplantation (allo-HSCT) may be useful to identify subpopulations who might benefit from targeted treatment strategies. The Gruppo Italiano Trapianto Midollo Osseo (GITMO) prospectively registered data on 1858 consecutive patients undergoing allo-HSCT between 2008 and 2010. Logistic regression analysis was performed to identify risk factors for proven/probable IFD (PP-IFD) during the early (days 0 to 40), late (days 41 to 100), and very late (days 101 to 365) phases after allo-HSCT and to evaluate the impact of PP-IFDs on 1-year overall survival. The cumulative incidence of PP-IFDs was 5.1% at 40 days, 6.7% at 100 days, and 8.8% at 12 months post-transplantation. Multivariate analysis identified the following variables as associated with PP-IFDs: transplant from an unrelated volunteer donor or cord blood, active acute leukemia at the time of transplantation, and an IFD before transplantation in the early phase; transplant from an unrelated volunteer donor or cord blood and grade II-IV acute graft-versus-host disease (GVHD) in the late phase; and grade II-IV acute GVHD and extensive chronic GVHD in the very late phase. The risk for PP-IFD was significantly higher when acute GVHD was followed by chronic GVHD and when acute GVHD occurred in patients undergoing transplantation with grafts from other than matched related donors. The presence of PP-IFD was an independent factor in long-term survival (hazard ratio, 2.90; 95% confidence interval, 2.32 to 3.62; P < .0001). Our findings indicate that tailored prevention strategies may be useful in subpopulations at differing levels of risk for PP-IFDs.
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Trasplante de Células Madre Hematopoyéticas/estadística & datos numéricos , Micosis/epidemiología , Adolescente , Adulto , Anciano , Niño , Preescolar , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Humanos , Incidencia , Lactante , Italia/epidemiología , Persona de Mediana Edad , Micosis/etiología , Estudios Prospectivos , Trasplante Homólogo , Resultado del Tratamiento , Adulto JovenRESUMEN
Fanconi anemia is an inherited disease characterized by congenital malformations, pancytopenia, cancer predisposition, and sensitivity to cross-linking agents. The molecular diagnosis of Fanconi anemia is relatively complex for several aspects including genetic heterogeneity with mutations in at least 16 different genes. In this paper, we report the mutations identified in 100 unrelated probands enrolled into the National Network of the Italian Association of Pediatric Hematoly and Oncology. In approximately half of these cases, mutational screening was carried out after retroviral complementation analyses or protein analysis. In the other half, the analysis was performed on the most frequently mutated genes or using a next generation sequencing approach. We identified 108 distinct variants of the FANCA, FANCG, FANCC, FANCD2, and FANCB genes in 85, 9, 3, 2, and 1 families, respectively. Despite the relatively high number of private mutations, 45 of which are novel Fanconi anemia alleles, 26% of the FANCA alleles are due to 5 distinct mutations. Most of the mutations are large genomic deletions and nonsense or frameshift mutations, although we identified a series of missense mutations, whose pathogenetic role was not always certain. The molecular diagnosis of Fanconi anemia is still a tiered procedure that requires identifying candidate genes to avoid useless sequencing. Introduction of next generation sequencing strategies will greatly improve the diagnostic process, allowing a rapid analysis of all the genes.
Asunto(s)
Proteínas del Grupo de Complementación de la Anemia de Fanconi/genética , Anemia de Fanconi/genética , Mutación , Sustitución de Aminoácidos , Línea Celular , Estudios de Cohortes , Biología Computacional , Bases de Datos de Ácidos Nucleicos , Efecto Fundador , Genotipo , Humanos , Italia , Mosaicismo , Polimorfismo de Nucleótido SimpleRESUMEN
BACKGROUND: Bone marrow has been shown to be superior to peripheral blood, as a stem cell source, in young patients (<20 years of age) with acquired aplastic anemia undergoing a matched sibling transplant. The aim of this study was to test whether this currently also holds true for older patients with acquired aplastic anemia. DESIGN AND METHODS: We analyzed 1886 patients with acquired aplastic anemia who received a first transplant from a human leukocyte antigen identical sibling between 1999 and 2009, with either bone marrow (n=1163) or peripheral blood (n=723) as the source of stem cells. RESULTS: In multivariate Cox analysis negative predictors for survival were: patient's age over 20 years (RR 2.0, P<0.0001), an interval between diagnosis and transplantation of more than 114 days (RR 1.3, P=0.006), no anti-thymocyte globulin in the conditioning (RR 1.6, P=0.0001), a conditioning regimen other than cyclophosphamide (RR=1.3, P=0.008) and the use of peripheral blood as the source of stem cells (RR 1.6, P<0.00001). The survival advantage for recipients of bone marrow rather than peripheral blood was statistically significant in patients aged 1-19 years (90% versus 76% P<0.00001) as well as in patients aged over 20 years (74% versus 64%, P=0.001). The advantage for recipients of bone marrow over peripheral blood was maintained above the age of 50 years (69% versus 39%, P=0.01). Acute and chronic graft-versus-host disease were more frequent in peripheral blood transplants. Major causes of death were graft-versus-host disease (2% versus 6% in bone marrow and peripheral blood recipients, respectively), infections (6% versus 13%), and graft rejection (1.5% versus 2.5%). CONCLUSIONS: This study shows that bone marrow should be the preferred stem cell source for matched sibling transplants in acquired aplastic anemia, in patients of all age groups.
Asunto(s)
Anemia Aplásica/mortalidad , Anemia Aplásica/terapia , Trasplante de Células Madre Hematopoyéticas , Hermanos , Adolescente , Adulto , Factores de Edad , Anciano , Suero Antilinfocítico/uso terapéutico , Trasplante de Médula Ósea/efectos adversos , Causas de Muerte , Niño , Preescolar , Femenino , Supervivencia de Injerto , Enfermedad Injerto contra Huésped/etiología , Enfermedad Injerto contra Huésped/terapia , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Humanos , Lactante , Masculino , Persona de Mediana Edad , Trasplante de Células Madre de Sangre Periférica/efectos adversos , Trasplante Homólogo , Adulto JovenRESUMEN
In order to assess the epidemiology of Hepatitis-Associated Aplasia (HAA) and compare treatment outcome of HAA with non-HAA patients, we evaluated 3916 aplastic anaemia patients reported to the European Registry between 1990 and 2007. Year, month, season of diagnosis, type and outcome of first-line therapy were analysed. Prevalence of HAA (n = 214) in Europe was 5%. Compared to non-HAA patients, HAA patients were younger (15 vs. 20 years, P < 0.001), with a male prevalence (68% vs. 58% P = 0.002), and were treated earlier after diagnosis (46 vs. 62 d; P < 0.001). No significant differences were found regarding the year or month of diagnosis. No geographic clusters could be identified. Actuarial survival at 10 years after first-line immunosuppression was 69%, and did not differ according to aetiology. The 10-year actuarial survival after transplantation was 70%, and was comparable in HAA and non-HAA patients, when stratified for age and donor type. In a multivariate Cox analysis, increasing age and delayed treatment were significant negative indicators for survival. In conclusion, the incidence of HAA was 5% and was evenly distributed over time and geographic areas in Europe. Treatment outcome and predictive variables, were comparable in patients with or without HAA.
Asunto(s)
Anemia Aplásica/etiología , Hepatitis/complicaciones , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Anemia Aplásica/epidemiología , Anemia Aplásica/terapia , Trasplante de Médula Ósea , Niño , Preescolar , Métodos Epidemiológicos , Europa (Continente)/epidemiología , Femenino , Hepatitis/epidemiología , Humanos , Inmunosupresores/uso terapéutico , Lactante , Masculino , Persona de Mediana Edad , Resultado del Tratamiento , Adulto JovenRESUMEN
BACKGROUND: We analyzed the outcome of 100 patients with acquired severe aplastic anemia undergoing an alternative donor transplant, after immune suppressive therapy had failed. DESIGN AND METHODS: As a conditioning regimen, patients received either a combination of fludarabine, cyclophosphamide, and antithymocyte globulin (n=52, median age 13 years) or this combination with the addition of low dose (2 Gy) total body irradiation (n=48, median age 27 years). RESULTS: With a median follow-up of 1665 and 765 days, the actuarial 5-year survival was 73% for the group that received fludarabine, cyclophosphamide, and antithymocyte globulin and 79% for the group given the conditioning regimen including total body irradiation. Acute graft-versus-host disease grade III-IV was seen in 18% and 7% of the groups, respectively. Graft failure was seen in 17 patients with an overall cumulative incidence of 17% in patients receiving conditioning with or without total body irradiation: 9 of these 17 patients survive in the long-term. The most significant predictor of survival was the interval between diagnosis and transplantation, with 5-year survival rates of 87% and 55% for patients grafted within 2 years of diagnosis and more than 2 years after diagnosis, respectively (P=0.0004). Major causes of death were graft failure (n=7), post-transplant-lymphoproliferative-disease (n=4) and graft-versus-host disease (n=4). CONCLUSIONS: This study confirms positive results of alternative donor transplants in patients with severe aplastic anemia, the best outcomes being achieved in patients grafted within 2 years of diagnosis. Prevention of rejection and Epstein-Barr virus reactivation may further improve these results.
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Anemia Aplásica/cirugía , Suero Antilinfocítico/uso terapéutico , Trasplante de Médula Ósea/métodos , Ciclofosfamida/uso terapéutico , Trasplante de Células Madre Hematopoyéticas/métodos , Vidarabina/análogos & derivados , Adolescente , Adulto , Anemia Aplásica/tratamiento farmacológico , Anemia Aplásica/mortalidad , Niño , Preescolar , Europa (Continente) , Femenino , Estudios de Seguimiento , Enfermedad Injerto contra Huésped/tratamiento farmacológico , Enfermedad Injerto contra Huésped/mortalidad , Enfermedad Injerto contra Huésped/prevención & control , Humanos , Donadores Vivos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Tasa de Supervivencia/tendencias , Acondicionamiento Pretrasplante/métodos , Vidarabina/uso terapéutico , Irradiación Corporal Total/métodos , Adulto JovenRESUMEN
In recent years, prospective studies have been conducted to assess the role of prophylaxis and treatment of invasive fungal diseases (IFD) in allogeneic hematopoietic stem cell transplantation (allo-HSCT). Although results of these studies have been encouraging, they have been unable to generate a consensus for optimal prophylaxis and treatment of IFD in the complex scenario of allo-HSCT. A consensus process was undertaken to describe and evaluate current information and practice regarding key questions on IFD management in allo-HSCT recipients; these questions were selected according to the criterion of relevance by group discussion. The Panel produced recommendations for risk stratification, prophylaxis, monitoring, and therapy of IFD and identified top priority issues for further investigation. The definition of the level of risk for IFD associated with the various types and phases of transplantation and the implementation of surveillance and diagnostic strategies are the critical determinants of the antifungal prophylactic and therapeutic approach for allo-HSCT recipients.
Asunto(s)
Antifúngicos/uso terapéutico , Quimioprevención/métodos , Micosis/tratamiento farmacológico , Micosis/prevención & control , Trasplante de Células Madre/efectos adversos , Trasplante Homólogo/efectos adversos , Humanos , Huésped Inmunocomprometido , ItaliaRESUMEN
BACKGROUND: Invasive pneumococcal disease is a life-threatening complication after allogeneic stem cell transplantation, and at least 20% of cases occur within 1 year after transplantation. The 23-valent pneumococcal polysaccharide vaccine (PPV23) has limited efficacy, especially during the first year after transplantation. The immune response to the conjugated vaccines is expected to be better than that to the polysaccharide vaccine, but the optimal timing of vaccination is not defined. Our objective was to show that a 7-valent pneumococcal conjugate vaccine (PCV7; Prevnar) was not inferior when first given 3 months after transplantation, compared with when first given 9 months after transplantation. METHODS: We performed a multicenter, randomized, noninferiority study involving 158 patients from 13 European Group for Blood and Marrow Transplantation centers who were randomly allocated at approximately 100 days after myeloablative stem cell transplantation to receive a series of vaccinations (3 doses of PCV7 given 1 month apart) that was started immediately (i.e., 3 months after transplantation) or 6 months later (i.e., 9 months after transplantation). The primary evaluation criterion was the rate of response (antibody level, > or = 0.15 microg/mL for each of the 7 serotypes) at 1 month after the third dose of PCV7. The noninferiority margin was 20%. All patients were followed up for 24 months after transplantation or until death, whichever occurred first. RESULTS: We found that the response rate was not lower after early vaccination (79% [45 of 57 patients]) than after late vaccination (82% [47 of 57 patients]) (difference, -3.5%; 90% confidence interval, -15.6 to 8.6; not significant). CONCLUSIONS: We conclude that PCV7 vaccination at 3 months after stem cell transplantation is not inferior to PCV7 vaccination at 9 months after transplantation. Because invasive pneumococcal disease can occur early, we recommend starting the PCV7 vaccination series at 3 months after transplantation to ensure earlier protection against Streptococcus pneumoniae. However, the early vaccination may result in only short-lasting response and may not prime for a 23-valent pneumococcal polysaccharide vaccine boost as efficiently as the late vaccination.
Asunto(s)
Esquemas de Inmunización , Inmunosupresores/uso terapéutico , Vacunas Neumococicas/inmunología , Trasplante de Células Madre , Adolescente , Adulto , Anticuerpos Antibacterianos/sangre , Niño , Europa (Continente) , Femenino , Vacuna Neumocócica Conjugada Heptavalente , Humanos , Inmunización Secundaria , Masculino , Persona de Mediana Edad , Vacunas Neumococicas/administración & dosificación , Factores de Tiempo , Adulto JovenRESUMEN
Ninety-one patients were studied serially for chimeric status following allogeneic stem cell transplantation (SCT) for severe aplastic anaemia (SAA) or Fanconi Anaemia (FA). Short tandem repeat polymerase chain reaction (STR-PCR) was used to stratify patients into five groups: (A) complete donor chimeras (n = 39), (B) transient mixed chimeras (n = 15) (C) stable mixed chimeras (n = 18), (D) progressive mixed chimeras (n = 14) (E) recipient chimeras with early graft rejection (n = 5). As serial sampling was not possible in Group E, serial chimerism results for 86 patients were available for analysis. The following factors were analysed for association with chimeric status: age, sex match, donor type, aetiology of aplasia, source of stem cells, number of cells engrafted, conditioning regimen, graft-versus-host disease (GvHD) prophylaxis, occurrence of acute and chronic GvHD and survival. Progressive mixed chimeras (PMCs) were at high risk of late graft rejection (n = 10, P < 0.0001). Seven of these patients lost their graft during withdrawal of immunosuppressive therapy. STR-PCR indicated an inverse correlation between detection of recipient cells post-SCT and occurrence of acute GvHD (P = 0.008). PMC was a bad prognostic indicator of survival (P = 0.003). Monitoring of chimeric status during cyclosporin withdrawal may facilitate therapeutic intervention to prevent late graft rejection in patients transplanted for SAA.
Asunto(s)
Anemia Aplásica/terapia , Rechazo de Injerto , Trasplante de Células Madre/efectos adversos , Adolescente , Adulto , Anemia Aplásica/genética , Anemia Aplásica/mortalidad , Niño , Preescolar , Quimerismo , Ciclosporina/uso terapéutico , Anemia de Fanconi/genética , Anemia de Fanconi/mortalidad , Anemia de Fanconi/terapia , Femenino , Estudios de Seguimiento , Humanos , Inmunosupresores/uso terapéutico , Masculino , Persona de Mediana Edad , Reacción en Cadena de la Polimerasa/métodos , Pronóstico , Modelos de Riesgos Proporcionales , Recurrencia , Tasa de Supervivencia , Secuencias Repetidas en Tándem , Factores de Tiempo , Acondicionamiento Pretrasplante , Trasplante Homólogo , Adulto JovenRESUMEN
Cytokine expression assessed by flow cytometry in 53 acquired aplastic anemia patients before and after combined immunosuppression (EBMT WPSAA protocols) showed that CD3(+) marrow cells containing TNF-alpha, IFN-gamma and IL4 were similar in subjects with disease at onset (DO) and responsive to treatment who had more CD3(+)/TNF-alpha(+) and CD 3(+)/IFN-gamma(+) cells than normal controls. In vitro block of TNF-alpha and/or IFN-gamma significantly increased BFU-e over baseline in 28 patients. In responsive to treatment patients only TNF-alpha block significantly incremented colonies over normal controls. Absolute marrow CD3(+)/TNF-alpha(+) and CD3(+)/IFN-gamma(+) cells prospectively tested in a group of 21 subjects declined significantly more in Responders than in Non Responders to immunosuppression at Response Evaluation Time respect to Diagnosis. Both in Responders and in Non Responders these cells remained higher than in normal controls. This study suggests that immunosuppression does not fully clear excess TNF-alpha and IFN-gamma from marrow of patients with good outcome and raises the hypothesis that additional cytokine blockade might be useful in immunosuppression for acquired aplastic anemia.
Asunto(s)
Anemia Aplásica/metabolismo , Terapia de Inmunosupresión/métodos , Interferón gamma/metabolismo , Interleucina-4/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo , Adolescente , Adulto , Anemia Aplásica/patología , Células de la Médula Ósea/metabolismo , Células de la Médula Ósea/patología , Complejo CD3/metabolismo , Proliferación Celular , Células Cultivadas , Niño , Preescolar , Femenino , Citometría de Flujo , Humanos , Masculino , Persona de Mediana Edad , Factores de Tiempo , Adulto JovenRESUMEN
Immunosuppressive therapy (IST) with antithymocyte globulin and cyclosporin A (CyA) is the standard treatment for children with acquired aplastic anaemia (AAA) lacking a matched donor. Survival rates of more than 80% at 5 years are achieved, but the response is drug-dependent in 15-25% of cases. This study, of 42 consecutive children with AAA treated with IST, assessed the incidence of CyA-dependence, CyA and granulocyte colony-stimulating factor (G-CSF) tapering schedules and the impact of drug accumulation on progression to myelodysplasia/acute myeloid leukaemia (MDS/AML). Overall survival was 83% at 10 years. CyA-dependence without a predictive marker was observed in 18% of responders. Probability of discontinuing CyA was 60.5% at 10 years; a slow CyA tapering schedule was performed in 84% of patients; the cumulative incidence of relapse was 16% at 10 years. Relapse risk was significantly associated with rapid CyA discontinuation: 60% compared to 7.6% in the slow tapering group (P = 0.001). Cumulative incidence of MDS/AML was 8% at 10 years, with a significant correlation with both G-CSF cumulative dose and second IST. This long-term follow-up of children with AAA shows that IST with a slow CyA tapering course is an effective treatment with a low-relapse rate in these cases.
Asunto(s)
Anemia Aplásica/tratamiento farmacológico , Ciclosporina/uso terapéutico , Inmunosupresores/uso terapéutico , Adolescente , Anemia Aplásica/sangre , Niño , Preescolar , Ciclosporina/administración & dosificación , Ciclosporina/sangre , Progresión de la Enfermedad , Esquema de Medicación , Evaluación de Medicamentos , Quimioterapia Combinada , Métodos Epidemiológicos , Femenino , Factor Estimulante de Colonias de Granulocitos/administración & dosificación , Factor Estimulante de Colonias de Granulocitos/uso terapéutico , Humanos , Inmunosupresores/administración & dosificación , Inmunosupresores/sangre , Lactante , Masculino , Recurrencia , Resultado del TratamientoRESUMEN
BACKGROUND AND OBJECTIVES: The treatment of acquired aplastic anemia (AA) is based on allogeneic bone marrow transplantation (BMT) and immunosuppressive therapy. The aim of this study was to assess the outcome of children and adults with AA treated in the last decade, and to determine whether results have improved in two sequential time periods,1991-1996 and 1997-2002. DESIGN AND METHODS: Two-thousands and seventy-nine consecutive patients with AA, classified according to first-line treatment: BMT (n=1567) or immunosuppressive therapy (n= 912), the patients for the two sequential time periods were studied. Analyses included variables related to patients, disease and transplant. RESULTS: The actuarial 10-year survival was 73% and 68% for BMT or immunosuppressive treatment, respectively (p=0.002). BMT outcome improved significantly with time (69% and 77%, p=001) for both matched sibling donor (MSD) (74% and 80%; p=0.003 ), alternative donor (38% and 65% p=0.0001), and was better in children (79% versus 68%, p<0.0001). Multivariate analysis: favorable predictors (p<0.001) were younger age, transplant beyond 1996, MSD, a short interval diagnosis-transplant , no irradiation. IS: no significant improvement over time (69% and 73% p=0.29). Survival was significantly better in children (81% versus 70%, p=0.001), especially in vSAA(83% versus 62%, p=0.0002). Combined IS was superior to single drug treatment (77% versus 62%, p=0.002). Multivariate analysis: significant predictors of survival: age > or =16 years (p=0.0009), longer interval between diagnosis -treatment (p=0.04), single drug versus combined IS (p=0.02). INTERPRETATION AND CONCLUSIONS: Outcome has improved in subsets of AA patients: those receiving first- line BMT and children with vSAA treated with IS. Age remains a major predictor for both treatments. Early intervention is associated with a significantly better outcome and is strongly recommended, whatever the first-line therapy.
Asunto(s)
Anemia Aplásica/terapia , Trasplante de Médula Ósea/métodos , Inmunosupresores/uso terapéutico , Adolescente , Adulto , Factores de Edad , Anciano , Anciano de 80 o más Años , Niño , Preescolar , Estudios de Cohortes , Europa (Continente) , Salud de la Familia , Humanos , Lactante , Persona de Mediana Edad , Estudios Retrospectivos , Acondicionamiento Pretrasplante , Trasplante HomólogoRESUMEN
Fifty-three patients with multiple myeloma (MM) underwent an allogeneic stem cell transplant (HSCT) from their HLA identical siblings using a reduced-intensity conditioning consisting of thioteopa 5 mg/kg, fludarabine 90 mg/m(2), and melphalan 80 mg/m(2). Their median age was 52 years (range 38 - 68) and the interval from diagnosis 12 months. Forty-three patients (82%) had advanced disease and 33 had previously been treated with high-dose therapy with one (N = 21), or more (N = 12) autologus transplants. Ten (18%) had their allograft programmed after induction chemotherapy. The majority (N = 44) received peripheral blood as stem cell source. Acute graft-versus-host disease (GVHD) grade II - IV developed in 45%, but grade III - IV in only 5%. Cumulative incidence of chronic GVHD was 64%. Sixty-two per cent were in complete remission (CR) following transplantation. Transplant-related mortality was 13%. Relapse incidence was 32%. With a median follow-up of 22 months, 3-year overall survival is 45% and progression free survival (PFS) 37%. The thiotepa, fludarabine, and melphalan conditioning regimen can produce remissions in the majority of MM patients with a limited transplant mortality rate. When used as first line treatment the results of transplantation appear even more encouraging.