RESUMEN
Aurora kinases regulate mitosis and are commonly overexpressed in leukemia. This phase I/IIa study of AT9283, a multikinase inhibitor, was designed to identify maximal tolerated doses, safety, pharmacokinetics, and pharmacodynamic activity in children with relapsed/refractory acute leukemia. The trial suffered from poor recruitment and terminated early, therefore failing to identify its primary endpoints. AT9283 caused tolerable toxicity, but failed to show clinical responses. Future trials should be based on robust preclinical data that provide an indication of which patients may benefit from the experimental agent, and recruitment should be improved through international collaborations and early combination with established treatment strategies.
Asunto(s)
Aurora Quinasas/antagonistas & inhibidores , Bencimidazoles/administración & dosificación , Bencimidazoles/farmacocinética , Leucemia/tratamiento farmacológico , Proteínas de Neoplasias/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/farmacocinética , Urea/análogos & derivados , Enfermedad Aguda , Adolescente , Bencimidazoles/efectos adversos , Niño , Preescolar , Femenino , Humanos , Lactante , Leucemia/enzimología , Masculino , Dosis Máxima Tolerada , Inhibidores de Proteínas Quinasas/efectos adversos , Urea/administración & dosificación , Urea/efectos adversos , Urea/farmacocinéticaRESUMEN
Health-related quality of life (HRQoL) assessment is recognized as an important outcome in the evaluation of different therapeutic regimens for persons with haemophilia. The Canadian Haemophilia Outcomes-Kids' Life Assessment Tool (CHO-KLAT) is a disease-specific measure of HRQoL for 4 to 18-year-old boys with haemophilia. The purpose of this study was to extend this disease-specific, child-centric, outcome measure for use in international clinical trials. We adapted the North American English CHO-KLAT version for use in five countries: France, Germany, the Netherlands, Spain and the United Kingdom (UK). The process included four stages: (i) translation; (ii) cognitive debriefing; (iii) validity assessment relative to the PedsQL (generic) and the Haemo-QoL (disease-specific) and (iv) assessment of inter and intra-rater reliability. Cognitive debriefing was performed in 57 boys (mean age 11.4 years), validation was performed in 144 boys (mean age 11.0 years) and reliability was assessed for a subgroup of 64 boys (mean age 12.0 years). Parents also participated. The mean scores reported by the boys were high: CHO-KLAT 77.0 (SD = 11.2); PedsQL 83.8 (SD = 11.9) and Haemo-QoL 79.6 (SD = 11.5). Correlations between the CHO-KLAT and PedsQL ranged from 0.63 in Germany to 0.39 in the Netherlands and Spain. Test-retest reliability (concordance) for child self-report was 0.67. Child-parent concordance was slightly lower at 0.57. The CHO-KLAT has been fully culturally adapted and validated for use in five different languages and cultures (in England, the Netherlands, France, Germany and Spain) where treatment is readily available either on demand or as prophylaxis.
Asunto(s)
Comparación Transcultural , Hemofilia A/epidemiología , Hemofilia B/epidemiología , Adolescente , Niño , Preescolar , Francia , Alemania , Humanos , Masculino , Países Bajos , Evaluación de Resultado en la Atención de Salud , Calidad de Vida , España , Encuestas y Cuestionarios , Reino UnidoAsunto(s)
Anticoagulantes/farmacocinética , Hidrocarburo de Aril Hidroxilasas/genética , Coagulación Sanguínea/efectos de los fármacos , Oxigenasas de Función Mixta/genética , Warfarina/farmacocinética , Adolescente , Factores de Edad , Anticoagulantes/administración & dosificación , Anticoagulantes/efectos adversos , Anticoagulantes/sangre , Hidrocarburo de Aril Hidroxilasas/metabolismo , Biotransformación , Niño , Preescolar , Estudios Transversales , Citocromo P-450 CYP2C9 , Monitoreo de Drogas/métodos , Inglaterra , Femenino , Frecuencia de los Genes , Predisposición Genética a la Enfermedad , Hemorragia/inducido químicamente , Hemorragia/genética , Humanos , Lactante , Relación Normalizada Internacional , Masculino , Oxigenasas de Función Mixta/metabolismo , Ontario , Farmacogenética , Fenotipo , Estudios Retrospectivos , Factores de Riesgo , Vitamina K Epóxido Reductasas , Warfarina/administración & dosificación , Warfarina/efectos adversos , Warfarina/sangreRESUMEN
A case of neonatal alloimmune thrombocytopenia (NAIT) secondary to human platelet antigen (HPA)-1a antibodies is reported. Additional multispecific HLA antibodies rendered volunteer donor platelet transfusions ineffective. Despite a high incidence of maternal HLA antibodies in the pregnant population, there is only one previous report of clinically significant HLA antibodies.
Asunto(s)
Anticuerpos/inmunología , Antígenos de Plaqueta Humana/inmunología , Trombocitopenia/inmunología , Humanos , Recién Nacido , Integrina beta3 , Transfusión de Plaquetas/métodos , Trombocitopenia/terapiaRESUMEN
We report the case of a 1-year-old girl with newly diagnosed beta-thalassaemia major. Following an initial blood transfusion with phenotypically matched blood, she developed a haemolytic anaemia which progressed with subsequent transfusions. The Direct Antiglobulin test (DAT) was strongly positive with C3d and weakly with IgG. The only free antibodies detected were a weak anti-H and a weak cold auto-antibody, which did not exhibit a wide thermal range. The indirect Donath-Landsteiner and Ham's tests were negative. There was no sustained clinical response to steroids, immunoglobulin infusions or splenectomy. An HLA identical sibling donor was available for allogeneic bone marrow transplantation (BMT) and the haemolysis resolved during the immunosuppressive transplant conditioning. Such hyperhaemolysis without significant red cell alloantibodies has previously been reported in patients with sickle cell anaemia, but only rarely in patients with beta-thalassaemia major.
Asunto(s)
Trasplante de Médula Ósea/fisiología , Hemólisis , Talasemia beta/sangre , Talasemia beta/terapia , Autoanticuerpos/sangre , Transfusión Sanguínea , Trasplante de Médula Ósea/inmunología , Complemento C3d/análisis , Femenino , Humanos , Inmunoglobulina G/sangre , Inmunoglobulinas Intravenosas/uso terapéutico , Inmunosupresores/uso terapéutico , Lactante , Donadores Vivos , Núcleo Familiar , Esplenectomía , Talasemia beta/inmunologíaRESUMEN
We report the case of a 10-year-old boy with congenital pure red cell aplasia (Diamond-Blackfan anaemia) who received an allogeneic bone marrow transplant (BMT) from his HLA-identical sister. The transplant was complicated by moderate veno-occlusive disease (VOD). Despite cytogenetic evidence of complete donor haemopoietic stem cell engraftment there was selective failure of red cell engraftment and he remains red cell transfusion-dependent. This is the first case of a stem cell transplant failing to correct the defect in this condition despite engraftment.