RESUMO
Early phase trials are crucial in developing new therapies for poor prognosis childhood malignancies. Outcomes and toxicities of children treated on phase I/II trials at the Royal Marsden, one of the largest pediatric oncology early phase trial units in Europe, were examined to provide a baseline dataset and generate hypotheses. All patients recruited over a 10-year period to December 2011 were included. Variables including baseline characteristics, time on study, survival, toxicities, and admissions were collected. Seventy-two patients were recruited to 21 trials (5 phase I, 16 phase II; overall 12 involved molecularly targeted agents). Median age at consent was 12.4 years. Dose-limiting toxicities were rare in phase I trial participants (2 of 15 evaluable patients, 13%); the most common reason for leaving trials was disease progression (76%), rather than drug toxicity (1.7%). Median time on trial was 1.3 months (phase I patients) and 3.3 months (phase II). Early phase trials in children are safe and unexpected toxic side effects are infrequent. Patients and their families are willing to travel to access novel therapies, although the overall prognosis for these individuals is poor. Continued expansion of the portfolio is needed ultimately to improve the outcomes for those with resistant disease.
Assuntos
Antineoplásicos/toxicidade , Ensaios Clínicos Fase I como Assunto , Ensaios Clínicos Fase II como Assunto , Descoberta de Drogas/métodos , Neoplasias/tratamento farmacológico , Adolescente , Adulto , Criança , Pré-Escolar , Desenho de Fármacos , Descoberta de Drogas/normas , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Feminino , Seguimentos , Hospitalização/estatística & dados numéricos , Humanos , Lactente , Masculino , Admissão do Paciente/estatística & dados numéricos , Pacientes Desistentes do Tratamento , Seleção de Pacientes , Estudos Retrospectivos , Resultado do Tratamento , Adulto JovemRESUMO
Outlining the treatment for an unclassifiable lymphoid malignancy is often difficult. A highly undifferentiated lymphomatous mass that relapsed in spite of intense chemotherapy and autologous transplant is reported. At relapse, there was differentiation into myeloid lineage. Though remission was achieved with AML-type reinduction chemotherapy, the mass recurred post allogenic cord blood stem cell transplant.
Assuntos
Transplante de Células-Tronco de Sangue do Cordão Umbilical/métodos , Linfoma/patologia , Neoplasias do Mediastino/patologia , Transplante de Células-Tronco de Sangue Periférico/métodos , Diferenciação Celular , Criança , Humanos , Linfoma/terapia , Masculino , Neoplasias do Mediastino/terapia , Células Mieloides/patologia , Recidiva , Transplante Autólogo , Transplante Homólogo , Falha de TratamentoRESUMO
PURPOSE: Dasatinib is a potent BCR-ABL inhibitor with proven efficacy in adults with newly diagnosed chronic myeloid leukemia (CML) in chronic phase (CP) and in imatinib-resistant/intolerant disease. This phase I study of the Innovative Therapies for Children with Cancer Consortium assessed dasatinib safety and efficacy in pediatric patients. PATIENTS AND METHODS: Escalating once-daily dasatinib doses (60 to 120 mg/m(2)) were administered to children (n = 58) with (i) imatinib-pretreated CML or Philadelphia chromosome (Ph)-positive acute lymhoblastic leukemia (ALL) and (ii) treatment-refractory Ph-negative ALL or acute myeloid leukemia (AML). RESULTS: Dasatinib safety and efficacy profiles compared favorably with those in adults. The most common drug-related nonhematologic adverse events were nausea (31%, all grades; 2%, grade 3 to 4), headache (22%, 3%), diarrhea (21%, 0%), and vomiting (17%, 2%). Of 17 patients with CML-CP, 14 (82%) achieved complete cytogenetic response (CCyR) and eight (47%) achieved major molecular response. After ≥ 24 months of follow-up, median complete hematologic response (CHR) and major cytogenetic response (MCyR) durations were not reached. Of 17 patients with advanced-phase CML or Ph-positive ALL, six (35%) achieved confirmed CHR and 11 (65%) achieved CCyR. Median MCyR duration was 4.6 months (95% CI, 2.1 to 17.4 months). No patient with Ph-negative ALL or AML responded. Dasatinib pediatric pharmacokinetic parameters were comparable with those in adult studies, showing rapid absorption (time to reach maximum concentration, 0.5 to 6.0 hours) and elimination (mean half-life, 3.0 to 4.4 hours). CONCLUSION: Dasatinib 60 mg/m(2) and 80 mg/m(2) once-daily dosing were selected for phase II studies in children with Ph-positive leukemias.
Assuntos
Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Pirimidinas/administração & dosagem , Pirimidinas/efeitos adversos , Tiazóis/administração & dosagem , Tiazóis/efeitos adversos , Adolescente , Antineoplásicos/farmacocinética , Benzamidas/administração & dosagem , Benzamidas/efeitos adversos , Criança , Pré-Escolar , Dasatinibe , Diarreia/induzido quimicamente , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Cefaleia/induzido quimicamente , Humanos , Mesilato de Imatinib , Lactente , Estimativa de Kaplan-Meier , Leucemia Mielogênica Crônica BCR-ABL Positiva/metabolismo , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/patologia , Masculino , Náusea/induzido quimicamente , Piperazinas/administração & dosagem , Piperazinas/efeitos adversos , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/efeitos adversos , Proteínas Tirosina Quinases/antagonistas & inibidores , Pirimidinas/farmacocinética , Tamanho da Amostra , Terapias em Estudo , Tiazóis/farmacocinética , Resultado do Tratamento , Vômito/induzido quimicamente , Adulto JovemRESUMO
Patients with childhood relapsed and refractory mature B-cell non-Hodgkin lymphoma (B-NHL) and acute lymphoblastic leukemia (B-ALL) are rare and have a dismal prognosis. The previous UK national analysis of 26 children over a 7-year period prior to 1996 had highlighted the poor outcome, with only three survivors. This 10-year multicenter study evaluated recent data, since 2000. Of 33 children, nine survived (27.3%), with a median follow-up of 4.3 years. On exclusion of six children treated with palliative intent, the survival was one-third (nine of 27; 33.3%). All patients with primary refractory disease (n = 7) and all except one with early relapse (n = 11) died. Administration of four doses of 375 mg/m(2) of rituximab was associated with a longer survival (p = 0.006). Response to reinduction (p < 0.001) and autologous hematopoietic stem cell transplant (auto-HSCT) (p = 0.003) were significant on multivariate analysis. Patients with a time to relapse of at least 6 months are potentially curable and must be offered intensive treatment with salvage chemotherapy, rituximab and auto-HSCT.
Assuntos
Linfoma de Células B/terapia , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Adolescente , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Criança , Pré-Escolar , Terapia Combinada , Progressão da Doença , Feminino , Transplante de Células-Tronco Hematopoéticas , Humanos , Linfoma de Células B/mortalidade , Linfoma de Células B/patologia , Masculino , Estadiamento de Neoplasias , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidade , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Recidiva , Indução de Remissão , Resultado do TratamentoRESUMO
Viral haemorrhagic cystitis (HC) is a significant complication after haematopoietic stem cell transplantation (HSCT), with a potential for major morbidity. The aim of this 7-year analysis of 1160 HSCT patients was to evaluate risk factors for the incidence, severity, toxicity of therapy, clinical course, and outcome of this condition. The overall incidence of HC was 5·8%, with most cases occurring after allogeneic HSCT. Unrelated donors (P = 0·001), non-peripheral blood stem cell source (P = 0·005), myeloablative conditioning (P<0·001), use of alemtuzumab in conditioning (P = 0·001), and severe acute graft versus host disease (P<0·001) were independent risk factors for an increased incidence of HC post-allogeneic transplant on multivariate analysis. Severe forms of HC were associated with grades II-IV acute graft versus host disease and a longer duration of haematuria. Contrary to previous studies which were carried out on smaller patient populations, busulphan, cyclophosphamide, anti-thymocyte globulin, and total body irradiation were not found to independently increase the risk of viral HC, unless used in a myeloablative combination. Neither duration of viriuria nor peak viral load in urine influenced the severity of HC on multivariate analysis. Severe HC contributed to the deaths of two patients. Overall survival was not statistically different between patient subgroups with non-severe and severe HC.