ABSTRACT
The molecular characterisation of medulloblastoma, the most common paediatric brain tumour, is crucial for the correct management and treatment of this heterogenous disease. However, insufficient tissue sample, the presence of tumour heterogeneity, or disseminated disease can challenge its diagnosis and monitoring. Here, we report that the cerebrospinal fluid (CSF) circulating tumour DNA (ctDNA) recapitulates the genomic alterations of the tumour and facilitates subgrouping and risk stratification, providing valuable information about diagnosis and prognosis. CSF ctDNA also characterises the intra-tumour genomic heterogeneity identifying small subclones. ctDNA is abundant in the CSF but barely present in plasma and longitudinal analysis of CSF ctDNA allows the study of minimal residual disease, genomic evolution and the characterisation of tumours at recurrence. Ultimately, CSF ctDNA analysis could facilitate the clinical management of medulloblastoma patients and help the design of tailored therapeutic strategies, increasing treatment efficacy while reducing excessive treatment to prevent long-term secondary effects.
Subject(s)
Brain Neoplasms/cerebrospinal fluid , Circulating Tumor DNA/cerebrospinal fluid , Medulloblastoma/cerebrospinal fluid , Biomarkers, Tumor/cerebrospinal fluid , Biomarkers, Tumor/genetics , Brain Neoplasms/diagnosis , Brain Neoplasms/genetics , Circulating Tumor DNA/genetics , DNA, Neoplasm/cerebrospinal fluid , DNA, Neoplasm/genetics , Genomics , Humans , Medulloblastoma/diagnosis , Medulloblastoma/geneticsABSTRACT
BACKGROUND: Despite remarkable progress in the treatment of newly-diagnosed classical Hodgkin's lymphoma and systemic anaplastic large-cell lymphoma, treatment of relapsed or refractory disease remains challenging. The aims of this study were to assess the safety, tolerability, recommended phase 2 dose, and efficacy of brentuximab vedotin in paediatric patients with relapsed or refractory Hodgkin's lymphoma or systemic anaplastic large-cell lymphoma. METHODS: This open-label, dose-escalation phase 1/2 study was done at 12 centres across eight countries (France, Germany, Italy, Mexico, The Netherlands, Spain, UK, and USA). We recruited paediatric patients aged 7-18 years with relapsed or refractory classical Hodgkin's lymphoma or systemic anaplastic large-cell lymphoma, for whom standard treatment was unavailable or no longer effective. Participants were allocated to receive brentuximab vedotin at 1·4 mg/kg (phase 1) or 1·8 mg/kg (phases 1 and 2) via intravenous infusion once every 3 weeks for up to 16 cycles. Dose escalation was done via a 3+3 design. Key exclusion criteria were stem-cell transplantation less than 3 months before administration of the first dose of study drug, presence of cytomegalovirus infection after allogeneic stem-cell transplantation, previous treatment with an anti-CD30 antibody, and concurrent immunosuppressive or systemic therapy for chronic graft-versus-host disease. Primary outcomes were safety profile in the safety-evaluable population and maximum tolerated dose, recommended phase 2 dose, pharmacokinetics (phase 1), and proportion of patients who achieved best overall response (phase 2; evaluated by an independent review facility) in the response-evaluable population. This trial is registered with ClinicalTrials.gov, number NCT01492088. FINDINGS: Between April 16, 2012, and April 4, 2016, we screened 41 paediatric patients and enrolled 36 (aged 7-18 years), of whom 19 had relapsed or refractory classical Hodgkin's lymphoma and 17 had relapsed or refractory systemic anaplastic large-cell lymphoma. At the data cutoff (Oct 12, 2016), all 36 patients had discontinued study drug treatment; the most common reason was progressive disease (15 patients). The maximum tolerated dose was not reached. The recommended phase 2 dose was 1·8 mg/kg. The proportion of patients who achieved overall response was 47% (95% CI 21-73) for classical Hodgkin's lymphoma and 53% (28-77) for systemic anaplastic large-cell lymphoma. All 36 patients had a treatment-emergent adverse event and 16 patients (44%) had at least one grade 3 or worse treatment-emergent adverse event. The most common treatment-emergent adverse events were pyrexia (16 [44%] of 36) and nausea (13 [36%]). The most common grade 3 or worse treatment-emergent adverse events were neutropenia (four [11%]), increased γ-glutamyl transpeptidase (two [6%]), and pyrexia (two [6%]). 12 (33%) patients had transient, limited-severity peripheral neuropathy. Eight patients (22%) had a serious adverse event; three (8%) had a drug-related serious adverse event. One patient died of cardiac arrest (disease progression of a large huge mediastinal mass, unrelated to the study drug). Paediatric pharmacokinetic profiles were consistent with those from studies of adult patients. INTERPRETATION: Brentuximab vedotin has manageable toxicity and is associated with clinically meaningful responses in paediatric patients with relapsed or refractory Hodgkin's lymphoma or systemic anaplastic large-cell lymphoma, and could allow subsequent stem-cell transplantation in some patients who were initially ineligible for stem-cell transplantation. FUNDING: Millennium Pharmaceuticals Inc.
Subject(s)
Hodgkin Disease/drug therapy , Immunoconjugates/therapeutic use , Lymphoma, Large-Cell, Anaplastic/drug therapy , Adolescent , Brentuximab Vedotin , Child , Child, Preschool , Female , Humans , Male , RecurrenceABSTRACT
Approximately 15,000 new cases of pediatric cancer are diagnosed yearly in Europe, with 8-10% corresponding to neuroblastoma, a rare disease with an incidence of 8-9 cases per million children <15 years of age. Although the survival rate for low-risk and intermediate-risk patients is excellent, half of children with high-risk, refractory, or relapsed tumors will be cured, and two-thirds of the other half will suffer major side effects and life-long disabilities. Epigenetic therapies aimed at reversing the oncogenic alterations in chromatin structure and function are an emerging alternative against aggressive tumors that are or will become resistant to conventional treatments. This approach proposes targeting epigenetic regulators, which are proteins that are involved in the creation, detection, and interpretation of epigenetic signals, such as methylation or histone post-translational modifications. In this review, we focused on the most promising epigenetic regulators for targeting and current drugs that have already reached clinical trials.
Subject(s)
Epigenesis, Genetic , Gene Expression Regulation, Neoplastic , Neuroblastoma/genetics , Animals , Child , DNA Methylation , Genetic Therapy , Histone Code , Histones/genetics , Humans , Molecular Targeted Therapy , Neuroblastoma/therapy , Protein Processing, Post-TranslationalABSTRACT
Non-medulloblastoma CNS embryonal tumors (former PNET/Pineoblastomas) are aggressive malignancies with poor outcome that have been historically treated with medulloblastoma protocols. The purpose of this study is to present a tumor-specific, real-world data cohort of patients with CNS-PNET/PB to analyze quality indicators that can be implemented to improve the outcome of these patients. Patients 0-21 years with CNS-PNET treated in eight large institutions were included. Baseline characteristics, treatment and outcome [progression-free and overall survival (PFS and OS respectively)] were analyzed. From 2005 to 2014, 43 patients fulfilled entry criteria. Median age at diagnosis was 3.6 years (range 0.0-14.7). Histology was pineoblastoma (9%), ependymoblastoma (5%), ETANTR (7%) and PNET (77%). Median duration of the main symptom was 2 weeks (range 0-12). At diagnosis, 28% presented with metastatic disease. Seventeen different protocols were used on frontline treatment; 44% had gross total resection, 42% craniospinal radiotherapy, 86% chemotherapy, and 33% autologous hematopoietic stem cell transplantation (aHSCT). Median follow-up for survivors was 3.5 years (range 1.7-9.3). 3-year PFS was 31.9% (95% CI 17-47%) and OS 35.1% (95% CI 20-50%). Age, extent of resection and radiotherapy were prognostic of PFS and OS in univariate analysis (p < 0.05). Our series shows a dismal outcome for CNS-PNET, especially when compared to patients included in clinical trials. Establishing a common national strategy, implementing referral circuits and collaboration networks, and incorporating new molecular knowledge into routine clinical practice are accessible measures that can improve the outcome of these patients.
Subject(s)
Brain Neoplasms/therapy , Pinealoma/therapy , Standard of Care , Adolescent , Brain Neoplasms/diagnosis , Child , Child, Preschool , Cohort Studies , Female , Humans , Male , Outcome and Process Assessment, Health Care , Pinealoma/diagnosis , Spain , Survival Analysis , Treatment OutcomeABSTRACT
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)
Subject(s)
Humans , Child , Drugs, Investigational , Drug Evaluation/trends , Antineoplastic Agents/pharmacology , Neoplasms/drug therapy , Clinical Trials as Topic/statistics & numerical data , Precision Medicine/trendsABSTRACT
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.
Subject(s)
Clinical Trials as Topic/statistics & numerical data , Neoplasms/drug therapy , Child , Clinical Trials as Topic/methods , Humans , Spain , Time FactorsABSTRACT
Rhabdomyosarcoma (RMS) is the most common type of soft tissue sarcoma in children. Circulating tumor cells in peripheral blood or disseminated to bone marrow, a concept commonly referred to as minimal residual disease (MRD), are thought to be key to the prediction of metastasis and treatment efficacy. To date, two MRD markers, MYOD and MYOGENIN, have been tested; however, MRD detection continues to be challenging mainly owing to the closeness of the detection limit and the discordance of both markers in some samples. Therefore, the addition of a third marker could be useful for more accurate MRD assessment. The PAX3 gene is expressed during embryo development in all myogenic precursor cells in the dermomyotome. As RMS cells are thought to originate from these muscle precursor cells, they are expected to be positive for PAX3. In this study, PAX3 expression was characterized in cancer cell lines and tumors, showing wide expression in RMS. Detection sensitivities by quantitative polymerase chain reaction (qPCR) of the previously proposed markers, MYOD and MYOGENIN, were similar to that of PAX3, thereby indicating the feasibility of its detection. Interestingly, the flow cytometry experiments supported the usefulness of this technique in the quantification of MRD in RMS using PAX3 as a marker. These results indicate that flow cytometry, albeit in some cases slightly less sensitive, can be considered a good approach for MRD assessment in RMS and more consistent than qPCR, especially owing to its greater specificity. Furthermore, fluorescence-activated cell sorting permits the recovery of cells, thereby providing material for further characterization of circulating or disseminated cancer cells.
Subject(s)
Biomarkers, Tumor/analysis , Flow Cytometry/methods , Rhabdomyosarcoma/diagnosis , Cell Line, Tumor , Humans , PAX3 Transcription Factor , Paired Box Transcription Factors/analysis , Real-Time Polymerase Chain Reaction , Reverse Transcriptase Polymerase Chain Reaction , Sensitivity and SpecificityABSTRACT
Tumors of the Ewing's sarcoma family (ESFT), such as Ewing's sarcoma (EWS) and primitive neuroectodermal tumors (PNET), are highly aggressive malignancies predominantly affecting children and young adults. ESFT express chimeric transcription factors encoded by hybrid genes fusing the EWS gene with several ETS genes, most commonly FLI-1. EWS/FLI-1 proteins are responsible for the malignant phenotype of ESFT, but only few of their transcriptional targets are known. Using antisense and short hairpin RNA-mediated gene expression knockdown, array analyses, chromatin immunoprecipitation methods, and reexpression studies, we show that caveolin-1 (CAV1) is a new direct target of EWS/FLI-1 that is overexpressed in ESFT cell lines and tumor specimens and is necessary for ESFT tumorigenesis. CAV1 knockdown led to up-regulation of Snail and the concomitant loss of E-cadherin expression. Consistently, loss of CAV1 expression inhibited the anchorage-independent growth of EWS cells and markedly reduced the growth of EWS cell-derived tumors in nude mice xenografts, indicating that CAV1 promotes the malignant phenotype in EWS carcinogenesis. Reexpression of CAV1 or E-cadherin in CAV1 knockdown EWS cells rescued the oncogenic phenotype of the original EWS cells, showing that the CAV1/Snail/E-cadherin pathway plays a central role in the expression of the oncogenic transformation functions of EWS/FLI-1. Overall, these data identify CAV1 as a key determinant of the tumorigenicity of ESFT and imply that targeting CAV1 may allow the development of new molecular therapeutic strategies for ESFT patients.
Subject(s)
Caveolin 1/physiology , Oncogene Proteins, Fusion/physiology , Proto-Oncogene Protein c-fli-1/physiology , Sarcoma, Ewing/pathology , Animals , Cadherins/biosynthesis , Cadherins/genetics , Caveolin 1/antagonists & inhibitors , Caveolin 1/genetics , Caveolin 1/metabolism , Cell Adhesion/genetics , Cell Growth Processes/genetics , Cell Line, Tumor , Chromatin Immunoprecipitation , Down-Regulation , Gene Expression Regulation, Neoplastic , HT29 Cells , Humans , Mice , Mice, Inbred BALB C , Mice, Nude , Oncogene Proteins, Fusion/genetics , Oncogene Proteins, Fusion/metabolism , Proto-Oncogene Protein c-fli-1/genetics , Proto-Oncogene Protein c-fli-1/metabolism , RNA, Antisense/genetics , RNA-Binding Protein EWS , Sarcoma, Ewing/genetics , Sarcoma, Ewing/metabolism , Snail Family Transcription Factors , Transcription Factors/biosynthesis , Transcription Factors/genetics , Up-RegulationABSTRACT
PURPOSE: To assess if molecular detection of minimal disseminated disease by real-time reverse transcription and polymerase chain reaction (RT-PCR) could contribute to a better treatment stratification in patients with rhabdomyosarcoma (RMS). METHODS: Relative quantification of the tumor-mRNA present in serial samples of bone marrow (BM) and peripheral blood (PB) from 16 patients with RMS (7 alveolar and 9 embryonal) was performed by a real-time RT-PCR assay. Expression of MyoD1 and acetylcholine receptor (AChR) was analyzed in all samples, along with PAX3/7-FKHR in samples from alveolar tumors. RESULTS: A good correlation was found between the expression of PAX3/7-FKHR and AChR, while MyoD1 was more sensitive but less specific. In this study, patients with positive PB at the end of treatment showed a poorer prognosis than patients with negative PB. Moreover, in this patient cohort, metastatic relapses were preceded by the detection of microcirculating disease in all cases. CONCLUSION: The detection of minimal circulating and micrometastatic disease by real-time RT-PCR, based on the expression of multiple genes, yields highly reproducible results. Patients with positive PB after treatment show poorer survival than patients without microcirculating disease.
Subject(s)
Bone Marrow Neoplasms/diagnosis , Bone Marrow Neoplasms/secondary , Neoplastic Cells, Circulating , Reverse Transcriptase Polymerase Chain Reaction/methods , Rhabdomyosarcoma, Alveolar/diagnosis , Rhabdomyosarcoma, Embryonal/diagnosis , Adolescent , Biomarkers, Tumor/genetics , Bone Marrow Neoplasms/genetics , Child , Child, Preschool , Cohort Studies , Disease Progression , Female , Follow-Up Studies , Gene Expression Profiling , Humans , Infant , Male , MyoD Protein/genetics , Neoplasm Staging , Neoplasm, Residual , Neoplastic Cells, Circulating/metabolism , Oncogene Proteins, Fusion/genetics , RNA, Messenger/biosynthesis , RNA, Messenger/genetics , Receptors, Nicotinic/genetics , Recurrence , Retrospective Studies , Rhabdomyosarcoma, Alveolar/blood , Rhabdomyosarcoma, Alveolar/genetics , Rhabdomyosarcoma, Embryonal/blood , Rhabdomyosarcoma, Embryonal/genetics , Sensitivity and Specificity , Survival RateABSTRACT
Molecular detection of microcirculating or microdisseminated disease (MDD) with a sensitive methodology could contribute to a better treatment for children with neuroblastoma. To detect circulating neuroblastoma cells, we developed a quantitative assay for the analysis of tyrosine hydroxylase (TH) gene expression. We analyzed 155 samples of peripheral blood (PB) from 25 patients with neuroblastoma in advanced stages (8 stage III and 17 stage IV). TH mRNA was analyzed by RT-PCR assay using TaqMan technology. PB samples (n=25) from donors were used for normalizing TH, and values <7 were considered negative. With a median follow-up of 40 months (range 15-73 months), 9 patients relapsed and 8 patients died of progressive disease. TH expression was detected in the PB of 16 patients (64%) at diagnosis. During treatment, 10 patients had positive samples and 9 patients were still positive for circulating tumor cells at the end of treatment. Actuarial 3-year event-free survival of patients with PB positive for TH mRNA after induction therapy (40%) (p=0.018) and at the completion of treatment (33%) (p=0.003) were significantly worse than the survival of TH-negative patients (86 and 87%, respectively). In multivariate analysis, MYCN status and TH expression in PB at the end of treatment remained significant prognostic factors. Our results show that patients with advanced neuroblastoma who have PB positive for TH at the end of treatment seem to have a worse prognosis compared with patients with undetectable TH. These results suggest the usefulness of MDD monitoring in neuroblastoma.
Subject(s)
Neoplastic Cells, Circulating/metabolism , Neuroblastoma/diagnosis , Neuroblastoma/metabolism , Reverse Transcriptase Polymerase Chain Reaction/methods , Tyrosine 3-Monooxygenase/blood , Adolescent , Child , Child, Preschool , Cohort Studies , Disease Progression , Disease-Free Survival , Female , Follow-Up Studies , Humans , Infant , Male , Microcirculation , Models, Statistical , Multivariate Analysis , Neuroblastoma/blood , Prognosis , RNA, Messenger/metabolism , Recurrence , Sensitivity and Specificity , Temperature , Time Factors , Treatment OutcomeABSTRACT
Overexpression of multidrug resistance-1 (MDR-1), and multidrug resistance-associated protein (MRP) genes has been linked with resistance to chemotherapy in vitro and in vivo. Their role in chemotherapy resistance in pediatric rhabdomyosarcoma is unclear. The study was undertaken to analyze the expression of MDR-1 and MRP genes in the embryonal and the alveolar subtypes of rhabdomyosarcoma and to elucidate its clinical relevance. Twenty-three rhabdomyosarcoma samples were analyzed for the expression of MDR-1 and MRP genes using a semi-quantitative competitive RT-PCR assay. MRP gene expression was associated with a reduction in survival (p=0.02). The overall survival of patients with tumors positive or negative for MRP expression were 50% (95% confidence interval, 30-70%) and 93% (95% confidence interval, 76-100%) respectively. In contrast, the expression of MDR-1 gene was not predictive of survival. These findings suggest that MRP expression could be a prognostic factor in patients with rhabdomyosarcoma.
Subject(s)
ATP Binding Cassette Transporter, Subfamily B, Member 1/genetics , Multidrug Resistance-Associated Proteins/genetics , Rhabdomyosarcoma/pathology , Adolescent , Child , Child, Preschool , Female , Gene Expression Regulation, Neoplastic , Humans , Infant , Male , RNA, Neoplasm/genetics , RNA, Neoplasm/metabolism , Reverse Transcriptase Polymerase Chain Reaction , Rhabdomyosarcoma/genetics , Survival AnalysisABSTRACT
BACKGROUND AND OBJECTIVES: Although chemotherapy in childhood acute myeloid leukemia (AML) has improved in the last decade, except for a group of better-risk patients (approximately one third), more than half the other patients relapse. The main objective of this study was to evaluate the results obtained with bone marrow transplants, either allogeneic (allo-BMT) or autologous (auto-BMT), following two intensive consolidation courses in a series of children with high-risk (HR) AML according to morphologic and early-response BFM criteria. A second objective was to compare the results of auto-BMT with those of allo-BMT. DESIGN AND METHODS: From April 1988 to May 2001, 79 children (< 15 years old) with de novo AML entered the prospective AML-88 trial in a single institution: 50 (63%) were qualified as having high-risk disease and are the subject of this study. After 1 or 2 induction courses, depending on early response, and two consolidations, patients with an HLA-identical sibling received an allo-BMT and all the others an auto-BMT. The conditioning regimen was cyclophosphamide and total body irradiation (TBI) in children over 3 years old and busulfan and etoposide in younger children. Bone marrow was purged with mafosfamide in auto-BMT and cyclosporine alone was given as graft-versus-host disease (GVHD) prophylaxis in allo-BMT. RESULTS: At the end of the chemotherapy phase (induction and consolidation ), 46 of the 50 HR patients (92%) had attained complete remission (CR) after one (n=29), two (n=11) or three (n=6) courses; 2 more were in partial remission (PR) and 2 had died. The 48 patients in CR or PR received either an allo-BMT (17) or an auto-BMT (31). Hematologic reconstitution was significantly slower in auto-BMT recipients. Forty-one percent of patients who received allo-BMT suffered acute GVHD grades II-IV. Toxic deaths and relapse rates were 5.9% and 17.6%, respectively, in allo-BMT and 3.2% and 25.8%, respectively, in auto-BMT. Post-transplant 8-year event-free survival (EFS) was 74.5% (54-96) in allo-BMT and 74.2% (59-89) in auto-BMT. EFS and OS in all the series (50 patients) were 71% (59-83) and 73% (61-85), respectively, with a median follow-up of 7.2 years. INTERPRETATION AND CONCLUSIONS: This study indicates that improved results in children with HR-AML can be obtained by either allo- or auto-BMT performed after two courses of intensive consolidation therapy provided good supportive therapy is given and reduced transplant -related mortality (TRM) is minimized.