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As a group, the leukaemias represent the most common malignant conditions of childhood. The treatment of childhood leukaemia, and in particular the treatment of acute lymphoblastic leukaemia (ALL), has shown tremendous improvement...
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As a group, the leukaemias represent the most common malignant conditions of childhood. The treatment of childhood leukaemia, and in particular the treatment of acute lymphoblastic leukaemia (ALL), has shown tremendous improvement in outcome in the last 40 years. Much of the success is due to the improvements in leukaemia therapy demonstrated in improved disease-free survival and reduced relapse rates in clinical trials but improvements in supportive care over the years have also had a very significant contribution. Over the last 30 years we have also seen reduced treatment related mortality due to better management of complications and better detection and treatment of infections. The emphasis of treatment as well as being cure is now focussing on targeting therapy to reduce the treatment burden in good risk disease and identify and intensify treatment for those with poor risk disease. The development of molecularly targeted therapies has changed the therapeutic landscape and this last decade has seen many improvements in outcome associated with these new agents. This review will give a brief overview of current treatment protocols used in childhood leukaemia, focussing specifically on the latest improvements and strategies in treating these conditions.
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Low-dose decitabine has encouraging activity and tolerability in adults with acute myeloid leukaemia (AML), but paediatric experience is lacking. We report our retrospective experience with decitabine in eight children and young a...
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Low-dose decitabine has encouraging activity and tolerability in adults with acute myeloid leukaemia (AML), but paediatric experience is lacking. We report our retrospective experience with decitabine in eight children and young adults (median age 4 years) with refractory/relapsed AML, who had failed multiple regimens or were not candidates for standard retrieval regimens due to prior toxicities. Three of eight patients (38%) had complete response (CR; 1 each of CR, CR with incomplete platelet recovery and CR with incomplete count recovery). Best responses were observed after a median of 2·5 cycles (range 1-4 cycles). Four patients received subsequent allogeneic stem cell transplant, and two remain in long-term CR.
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We read with interest the tumour lysis syndrome (TLS) guidelines published by Cairo et al (2010), which updated earlier publications (Cairo & Bishop, 2004; Coiffier et al, 2008). We were particularly struck by the guidelines regarding TLS manag...
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We read with interest the tumour lysis syndrome (TLS) guidelines published by Cairo et al (2010), which updated earlier publications (Cairo & Bishop, 2004; Coiffier et al, 2008). We were particularly struck by the guidelines regarding TLS management for patients with acute lymphoblastic leukaemia (ALL) or acute myeloid leukaemia (AML) and a diagnostic white blood cell count (WBC) < 100 x 109/l. The new guidelines are risk stratified by lactate dehydrogenase (LDH) and recommend prophylactic rasburicase in all ALL patients with LDH level >2x upper limit of normal (ULN). In addition, AML patients with laboratory TLS are to receive rasburicase, regardless of the presenting WBC and clinical findings. The guidelines for the prophylactic use of rasburicase also potentially include patients with hyperkalaemia and/or hyper-phosphataemia without concomitant hypemricaemia (Fig 4 and text, Cairo et al, 2010). And lastly, the recommendation for prophylactic rasburicase in the defined high-risk subgroup is stated to be a grade A recommendation, yet no systematic review is identified (Cairo et al, 2010).
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Hereditary GATA2 mutations show predisposition to acute myeloid leukaemia (AML) and myelodysplastic syndrome (MDS) (Hahn et al, 2011). These mutations have also been reported in chronic myeloid leukaemia (Zhang et al, 2008) and mo...
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Hereditary GATA2 mutations show predisposition to acute myeloid leukaemia (AML) and myelodysplastic syndrome (MDS) (Hahn et al, 2011). These mutations have also been reported in chronic myeloid leukaemia (Zhang et al, 2008) and monocytopenia and mycobacterial infection (MonoMAC) syndrome (Hsu et al, 2011). More recently, GATA2 mutations have been identified in de novo AML, especially in adult patients with biallelic CEBPA mutations (Greif et al, 2012; Green et al, 2013). GATA2 and CEBPA are transcription factors that are crucial for haematopoietic development. These findings prompted us to identify possible GATA2 and CEBPA mutations in patients with various paediatric leukaemias.
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Summary To create a personal prognostic model and modify the risk stratification of paediatric acute myeloid leukaemia, we downloaded the clinical data of 597 patients from the Therapeutically Applicable Research to Generate Effec...
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Summary To create a personal prognostic model and modify the risk stratification of paediatric acute myeloid leukaemia, we downloaded the clinical data of 597 patients from the Therapeutically Applicable Research to Generate Effective Treatments (TARGET) database as a training set and included 189 patients from our centre as a validation set. In the training set, age at diagnosis, ‐7/del(7q) or ‐5/del(5q), core binding factor fusion genes, FMS‐like tyrosine kinase 3‐internal tandem duplication (FLT3‐ITD)/nucleophosmin 1 (NPM1) status, Wilms tumour 1 (WT1) mutation, biallelic CCAAT enhancer binding protein alpha (CEBPA) mutation were strongly correlated with overall survival and included to construct the model. The prognostic model demonstrated excellent discriminative ability with the Harrell's concordance index of 0.68, 3‐ and 5‐year area under the receiver operating characteristic curve of 0.71 and 0.72 respectively. The model was validated in the validation set and outperformed existing prognostic systems. Additionally, patients were stratified into three risk groups (low, intermediate and high risk) with significantly distinct prognosis, and the model successfully identified candidates for haematopoietic stem cell transplantation. The newly developed prognostic model showed robust ability and utility in survival prediction and risk stratification, which could be helpful in modifying treatment selection in clinical routine.
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Summary Comprehensive cataloguing of the acute myeloid leukaemia (AML) genome has revealed a high frequency of mutations and deletions in epigenetic factors that are frequently linked to treatment resistance and poor patient outco...
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Summary Comprehensive cataloguing of the acute myeloid leukaemia (AML) genome has revealed a high frequency of mutations and deletions in epigenetic factors that are frequently linked to treatment resistance and poor patient outcome. In this review, we discuss how the epigenetic mechanisms that underpin normal haematopoiesis are subverted in AML, and in particular how these processes are altered in childhood and adolescent leukaemias. We also provide a brief summary of the burgeoning field of epigenetic‐based therapies, and how AML treatment might be improved through provision of better conceptual frameworks for understanding the pleiotropic molecular effects of epigenetic disruption.
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The World Health Organization (WHO) classification of myeloid leukaemia was revised in 2008. It incorporates newly recognized entities and emphasizes the pivotal role of cytogenetic abnormalities. The aim of this study was to eval...
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The World Health Organization (WHO) classification of myeloid leukaemia was revised in 2008. It incorporates newly recognized entities and emphasizes the pivotal role of cytogenetic abnormalities. The aim of this study was to evaluate the usability of the WHO classification when applied to a large population-based paediatric acute myeloid leukaemia (AML) cohort. We included children diagnosed with de novo AML, 0-18years of age from the Nordic countries and Hong Kong from 1993 to 2012. Data were retrieved from the Nordic Society for Paediatric Haematology and Oncology AML database and patients classified according to the WHO 2008 classification. A successful karyotype was available in 97% of the cases. AML with recurrent genetic abnormalities were present in 262 (41%) and 94 (15%) were classified as AML with myelodysplasia-related changes (AML-MDS). WHO classifies patients with monosomy 7 and del(7q) into one group. We found that -7 (n=14) had significantly poorer outcome than del(7q) (n=11); 5-year event-free survival 26% vs. 67%, (P=002), and 5-year overall survival 51% vs. 90%, (P=004). The largest group was the highly heterogeneous AML not otherwise specified (NOS) (n=280) (44%). In conclusion, the WHO classification allocated 15% to AML-MDS, 44% to NOS and grouped together entities with clearly different outcome, therefore limiting the applicability of the current WHO classification in children with AML.
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Ectopic viral integration site-1 (EVI1) is highly expressed in certain cytogenetic subsets of adult acute myeloid leukaemia (AML), and has been associated with inferior survival. We sought to examine the clinical and biological as...
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Ectopic viral integration site-1 (EVI1) is highly expressed in certain cytogenetic subsets of adult acute myeloid leukaemia (AML), and has been associated with inferior survival. We sought to examine the clinical and biological associations of EVI1high, defined as expression in excess of normal controls, in paediatric AML. EVI1 mRNA expression was measured via quantitative real-time polymerase chain reaction in diagnostic specimens obtained from 206 patients. Expression levels were correlated with clinical features and outcome. EVI1high was present in 58/206 (28%) patients. MLL rearrangements occurred in 40% of EVI1high patients as opposed to 12% of the EVI1low/absent patients (P < 0·001). No abnormalities of 3q26 were found in EVI1high patients by conventional cytogenetic analysis, nor were cryptic 3q26 abnormalities detected in a subset of patients screened by next-generation sequencing. French-American-British class M7 was enriched in the EVI1high group, accounting for 24% of these patients. EVI1high patients had significantly lower 5-year overall survival from study entry (51% vs. 68%, P = 0·015). However, in multivariate analysis including other established prognostic markers, EVI1 expression did not retain independent prognostic significance. EVI1 expression is currently being studied in a larger cohort of patients enrolled on subsequent Children's Oncology Group trials, to determine if EVI1high has prognostic value in MLL-rearranged or intermediate-risk subsets.
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The importance of epigenetic mechanisms, such as DNA methylation and histone acetylation, in human cancer development is becoming increasingly clear (Bolden et al, 2006; Chen et al, 2010). Genomic analyses of patient samples have ...
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The importance of epigenetic mechanisms, such as DNA methylation and histone acetylation, in human cancer development is becoming increasingly clear (Bolden et al, 2006; Chen et al, 2010). Genomic analyses of patient samples have revealed that genes encoding chromatin modifier proteins are among the most frequently mutated genes in cancer (Morin et al, 2011; Mullighan et al, 2011; Pasqualucci et al, 2011). In particular, a reduced level of histone acetylation is widespread among cancers (Fraga et al, 2005). Consequently, drugs that enhance histone acetylation, termed histone deacetylase inhibitors (HDACi) (Bolden et al, 2006), have been clinically tested, and two of them, vorinostat and romidepsin, have received approval by the US Food and Drug Administration as second-line treatments for cutaneous T cell lymphoma.
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