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Supportive care utilization and treatment toxicity in children with Down syndrome and acute lymphoid leukaemia at free-standing paediatric hospitals in the United States.

ABSTRACT: Although inferior outcomes of children with Down syndrome (DS) and acute lymphoid leukaemia (ALL) are established, national supportive care patterns for these patients are unknown. A validated retrospective cohort of paediatric patients diagnosed with ALL from 1999 to 2011 was assembled from the US Pediatric Health Information System (PHIS) database to examine organ toxicity, sepsis, and resource utilization in children with and without DS. Among 10699 ALL patients, 298 had DS-ALL (2·8%). In a multivariate model, DS was associated with increased risk of cardiovascular (odds ratio [OR] 2·0, 95% confidence interval [CI] 1·6-2·7), respiratory (OR 2·1, 95% CI: 1·6-2·9), neurologic (OR 3·4, 95% CI 1·9-6·2), and hepatic (OR 1·4, 95% CI 1·0-1·9) dysfunction and sepsis (OR 1·8, 95% CI: 1·4-2·4). Children with DS-ALL used significantly more respiratory support, insulin, and anti-infectives, including broad-spectrum Gram-positive agents, quinolones, and azoles. They used significantly fewer analgesics and antiemetics compared to non-DS-ALL children. Ultimately, this study confirms the increased risk of infectious and end-organ toxicity in children with DS-ALL and quantifies important differences in resource utilization between children with DS and non-DS ALL. These findings highlight the importance of investigating the impact of these care variations and developing specific supportive care guidelines for this population.

SUBMITTER: Salazar EG

PROVIDER: S-EPMC5684439 | biostudies-literature | 2016 Aug

REPOSITORIES: biostudies-literature

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Supportive care utilization and treatment toxicity in children with Down syndrome and acute lymphoid leukaemia at free-standing paediatric hospitals in the United States.

Salazar Elizabeth G EG Li Yimei Y Fisher Brian T BT Rheingold Susan R SR Fitzgerald Julie J Seif Alix E AE Huang Yuan-Shung YS Bagatell Rochelle R Aplenc Richard R

British journal of haematology 20160510 4

Although inferior outcomes of children with Down syndrome (DS) and acute lymphoid leukaemia (ALL) are established, national supportive care patterns for these patients are unknown. A validated retrospective cohort of paediatric patients diagnosed with ALL from 1999 to 2011 was assembled from the US Pediatric Health Information System (PHIS) database to examine organ toxicity, sepsis, and resource utilization in children with and without DS. Among 10699 ALL patients, 298 had DS-ALL (2·8%). In a m ...[more]

PMID: 27161549

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Project description:BackgroundAcute Myeloid Leukaemia (AML) is a highly heterogeneous disease. Studies in adult AML have identified epigenetic changes, specifically DNA methylation, associated with leukaemia subtype, age of onset and patient survival which highlights this heterogeneity. However, only limited DNA methylation studies have elucidated any associations in paediatric AML.MethodsWe interrogated DNA methylation on a cohort of paediatric AML FAB subtype M5 patients using the Illumina HumanMethylation450 (HM450) BeadChip, identifying a number of target genes with p <0.01 and ?? >0.4 between leukaemic and matched remission (n?=?20 primary leukaemic, n?=?13 matched remission). Amongst those genes identified, we interrogate DLEU2 methylation using locus-specific SEQUENOM MassARRAY® EpiTYPER® and an increased validation cohort (n?=?28 primary leukaemic, n?=?14 matched remission, n?=?17 additional non-leukaemic and cell lines). Following methylation analysis, expression studies were undertaken utilising the same patient samples for singleplex TaqMan gene and miRNA assays and relative expression comparisons.ResultsWe identified differential DNA methylation at the DLEU2 locus, encompassing the tumour suppressor microRNA miR-15a/16-1 cluster. A number of HM450 probes spanning the DLEU2/Alt1 Transcriptional Start Site showed increased levels of methylation in leukaemia (average over all probes >60%) compared to disease-free haematopoietic cells and patient remission samples (<24%) (p?<?0.001). Interestingly, DLEU2 mRNA down-regulation in leukaemic patients (p?<?0.05) was independent of the embedded mature miR-15a/16-1 expression. To assess prognostic significance of DLEU2 DNA methylation, we stratified paediatric AML patients by their methylation status. A subset of patients recorded methylation values for DLEU2 akin to non-leukaemic specimens, specifically patients with sole trisomy 8 and/or chromosome 11 abnormalities. These patients also showed similar miR-15a/16-1 expression to non-leukaemic samples, and potential improved disease prognosis.ConclusionsThe DLEU2 locus and embedded miRNA cluster miR-15a/16-1 is commonly deleted in adult cancers and shown to induce leukaemogenesis, however in paediatric AML we found the region to be transcriptionally repressed. In combination, our data highlights the utility of interrogating DNA methylation and microRNA in combination with underlying genetic status to provide novel insights into AML biology.

Dataset Information

Supportive care utilization and treatment toxicity in children with Down syndrome and acute lymphoid leukaemia at free-standing paediatric hospitals in the United States.

Publications

Supportive care utilization and treatment toxicity in children with Down syndrome and acute lymphoid leukaemia at free-standing paediatric hospitals in the United States.

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