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A validated novel continuous prognostic index to deliver stratified medicine in pediatric acute lymphoblastic leukemia

Lookup NU author(s): Dr Amir Enshaei, Professor Christine Harrison FRCPath FMedSci, Claire Schwab, Professor Anthony Moorman

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This is the authors' accepted manuscript of an article that has been published in its final definitive form by American Society of Hematology, 2020.

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Abstract

Risk stratification is essential for the delivery of optimal treatment in childhood acute lymphoblastic leukemia. However, current risk stratification algorithms dichotomise variables and apply risk factors independently which may wrongly assume identical associations across biologically heterogeneous subsets and reduce statistical power. Accordingly, we developed and validated a prognostic index (PIUKALL) which integrates multiple risk factors and uses continuous data. We created discovery (n=2,405) and validation (n=2,313) cohorts using data from four recent trials (UKALL2003, COALL-03, DCOG-ALL10, NOPHO-ALL2008). Using the discovery cohort, multivariate Cox regression modelling defined a minimal model that included white cell count at diagnosis, pre-treatment cytogenetics and end of induction minimal residual disease. Using this model we defined PIUKALL - a continuous variable that assigns personalised risk scores. The PIUKALL correlated with risk of relapse and validated in an independent cohort. Using PIUKALL to risk stratify patients improved the C-index for all endpoints compared to the traditional algorithms. We used PIUKALL to define four clinically relevant risk groups which had differential relapse rates at 5 years and were similar between the two cohorts: discovery - low 3% (95% CI 2-4), standard 8%(6-10), intermediate 17%(14-21), high 48%(36-60) and validation low 4%(3-6), standard 9%(6-12), intermediate 17%(14-21), high 35%(24-48). An analysis of the area under the curve confirmed the PIUKALL groups were significantly better at predicting outcome than the algorithms employed in each trial. The PIUKALL developed in this study provides an accurate method for predicting outcome and a more flexible method for defining risk groups in future studies.


Publication metadata

Author(s): Enshaei A, O'Connor D, Bartram J, Hancock J, Harrison CJ, Hough R, Samarasinghe S, den Boer ML, Boer JM, de Groot-Kruseman HA, Marquart HV, Noren-Nystrom U, Schmiegelow K, Schwab C, Horstmann MA, Escherich G, Heyman M, Pieters R, Vora A, Moppett J, Moorman AV

Publication type: Article

Publication status: Published

Journal: Blood

Year: 2020

Volume: 135

Issue: 17

Pages: 1438-1446

Online publication date: 13/02/2020

Acceptance date: 01/02/2020

Date deposited: 25/02/2020

ISSN (print): 0006-4971

ISSN (electronic): 1528-0020

Publisher: American Society of Hematology

URL: https://doi.org/10.1182/blood.2019003191

DOI: 10.1182/blood.2019003191


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