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Rigshospitalet - a part of Copenhagen University Hospital
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A validated novel continuous prognostic index to deliver stratified medicine in pediatric acute lymphoblastic leukemia

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  • Amir Enshaei
  • David O'Connor
  • Jack Bartram
  • Jeremy Hancock
  • Christine J Harrison
  • Rachael Hough
  • Sujith Samarasinghe
  • Monique L den Boer
  • Judith M Boer
  • Hester A de Groot-Kruseman
  • Hanne V Marquart
  • Ulrika Noren-Nystrom
  • Kjeld Schmiegelow
  • Claire Schwab
  • Martin A Horstmann
  • Gabriele Escherich
  • Mats Heyman
  • Rob Pieters
  • Ajay Vora
  • John Moppett
  • Anthony V Moorman
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Risk stratification is essential for the delivery of optimal treatment in childhood acute lymphoblastic leukemia. However, current risk stratification algorithms dichotomize variables and apply risk factors independently, which may incorrectly assume identical associations across biologically heterogeneous subsets and reduce statistical power. Accordingly, we developed and validated a prognostic index (PIUKALL) that integrates multiple risk factors and uses continuous data. We created discovery (n = 2405) and validation (n = 2313) cohorts using data from 4 recent trials (UKALL2003, COALL-03, DCOG-ALL10, and NOPHO-ALL2008). Using the discovery cohort, multivariate Cox regression modeling defined a minimal model including white cell count at diagnosis, pretreatment cytogenetics, and end-of-induction minimal residual disease. Using this model, we defined PIUKALL as a continuous variable that assigns personalized risk scores. PIUKALL correlated with risk of relapse and was validated in an independent cohort. Using PIUKALL to risk stratify patients improved the concordance index for all end points compared with traditional algorithms. We used PIUKALL to define 4 clinically relevant risk groups that had differential relapse rates at 5 years and were similar between the 2 cohorts (discovery: low, 3% [95% confidence interval (CI), 2%-4%]; standard, 8% [95% CI, 6%-10%]; intermediate, 17% [95% CI, 14%-21%]; and high, 48% [95% CI, 36%-60%; validation: low, 4% [95% CI, 3%-6%]; standard, 9% [95% CI, 6%-12%]; intermediate, 17% [95% CI, 14%-21%]; and high, 35% [95% CI, 24%-48%]). Analysis of the area under the curve confirmed the PIUKALL groups were significantly better at predicting outcome than algorithms employed in each trial. PIUKALL provides an accurate method for predicting outcome and more flexible method for defining risk groups in future studies.

Original languageEnglish
JournalBlood
Volume135
Issue number17
Pages (from-to)1438-1446
Number of pages9
ISSN0006-4971
DOIs
Publication statusPublished - 23 Apr 2020

    Research areas

  • Adolescent, Biomarkers, Tumor/analysis, Child, Child, Preschool, Combined Modality Therapy, Female, Follow-Up Studies, Humans, Infant, Male, Neoplasm Recurrence, Local/pathology, Neoplasm, Residual/pathology, Outcome Assessment, Health Care/statistics & numerical data, Patient Selection, Precursor Cell Lymphoblastic Leukemia-Lymphoma/pathology, Prognosis, Retrospective Studies, Risk Factors, Survival Rate

ID: 62240457