Accurate risk assignment in childhood acute lymphoblastic leukaemia is essential to avoid under- or over-treatment. We hypothesized that time-series gene expression profiles (GEPs) of bone marrow samples during remission-induction therapy can measure the response and be used for relapse prediction. We computed the time-series changes from diagnosis to Day 8 of remission-induction, termed Effective Response Metric (ERM-D8) and tested its ability to predict relapse against contemporary risk assignment methods, including National Cancer Institutes (NCI) criteria, genetics and minimal residual disease (MRD). ERM-D8 was trained on a set of 131 patients and validated on an independent set of 79 patients. In the independent blinded test set, unfavourable ERM-D8 patients had >3-fold increased risk of relapse compared to favourable ERM-D8 (5-year cumulative incidence of relapse 38·1% vs. 10·6%; P = 2·5 × 10-3 ). ERM-D8 remained predictive of relapse [P = 0·05; Hazard ratio 4·09, 95% confidence interval (CI) 1·03-16·23] after adjusting for NCI criteria, genetics, Day 8 peripheral response and Day 33 MRD. ERM-D8 improved risk stratification in favourable genetics subgroups (P = 0·01) and Day 33 MRD positive patients (P = 1·7 × 10-3 ). We conclude that our novel metric - ERM-D8 - based on time-series GEP after 8 days of remission-induction therapy can independently predict relapse even after adjusting for NCI risk, genetics, Day 8 peripheral blood response and MRD.

2nd Faculty of Medicine Charles University Prague Czech Republic

Centre for Translational Research in Acute Leukaemia Department of Paediatrics Yong Loo Lin School of Medicine National University of Singapore Singapore Viva University Children's Cancer Centre Khoo Teck Puat National University Children's Medical Institute National University Hospital National University Health System Singapore

Centre for Translational Research in Acute Leukaemia Department of Paediatrics Yong Loo Lin School of Medicine National University of Singapore Singapore Viva University Children's Cancer Centre Khoo Teck Puat National University Children's Medical Institute National University Hospital National University Health System Singapore Cancer Science Institute of Singapore National University of Singapore Singapore

Department of Paediatrics KK Women's and Children's Hospital Singapore

Faculty of Medicine University of Malaya Cancer Research Institute University of Malaya Kuala Lumpur Malaysia

School of Computing National University of Singapore Singapore

Sime Darby Medical Centre Subang Jaya Malaysia

References provided by Crossref.org