Ultra-deep sequencing (>3000x) in all the newly diagnosed B-ALL cases using a custom NGS panel for the KRAS, NRAS, TP53, UHRF1 and CREBBP genes, followed by prospective testing of sequential samples (3-monthly) with a panel with additional NT5C2, PMS2, KMT2D, ETV6 and PAX5 genes will likely help to identify a significant proportion of cases with impending relapse, although this strategy might require dynamic modification based on prospective data emerging from the relapse biology in our setting. This evidence concerns the gene KMT2D and precursor B-cell acute lymphoblastic leukemia.