CpG island methylator phenotype classification improves risk assessment in pediatric T-cell Acute Lymphoblastic Leukemia [methylation array]. CpG island methylator phenotype classification improves risk assessment in pediatric T-cell Acute Lymphoblastic Leukemia [methylation array]

Current intensive treatment of pediatric T-cell acute lymphoblastic leukemia (T-ALL) has substantial side-effects, highlighting a need for novel biomarkers to improve risk stratification. Canonical biomarkers such as genetics and immunophenotype are largely not used in pediatric T-ALL stratification. This study aimed to validate the prognostic relevance of DNA methylation CpG island methylator phenotype (CIMP) risk stratification in two pediatric T-ALL patient cohorts: the Nordic NOPHO ALL2008 T-ALL study cohort (n=192) and the Dutch DCOG ALL-10/ALL-11 validation cohorts (n=156). Both cohorts showed that combining CIMP classification at diagnosis with measurable residual disease (MRD) at treatment day 29 or 33 significantly improved outcome prediction. The poor prognosis subgroup, characterized by CIMP low/D29 or D33 MRD≥0.1%, showed a cumulative incidence of relapse (pCIR5yr) of 29.0% and 23%, and overall survival (pOS5yr) of 59.7% and 65.4%, in NOPHO and DCOG, respectively. Conversely, a good prognosis subgroup was also identified representing CIMP high/D29 or D33 MRD 1-year-old and < 18-years-old) T-ALL samples taken at diagnosis (n = 128), and cell-sorted CD34+ and CD3+ cells and a fresh frozen lymph node as control samples (n = 3), analyzed on Illumina EPIC v1.0 DNA methylation arrays (Illumina, CA, USA). T-ALL samples analyzed by Illumina 450K DNA methylation arrays (Illumina, CA, USA) (n = 64) are available in GSE69954 (GSM1713872 T-ALL Sample 85 was excluded due to mislabeling). For the validation DCOG cohort, n = 156 samples (≥1 and <18 years-old) stored in the Princess Máxima biobank were analyzed using Illumina EPICv.2.0 arrays (Illumina, CA, USA). ***Submitters state that raw *.idat files will not be submitted to a repository because the patients providing the samples were not consented for raw data deposition****