Identification of favorable subgroups of childhood high-hyperdiploid acute lymphoblastic leukemia in a modern therapy era – A retrospective international study of 3,231 patients

B-cell acute lymphoblastic leukemia (B-ALL) with high-hyperdiploidy (HHD) represents the most prevalent genetic subtype of childhood ALL. This retrospective international study aimed to identify the HHD subgroup(s) having both the highest proportion of B-ALL cases and the best outcome.Data from 11,530 B-ALL patients, including 3,231 with HHD-B-ALL, treated between 1998 and 2018 in eight trials from seven international Berlin-Frankfurt-Münster Group members were analyzed. Eight HHD subgroups – including double and triple trisomies, trisomy 18, UK-good-risk (UK-GR) profile, and four different modal chromosome number (MCN) categories – were evaluated for 5-year event-free survival (EFS), overall survival, and relapse. Each subgroup was ranked by outcome measures and prevalence within the B-ALL trial cohorts.HHD frequency ranged from 19–35%. MCN 54–67 and UK-GR profile achieved the lowest overall ranking scores corresponding to the largest (up to 28% for MCN 54–67 and 26% for UK-GR among total B-ALL trial cohorts) and best HHD subgroups (EFS ranged from 80.5–92.8% for MCN 54–67 and 80.5–93.5% for UK-GR).Both an MCN of 54–67 and UK-GR profile define large, reproducible subgroups of HHD B-ALL with good prognosis. They represent strong candidates for risk-stratification of treatment de-intensification trials in the modern immunotherapy era.