Determination of prognostic and therapeutic implications of novel leukemia subtypes in children with acute lymphoblastic leukemia (ALL) treated with contemporary minimal residual disease (MRD)-directed therapy can improve outcome. In this study, we evaluated the clinical impact of identification of the full genomic spectrum of leukemia subtypes and MRD assessment to guide risk-directed therapy. A retrospective cohort study was conducted in 598 consecutive patients enrolled on Total Therapy Study 16 in a single center from October 29, 2007 to March 26, 2017, with a median follow-up of 7 years. High-hyperdiploid and ETV6-RUNX1 ALL were provisionally classified to be low-risk; TCF3-PBX1, hypodiploid<44 chromosomes and T-ALL standard-risk; and BCR-ABL1, infant KMT2A-rearranged and ETP ALL high-risk. Single nucleotide polymorphism arrays, exome and transcriptome sequencing were used to identify novel leukemia subtypes. Final risk assignment was based on MRD levels measured in bone marrow samples on day 15 of induction and day 42 (end of induction). Patients with MRD≥1% on day 15 or 0.01% to <1% on day 42 were assigned to standard-risk and those with MRD≥1% to high-risk group. MRD was determined in blood samples on day 8 for a research aim. The primary outcome was event-free survival. The secondary outcomes were relapse and overall survival. We identified 17 genetic subtypes, 8 of which were novel. Patients with ETV6-RUNX1, high-hyperdiploid and DUX4-rearranged B-ALL had the best 5-year event-free survival: 98.4%, 95.3%, and 95.0%, respectively. Those with TCF3-PBX1, PAX5alt, ETP, iAMP21, hypodiploid and T-ALL had intermediate rates (80.0% to 88.2%), while those with KMT2A-rearranged, BCR-ABL1, BCR-ABL1-like and ETV6-RUNX1-like ALL had the worst rates (64.1% to 76.2%). All but three of the 142 patients with day-8 blood MRD<0.01% remained in continuous remission. Among novel subtypes, intensified therapy based on day-15 MRD≥1% improved outcome of patients with DUX4-rearranged, BCR-ABL1-like, and ZNF384-rearranged ALL, and achievement of day-42 MRD<0.01% did not preclude relapse of those with PAX5alt, MEF2D-rearranged and ETV6-RUNX1-like ALL. Comprehensive genomic analyses identify novel subtypes, such as DUX4-rearranged, PAX5alt, BCR-ABL1-like, ETV6-RUNX1-like, M2F2D-rearranged and ZNF384-rearranged ALL, which have prognostic and therapeutic implications.

Citation Format: Sima Jeha, John K. Choi, Deqing Pei, Elaine Coustan-Smith, Hiroto Inaba, Jeffrey E. Rubnitz, Raul C. Ribiero, Tanja A. Gruber, Susana C. Raimondi, Seth E. Karol, Kathryn G. Roberts, Jun J. Yang, Cheng Cheng, James R. Downing, William E. Evans, Mary V. Relling, Dario Campana, Charles G. Mullighan, Ching-Hon Pui. Prognostic and therapeutic significance of leukemia subtypes in the context of risk-directed therapy based on minimal residual disease levels in pediatric acute lymphoblastic leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT146.