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We evaluate clinical significance of recently identified subtypes of acute lymphoblastic leukemia (ALL) in 598 children treated with minimal residual disease (MRD)-directed therapy. Among the 16 B-ALL and 8 T-ALL subtypes identified by next generation sequencing, ETV6-RUNX1 , high-hyperdiploid and DUX4 -rearranged B-ALL had the best five-year event-free survival rates (95% to 98.4%); TCF3-PBX1 , PAX5alt, T-cell, ETP, iAMP21, and hypodiploid ALL intermediate rates (80.0% to 88.2%); and BCR-ABL1 , BCR-ABL1 -like and ETV6-RUNX1 -like and KMT2A -rearranged ALL the worst rates (64.1% to 76.2%). All but three of the 142 patients with day-8 blood MRD &lt;0.01% remained in remission. Among new subtypes, intensified therapy based on day-15 MRD≥1% improved outcome of DUX4 -rearranged, BCR-ABL1 -like, and ZNF384 -rearranged ALL, and achievement of day-42 MRD&lt;0.01% did not preclude relapse of PAX5alt, MEF2D -rearranged and ETV6-RUNX1 -like ALL. Thus, new subtypes including DUX4 -rearranged, PAX5alt, BCR-ABL1 -like, ETV6-RUNX1 -like, MEF2D -rearranged and ZNF384 -rearranged ALL have important prognostic and therapeutic implications.

Clinical Significance of Novel Subtypes of Acute Lymphoblastic Leukemia in the Context of Minimal Residual Disease–Directed Therapy