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, , high-hyperdiploid and -rearranged B-ALL had the best five-year event-free survival rates (95% to 98.4%); , PAX5alt, T-cell, ETP, iAMP21, and hypodiploid ALL intermediate rates (80.0% to 88.2%); and , -like and -like and -rearranged ALL the worst rates (64.1% to 76.2%). All but three of the 142 patients with day-8 blood MRD <0.01% remained in remission. Among new subtypes, intensified therapy based on day-15 MRD≥1% improved outcome of -rearranged, -like, and -rearranged ALL, and achievement of day-42 MRD<0.01% did not preclude relapse of PAX5alt, -rearranged and -like ALL. Thus, new subtypes including -rearranged, PAX5alt, -like, -like, -rearranged and -rearranged ALL have important prognostic and therapeutic implications.