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

Abstract

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, <i>ETV6-RUNX1</i>, high-hyperdiploid and <i>DUX4</i>-rearranged B-ALL had the best five-year event-free survival rates (95% to 98.4%); <i>TCF3-PBX1</i>, PAX5alt, T-cell, ETP, iAMP21, and hypodiploid ALL intermediate rates (80.0% to 88.2%); and <i>BCR-ABL1</i>, <i>BCR-ABL1</i>-like and <i>ETV6-RUNX1</i>-like and <i>KMT2A</i>-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 <i>DUX4</i>-rearranged, <i>BCR-ABL1</i>-like, and <i>ZNF384</i>-rearranged ALL, and achievement of day-42 MRD<0.01% did not preclude relapse of PAX5alt, <i>MEF2D</i>-rearranged and <i>ETV6-RUNX1</i>-like ALL. Thus, new subtypes including <i>DUX4</i>-rearranged, PAX5alt, <i>BCR-ABL1</i>-like, <i>ETV6-RUNX1</i>-like, <i>MEF2D</i>-rearranged and <i>ZNF384</i>-rearranged ALL have important prognostic and therapeutic implications.