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

Abstract

We evaluated 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-cell ALL (B-ALL) and 8 T-cell ALL subtypes identified by next-generation sequencing, ETV6-RUNX1, high-hyperdiploid, and DUX4-rearranged B-ALL had the best 5-year eventfree survival rates (95.0%-98.4%); TCF3-PBX1, PAX5-altered (PAX5alt), T-cell, early T-cell precursor (ETP), intrachromosomal amplification of chromosome 21 (iAMP21), and hypodiploid ALL intermediate rates (80.0%-88.2%); and BCR-ABL1, BCR-ABL1-like, ETV6-RUNX1-like, and KMT2A-rearranged ALL the worst rates (64.1%-76.2%). All but 3 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 DUX4-rearranged, BCR-ABL1-like, and ZNF384-rearranged ALL, and achievement of day 42 MRD <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.