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, ETV6-RUNX1, highhyperdiploid 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 KMT2Arearranged 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 DUX4-rearranged, BCR-ABL1-like, and ZNF384rearranged 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 DUX4rearranged, PAX5alt, BCR-ABL1-like, ETV6-RUNX1-like, MEF2D-rearranged and ZNF384rearranged ALL have important prognostic and therapeutic implications. SIGNIFICANCE:Genomic analyses and MRD should be used together for risk-directed treatment. Six recently described subtypes --DUX4-rearranged, PAX5alt, BCR-ABL1-like, ETV6-RUNX1-like, MEF2Drearranged, and ZNF384-rearranged ALL --had prognostic and therapeutic significance with contemporary risk-directed treatment.

Genetic Alterations in Childhood Acute Lymphoblastic Leukemia: Interactions with Clinical Features and Treatment Response

“…Surprisingly, although it has a similar GEP to ETV6-RUNX1, ETV6-RUNX1-like has poorer outcomes. In fact, in the recent Total 16 study, ETV6-RUNX1like patients had amongst the highest relapse rates (5-year CIR 22%) [57], consistent with the poor outcomes from earlier reports [55].…”

Advances in the Diagnosis and Treatment of Pediatric Acute Lymphoblastic Leukemia

“…The revolutionized approach to genomic analysis subdivides pediatric ALL into more than 30 genetic subgroups [9][10][11]. In B-ALL, recurrent genomic subtypes are characterized by chromosomal aneuploidy, i.e., hyperdiploidy (>50 chromosomes) or hypodiploidy (<44 chromosomes), and by rearrangements: ETV6/RUNX1 fusion, TCF3/PBX1 fusion, BCR/ABL1 fusion, and KMT2A (MLL) rearrangement (Figure 2 and Table 2).…”

“…Patients with ETV6/RUNX1 fusion and hyperdiploidy and negative MRD on day 15 (as in St. Jude Total Therapy XVI) or day 19 (as in Total Therapy XV) and at the end of induction therapy have an excellent prognosis [11,17,18]. In St. Jude Total Therapy studies, patients with ETV6/RUNX1 fusion and hyperdiploidy are provisionally treated in the low-risk (National Cancer Institute [NCI] standard-risk) arm regardless of their age or WBC count at diagnosis, but those patients with high MRD levels on day 15 (≥1%) or at the end of induction therapy (≥0.01%) or with extramedullary (central nervous system or testis) involvement are subsequently treated in the standard-risk (NCI high-risk) arm.…”

“…In St. Jude Total Therapy studies, patients with ETV6/RUNX1 fusion and hyperdiploidy are provisionally treated in the low-risk (National Cancer Institute [NCI] standard-risk) arm regardless of their age or WBC count at diagnosis, but those patients with high MRD levels on day 15 (≥1%) or at the end of induction therapy (≥0.01%) or with extramedullary (central nervous system or testis) involvement are subsequently treated in the standard-risk (NCI high-risk) arm. This approach has been successful, with excellent outcomes for both subgroups [11,13,17].…”

“…Furthermore, as seen in ETV6/RUNX1rearranged and hyperdiploid ALL, some patients with favorable genetics but slow MRD clearance can be cured by intensifying their post-remission chemotherapy [11,17,27]. Conversely, patients with high-risk genetics have inferior outcomes even when they have undetectable MRD at the end of induction therapy [11,17,18]. It is also important to evaluate whether more sensitive NGS MRD can identify patients with better outcomes among those patients with high-risk genetic features.…”