Outcomes in patients with ETV6::RUNX1 or high-hyperdiploid B-ALL treated in the St. Jude Total Therapy XV/XVI studies

• Among NCI high-risk patients, 93% with ETV6::RUNX1 and 54% with hyperdiploid B-ALL had excellent outcomes with low-intensity therapy.

• NCI high-risk patients with hyperdiploid B-ALL and slow early MRD response had worse outcomes and, therefore, require new approaches.

Children with ETV6::RUNX1 or high-hyperdiploid B-cell acute lymphoblastic leukemia (B-ALL) have favorable outcomes. The St. Jude (SJ) classification considers these patients low risk, regardless of their National Cancer Institute (NCI) risk classification, except when there is slow minimal residual disease (MRD) response or central nervous system/testicular involvement. We analyzed outcomes in children (aged 1-18.99 years) with these genotypes in the SJ Total XV/XVI studies (2000-2017). Patients with ETV6::RUNX1 (n = 222) or high-hyperdiploid (n = 296) B-ALL had 5-year event-free survival (EFS) of 97.7% ± 1.1% and 94.7% ± 1.4%, respectively. For ETV6::RUNX1, EFS was comparable between NCI standard-risk and high-risk patients and between SJ low-risk and standard-risk patients. Of the 40 NCI high-risk patients, 37 who received SJ low-risk therapy had excellent EFS (97.3% ± 2.8%). For high-hyperdiploid B-ALL, NCI high-risk patients had worse EFS than standard-risk patients (87.6% ± 4.5% vs 96.4% ± 1.3%; P = .016). EFS was similar for NCI standard-risk and high-risk patients classified as SJ low risk (96.0% ± 1.5% and 96.9% ± 3.2%; P = .719). However, EFS was worse for NCI high-risk patients than for NCI standard-risk patients receiving SJ standard/high-risk therapy (77.4% ± 8.2% vs 98.0% ± 2.2%; P = .004). NCI high-risk patients with ETV6::RUNX1 or high-hyperdiploid B-ALL who received SJ low-risk therapy had lower incidences of thrombosis (P = .013) and pancreatitis (P = .011) than those who received SJ standard/high-risk therapy. MRD-directed therapy yielded excellent outcomes, except for NCI high-risk high-hyperdiploid B-ALL patients with slow MRD response, who require new treatment approaches. Among NCI high-risk patients, 93% with ETV6::RUNX1 and 54% with high-hyperdiploid B-ALL experienced excellent outcomes with a low-intensity regimen. These trials were registered at www.clinicaltrials.gov as #NCT00137111 and #NCT00549848.