Refining risk in historically high-risk pediatric B-cell acute lymphoblastic leukemia: response kinetics and outcomes.
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Outcomes in pediatric acute lymphoblastic leukemia (ALL) have improved substantially with contemporary risk-adapted therapy. However, the prognosis for historically high-risk subtypes, including KMT2A-rearranged (KMT2A-r) and hypodiploid ALL, remains uncertain. We performed a post hoc analysis of 28 patients with KMT2A-r ALL and 27 with hypodiploid ALL enrolled in the nationwide Japan Children's Cancer Group ALL-B12 trial to characterize early treatment response, measurable residual disease (MRD) kinetics, transplant exposure, and clinical outcomes. The 5-year event-free and overall survival were 85.7% and 89.3% for KMT2A-r ALL and 85.2% and 85.2% for hypodiploid ALL, respectively. Clinical behavior was heterogeneous within each subtype. In KMT2A::AFF1 ALL, prednisolone poor response or persistent MRD was associated with a high risk of relapse despite hematopoietic stem cell transplantation (HSCT). Even among prednisolone good responders, patients with MRD ≥10-3 at time point 1 remained at increased risk of relapse, whereas those with MRD ≥10-4 but <10-3 generally showed favorable outcomes. In contrast, non-AFF1 KMT2A-r patients demonstrated rapid MRD clearance and excellent survival. Among patients with hypodiploid ALL, those with low-diploid ALL showed excellent outcomes without HSCT. In other hypodiploid subgroups, some patients with favorable early response achieved long-term survival without transplantation. These findings suggest that historically high-risk ALL subtypes are clinically heterogeneous and that early response kinetics may help refine risk stratification and treatment intensification strategies, including indications for HSCT.