Orgel E, Alexander TB, Wood BL, et al. - Using a retrospective cohort, assembled by the Children's Oncology Group (COG) Acute Leukemia of Ambiguous Lineage Task Force, including centrally reviewed World Health Organization 2016 (WHO2016) mixed-phenotype acute leukemia (MPAL) cases identified from banking investigations for acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML), researchers evaluated the relative efficacy of chemotherapy types for treating pediatric MPAL. Remission was attained with aLL induction regimens in 72% of the cases (28 of 39), whereas remission was achieved with AML regimens in 69% (9 of 13). For the whole cohort, the 5-year event-free survival (EFS) and overall survival (OS) rates were estimated to be 72% ± 8% and 77% ± 7%, respectively. Among patients taking ALL chemotherapy alone without hematopoietic stem cell transplantation (HSCT) (n = 21), the estimated EFS was 75% ± 13% and OS was 84% ± 11%. The preferred initial treatment may be ALL chemotherapy without HSCT, as indicated by the findings of the COG MPAL cohort and a literature review. To examine this approach, a prospective trial within the COG was proposed; for cases with treatment failure, as evaluated by minimal residual disease, AML chemotherapy and/or HSCT will be reserved. Further understanding of MPAL genomics will be afforded by embedded biology studies.