Abstract ETV6::RUNX1 ‐like ALL is defined by a gene expression signature similar to that of ETV6::RUNX1 ‐positive ALL and absence of all genetic subtype‐defining aberrations, including the ETV6::RUNX1 fusion. Within the International BFM Study Group, we assembled and analyzed a cohort of 100 patients (including 97 children) with ETV6::RUNX1 ‐like ALL. We describe their diverse genetic landscape, centered around ETV6 aberrations with frequent IKZF1 disruptions, as previously shown, but including various rare non‐ ETV6 /non‐ IKZF1 gene fusions, and rearrangements of CRLF2 ( CRLF2 r). We show that ETV6 and IKZF1 aberrations do not occur exclusively in this subtype, which hampers its classification based solely on genomic data. We confirm our previous observation of a strong association of the CD27‐positive/CD44low‐negative immunophenotype with ETV6 :: RUNX1 (‐like) subtype. Compared to ETV6::RUNX1 ‐positive ALL, patients with ETV6::RUNX1 ‐like ALL are younger, have higher white blood cell counts at diagnosis, and have an inferior early treatment response. While overall survival is comparable, event‐free survival is significantly lower in patients with ETV6::RUNX1 ‐like ALL, with NCI risk, early treatment response, IKZF1 deletions, CRLF2r, and JAK2 mutations having prognostic relevance. Notably, Down syndrome is highly prevalent and associated with a worse outcome in ETV6::RUNX1 ‐like ALL. In conclusion, we provide biological, demographic, and clinical characteristics of the largest ETV6::RUNX1 ‐like cohort presented to date.
Zaliova et al. (2026) studied this question.