Genomic alterations of IKZF1 are common and associated with adverse clinical features in B-progenitor acute lymphoblastic leukemia (B-ALL). The relationship between the type of IKZF1 alteration, B-ALL genomic subtype and outcome are incompletely understood. B-ALL subtype and genomic alterations were determined using transcriptome and genomic sequencing, and SNP microarray analysis in 688 pediatric patients with B-ALL in the St. Jude Total Therapy XV and 16 studies. IKZF1 alterations were identified in 115 (16.7%) patients, most commonly in BCR::ABL1 (78%) and CRLF2-rearranged, BCR::ABL1-like B-ALL (70%). These alterations were associated with 5-year cumulative incidence of relapse (CIR) of 14.8 ± 3.3% compared to 5.0 ± 0.9% for patients without any IKZF1 alteration (P <
0.0002). In separate multivariable analyses adjusting for genetic subtype groups and other factors, IKZF1 deletions of exons 4-7 (P = 0.0002), genomic IKZF1