IKZF1PLUS alterations contribute to outcome disparities in Hispanic/Latino children with B‐lymphoblastic leukemia

Abstract Background Compared to other ethnicities, Hispanics/Latinos (H/L) have a high incidence of acute lymphoblastic leukemia (ALL), enrichment of unfavorable ALL genetic subtypes, and worse outcomes, even after correcting for socioeconomic factors. We previously demonstrated increased incidence of the high‐risk genetic drivers IKZF1 deletion and IGH::CRLF2 rearrangement in H/L compared to non‐H/L children with B‐ALL. Here in an expanded pediatric cohort, we sought to identify novel genetic drivers and secondary genetic alterations in B‐ALL associated with H/L ethnicity. Procedure Comprehensive clinicopathologic data from patients with B‐ALL treated from 2016 to 2020 were analyzed. Subtype was determined from karyotype, fluorescence in situ hybridization (FISH), chromosome microarray (CMA), and our next‐generation sequencing (NGS) panel (OncoKids). Non‐driver genetic variants were also examined. p ‐Values less than .05 (Fisher's exact test) were considered significant. Results Among patients with B‐ALL at diagnosis ( n = 273), H/L patients (189, 69.2%) were older ( p = .018), more likely to present with CNS2 or CNS3 disease ( p = .004), and NCI high‐risk ALL ( p = .014) compared to non‐H/L patients. Higher incidence of IGH::CRLF2 rearrangement (B‐ALL, BCR::ABL1‐like, unfavorable; p = .016) and lower incidence of ETV6::RUNX1 rearrangement (favorable, p = .02) were also associated with H/L ethnicity. Among secondary (non‐subtype‐defining) genetic variants, B‐ALL in H/L was associated with IKFZ1 deletion alone ( p = .001) or with IGH::CRLF2 rearrangement ( p = .003). The IKZF1 PLUS profile ( IKZF1 deletion plus CDKN2A/2B del, PAX5 del, or P2RY8::CRLF2 rearrangement without DUX4 rearrangement) was identified as a novel high‐risk feature enriched in H/L patients ( p = .001). Conclusions Our study shows enrichment of high‐risk genetic variants in H/L B‐ALL and raises consideration for novel therapeutic targets.