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 IGHCRLF2 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 IGHCRLF2 rearrangement (B-ALL, BCRABL1-like, unfavorable; p = .016) and lower incidence of ETV6RUNX1 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 IGHCRLF2 rearrangement (p = .003). The IKZF1PLUS profile (IKZF1 deletion plus CDKN2A/2Bdel, PAX5del, or P2RY8CRLF2 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.