25. High-risk genetic variants underlie unfavorable prognosis of B-lymphoblastic leukemia patients of Hispanic ethnicity

Maximilian Wengyn



Maximilian Wengyn, Alexandra E. Kovach, Andrew Doan, My H. Vu, Gordana Raca, Deepa Bhojwani

Children’s Hospital Los Angeles, Los Angeles, CA, United States

Compared to other ethnicities, Hispanics have a high incidence of acute lymphoblastic leukemia (ALL), enrichment of unfavorable ALL genetics 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 Hispanics compared to non-Hispanic children with B-ALL (Raca et al. Leukemia 2021). Here in an expanded cohort, we sought to 1) validate this finding and 2) identify novel genetic drivers and secondary genetic alterations in B-ALL associated with Hispanic ethnicity.

Comprehensive clinicopathologic data from B-ALL patients (2016-2020) treated at our institution were analyzed. Subtype was determined from karyotype, FISH, CMA and our NGS panel (OncoKids). Non-driver genetic variants were also examined. P-values <0.05 (Fisher’s Exact Test) were considered significant.

Among B-ALL patients at diagnosis (n=274), Hispanics (231, 69.0%) were older (p=0.019), more likely to present with CNS involvement (p=0.005) and had a higher rate of minimal/measurable residual disease (MRD) at end of Induction (p=0.021) compared to non-Hispanics. Presence of IGH::CRLF2 rearrangement (B-ALL, BCR::ABL1-like, unfavorable; p=0.015) and absence of ETV6::RUNX1 rearrangement (favorable, p=0.022) were associated with Hispanic ethnicity. Among secondary (non-subtype-defining) variants, B-ALL in Hispanics was associated with IKFZ1 deletion alone (p=0.001) or with IGH::CRLF2 rearrangement (p=0.003). Additionally, IKZF1-PLUS profile (IKZF1 deletion plus CDKN2A/2B deletion, PAX5 deletion or P2RY8::CRLF2 rearrangement without DUX4 rearrangement) was identified as a novel high-risk feature enriched in Hispanic patients (p=0.001).

Our study confirms enrichment of high-risk genetic variants in Hispanic B-ALL and raises consideration for novel therapeutic targets