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