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. 2025 Jun;72(6):e31668.
doi: 10.1002/pbc.31668. Epub 2025 Mar 22.

Amino Acid Stress Response Genes Contribute to a 25-Fold Increased Risk of L-Asparaginase-Induced Hypersensitivity

Spencer J Anderson  1   2 , Erika N Scott  1   2   3 , Edward J Raack  1   2 , Wan-Chun Chang  2   3   4 , Miguel Córdova-Delgado  2   3   4 , Jessica N Trueman  2   4 , Catrina M Loucks  2   3   5 , S Rod Rassekh  2   6 , Colin J D Ross  1   2   7 , Bruce C Carleton  1   2   3   4 ; Canadian Pharmacogenomics Network for Drug Safety (CPNDS) consortium
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Amino Acid Stress Response Genes Contribute to a 25-Fold Increased Risk of L-Asparaginase-Induced Hypersensitivity

Spencer J Anderson et al. Pediatr Blood Cancer. 2025 Jun.

Abstract

Background: L-asparaginase is essential in treating pediatric acute lymphoblastic leukemia (ALL) but is limited by hypersensitivity reactions in up to 70% of patients, leading to severe, dose-limiting complications and compromised event-free survival.

Procedure: This study conducted a genome-wide association study (GWAS) in a discovery cohort of 221 pediatric cancer patients who experienced l-asparaginase-induced hypersensitivity reactions (≥CTCAE grade 2) and 705 controls without hypersensitivity despite equivalent exposure. Results were replicated in an independent cohort of 41 cases and 139 controls.

Results: Significant associations were identified between hypersensitivity and four genes crucial for amino acid stress response: CYP1B1 (rs59569490; odds ratio [OR] = 8.5; 95% confidence interval [CI], 3.9-18.5; p = 1.5 × 10-10), SEC16B (rs115461320; OR = 4.2; 95% CI, 2.5-7.9; p = 1.2 × 10-6), OPLAH (rs11993268; OR = 4.8; 95% CI, 2.4-9.9; p = 2.0 × 10-6), and SORCS2 (rs11940340; OR = 6.7; 95% CI, 2.8-15.7; p = 5.7 × 10-7). Variants in SEC16B, OPLAH, and SORCS2 remained significant in the analysis of the replication cohort (p < 0.05). Patients who carried risk alleles in two or more of these genes experienced an 86.4% increased incidence of hypersensitivity reactions in the discovery cohort (OR = 25.2; 95% CI, 7.4-86.2; p = 1.0 × 10-10), which was replicated in the independent cohort with a 100% incidence in carriers (p = 0.04).

Conclusions: The cumulative incidence of these large effect variants highlights their significance for the identification of patients at high risk of l-asparaginase-induced hypersensitivity. Successfully identifying patients at increased risk of hypersensitivity reactions can inform personalized treatment strategies and limit these harmful dose-limiting reactions in pediatric ALL.

Keywords: acute lymphoblastic leukemia; hypersensitivity; l‐asparaginase; pediatrics.

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References

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