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

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.

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.

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).

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.