Patients carrying both the HLA-DRB1 rs17885382 and NFATC2 rs6021191 variant have a higher risk of developing asparaginase hypersensitivity compared with patients with no risk variant. The risk of developing hypersensitivity was determined for patients carrying a single-risk variant (HLA-DRB1 rs17885382 or NFATC2 rs6021191) or for patients carrying both risk variants (NFATC2 rs6021191 and HLA-DRB1 rs17885382). The risk of hypersensitivity was higher in patients carrying a single variant (OR_rs6021191 = 3.07, CI_rs6021191 = 1.87-4.94, P_rs6021191 = 5.4 × 10⁻⁶; OR_rs17885382 = 1.66, CI_rs17885382 = 1.3-2.1, P_rs17885382 = 3.5 × 10⁻⁵) or both variants (OR = 8.58, CI = 3.14-22.92, P = 1.7 × 10⁻⁵) compared with patients with no risk alleles. The associations were determined using a general linear model adjusted for treatment, ALL immunophenotype, gender, age group, and ancestry.