HLA-DRB1*07:01-HLA-DQA1*02:01-HLA-DQB1*02:02 haplotype is associated with a high risk of asparaginase hypersensitivity in acute lymphoblastic leukemia.

Hypersensitivity reactions are the most frequent dose-limiting adverse reactions to -derived asparaginase in pediatric acute lymphoblastic leukemia (ALL) patients. The aim of the present study was to identify associations between sequence-based Human Leukocyte Antigen Class II region alleles and asparaginase hypersensitivity in a Hungarian ALL population. Four-digit typing of and loci was performed in 359 pediatric ALL patients by using next-generation sequencing method. Based on genotypic data of the two loci, haplotype reconstruction was carried out. In order to investigate the possible role of the HLA-DQ complex, the alleles were also inferred. Multivariate logistic regression analysis and a Bayesian network-based approach were applied to identify relevant genetic risk factors of asparaginase hypersensitivity. Patients with and alleles had significantly higher risk of developing asparaginase hypersensitivity compared to non-carriers [=4.56×10; OR=2.86 (1.73-4.75) and =1.85×10; OR=2.99 (1.68-5.31); n=359, respectively]. After haplotype reconstruction, the haplotype was associated with an increased risk. After inferring the alleles the haplotype was associated with the highest risk of asparaginase hypersensitivity [=1.22×10; OR=5.00 (2.43-10.29); n=257]. Significantly fewer T-cell ALL patients carried the allele and the associated haplotype than did pre-B-cell ALL patients (6.5%; 19.2%, respectively; =0.047). In conclusion, we identified a haplotype in the Human Leukocyte Antigen Class II region associated with a higher risk of asparaginase hypersensitivity. Our results confirm that variations in HLA-D region might influence the development of asparaginase hypersensitivity.