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

Abstract

Hypersensitivity reactions are the most frequent dose-limiting adverse reactions to <i>Escherichia coli</i>-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 <i>HLA-DRB1</i> and <i>HLA-DQB1</i> 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 <i>HLA-DQA1</i> 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 <i>HLA-DRB1*07:01</i> and <i>HLA-DQB1*02:02</i> alleles had significantly higher risk of developing asparaginase hypersensitivity compared to non-carriers [<i>P</i>=4.56×10^-5; OR=2.86 (1.73-4.75) and <i>P</i>=1.85×10^-4; OR=2.99 (1.68-5.31); n=359, respectively]. After haplotype reconstruction, the <i>HLA-DRB1*07:01-HLA-DQB1*02:02</i> haplotype was associated with an increased risk. After inferring the <i>HLA-DQA1</i> alleles the <i>HLA-DRB1*07:01-HLA-DQA1*02:01-HLA-DQB1*02:02</i> haplotype was associated with the highest risk of asparaginase hypersensitivity [<i>P</i>=1.22×10^-5; OR=5.00 (2.43-10.29); n=257]. Significantly fewer T-cell ALL patients carried the <i>HLA-DQB1*02:02</i> allele and the associated haplotype than did pre-B-cell ALL patients (6.5%; <i>vs.</i> 19.2%, respectively; <i>P</i>=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.