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

Figure 1.

Frequencies of HLA-DRB1, HLA-DQB1 and HLA-DQA1 alleles in pediatric patients with acute lymphoblastic leukemia. High-resolution sequence-based typing of HLA class II alleles resulted in 35 unique HLA-DRB1 (A) and 19 unique HLA-DRB1 (B) alleles in 359 patients. HLA-DQA1 alleles were inferred in 257 patients and resulted in 7 unique alleles (C).

Figure 2.

Association of HLA-DQB1 and HLA-DQB1 alleles with E. coli asparaginase hypersensitivity. Multivariate logistic regression was applied to assess the association of HLA class II alleles with asparaginase hypersensitivity. Sex, age, treatment protocol, risk group, acute lymphoblastic leukemia (ALL) immunophenotype were included in the analysis as categorical covariates. The dashed horizontal line indicates the Bonferroni-corrected statistical significance threshold. HLA-DRB1*07:01 and HLA-DQB1*02:02 alleles were significantly associated with asparaginase hypersensitivity (n=359; P=4.56×10⁻⁵ and 1.85×10⁻⁴, respectively).

Figure 3.

Patients carrying the HLA-DRB1*07:01 or HLA-DQB1*02:02 alleles had strong association with asparaginase hypersensitivity. The incidence of hypersensitivity reactions was 57% (52 of 92) and 33% (88 of 267) for patients carrying HLA-DRB1*07:01 allele and for non-carriers, respectively. In the case of patients with HLA-DQB1*02:02 allele, the incidence of asparaginase hypersensitivity was 60% (39 of 65), while it was 34% (101 of 294) for patients who did not have the allele. Odds ratios (OR) and 95% confidence intervals were estimated by using multivariate logistic regression analysis.

Figure 4.

A posteriori strong relevance of predictors to asparaginase hypersensitivity. The BN-BMLA approach was used to investigate the different dependency relations between HLA alleles, age, acute lymphoblastic leukemia (ALL) immunophenotype, sex, treatment protocol, risk group and asparaginase hypersensitivity. HLA-DQB1*02:02 allele and risk group had direct strong relevance to asparaginase hypersensitivity (P=0.95 and 1.00, respectively).