In a retrospective study involving patients with immune aplastic anemia (AA), researchers from the National Institutes of Health (NIH) identified correlations between human leukocyte antigen (HLA) mutations and clinical features. The study’s results were recently published in the journal Blood.

The study was an analysis of patients with AA who were seen at the NIH Clinical Center in Bethesda, Maryland, and who received immunosuppressive therapy (IST) across multiple clinical trials ( Identifiers: NCT00001964, NCT00061360, NCT00195624, NCT00260689, NCT00944749, NCT01193283, and NCT01623167). The researchers assessed somatic loss of HLA class I alleles using flow cytometry and sequencing methods. They then evaluated patterns of HLA loss, HLA genotypes arising from mutations, and clinical features and outcomes in these patients following IST.

A total of 544 patients were included in this analysis, among whom 416 patients received horse antithymocyte globulin (hATG)-based IST. HLA loss was evaluated in 412 patients, of whom 322 had received hATG-based IST. The majority (95%) of patients had treatment-naïve severe AA prior to IST.

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Most patients did not show HLA loss. HLA gene mutation alone was seen in 13% of patients. Another 7% of patients showed a gene mutation and loss of heterozygosity of chromosome 6p, and another 3% of patients showed loss of heterozygosity of chromosome 6p only.

A total of 393 HLA gene mutations and 40 cases of loss of heterozygosity were found. HLA-B*14:02, HLA-A*02:01, HLA-B*40:02, HLA-B*07:02, and HLA-B*08:01 were the most commonly impacted alleles. In an analysis of allele frequencies, the HLA-B*14:02, HLA-B*40:02, and HLA-B*07:02 alleles were significantly more frequent in patients with AA than they were in a dataset of healthy control individuals used for comparison.

Correlations were found between high-risk clonal evolution and HLA loss, the HLA-B*14:02 genotype, and older age. The researchers were able to use these relationships to construct a predictive model for high-risk clonal evolution that resulted in 3 distinct risk groups. Additional correlations were seen between specific alleles and clinical features. These included elevated blood counts being seen more often with HLA-B*14:02 loss, and mutated genotypes of HLA-B*07:02 and HLA-B*40:01 showing possible associations with later disease onset.

The researchers considered the study’s findings to support the notion that certain pathogenic pathways may exist in relation to HLA genotype and loss in patients with AA. “Most important in the clinic was the relationship between high-risk malignant clonal evolution and class I-mediated immunity, as for the most frequently inactivated HLA-B*14:02 genotype and HLA loss in general, which provide a simple prediction tool for this serious complication,” the researchers concluded in their report.


Zaimoku Y, Patel B, Adams SD, et al. HLA associations, somatic loss of HLA expression, and clinical outcomes in immune aplastic anemia. Blood. 2021;138(26):2799-2809. doi:10.1182/blood.2021012895