Monday, May 29, 2023
| n | Value, n (%) | |
|---|---|---|
| Age, y | 544 | 29 (18–54) |
| Range | 2–82 | |
| Male sex | 544 | 304 (56) |
| Ethnicity | 544 | |
| White | 275 (51) | |
| African American | 120 (22) | |
| Hispanic | 109 (20) | |
| Asian | 35 (6) | |
| Other | 5 (1) | |
| Disease status | 544 | |
| Treatment naïve severe AA | 515 (95) | |
| Relapsed or refractory AA | 29 (5) | |
| Pretreatment blood values | ||
| Neutrophil count, ×109/L | 515 | 0.29 (0.09–0.51) |
| Lymphocyte count, ×109/L | 515 | 1.27 (0.92–1.63) |
| Reticulocyte count, ×109/L | 515 | 15.3 (6.5–32.0) |
| Platelet count, ×109/L | 515 | 9 (5–13) |
| Thrombopoietin, ng/mL | 140 | 2610 (2220–3080) |
| PNH clone ≥1% | 470 | 177 (38) |
| hATG-based IST | 416 | |
| hATG and CsA | 102 (25) | |
| hATG, CsA, and MMF | 103 (25) | |
| hATG, CsA, and rapamycin | 35 (8) | |
| hATG, CsA, and EPAG | 176 (42) | |
| Response to IST | 416 | |
| Overall response | 293 (70) | |
| Complete response | 101 (24) | |
| Clonal evolution | 416 | |
| High-risk clonal evolution | 31 (7) | |
| Low-risk clonal evolution | 26 (6) |
Table 1. Clinical characteristics of patients
Values are n (%) or median (IQR).
CsA, cyclosporine; MMF, mycophenolate mofetil.
| HLA allele | Allele frequency, % (phenotype frequency, %) | Odds ratio of allele frequency (95% CI) | |||||||
|---|---|---|---|---|---|---|---|---|---|
| White | African American | Hispanic | Asian | ||||||
| AA n = 275 | Control n = 3 912 440 | AA n = 120 | Control n = 505 250 | AA n = 109 | Control n = 712 764 | AA n = 35 | Control n = 568 597 | ||
| HLA-B*14:02 | 7.3 (12.7) | 2.7 (5.4) | 5.0 (10.0) | 2.2 (4.3) | 7.8 (14.7) | 4.2 (8.3) | 0.0 (0) | 0.2 (0.3) | 2.44 (1.91–3.12) |
| HLA-B*40:02 | 2.4 (4.7) | 1.3 (2.7) | 0.4 (0.8) | 0.3 (0.7) | 7.3 (13.8) | 5.0 (9.7) | 11.4 (20.0) | 2.4 (4.8) | 1.88 (1.36–2.61) |
| HLA-B*07:02 | 17.6 (32.4) | 12.5 (23.4) | 8.8 (15.8) | 7.3 (14.0) | 8.3 (16.5) | 5.8 (11.2) | 1.4 (2.9) | 2.9 (5.8) | 1.42 (1.19–1.70) |
| HLA-A*02:01 | 28.4 (50.5) | 27.2 (46.9) | 12.9 (24.2) | 12.2 (23.0) | 17.0 (29.4) | 21.0 (37.5) | 7.1 (11.4) | 8.4 (16.2) | 0.99 (0.86–1.15) |
| HLA-B*08:01 | 9.5 (17.8) | 10.6 (20.0) | 3.8 (7.5) | 3.7 (7.2) | 4.6 (9.2) | 4.2 (8.2) | 0 (0) | 1.8 (3.5) | 0.92 (0.72–1.17) |
Table 2. HLA allele frequencies in patients with AA and healthy individuals in the NMDP dataset
Allele frequency is copy number/2n. The phenotype frequency in the NMDP donors was estimated by the equation of (phenotype frequency) = 1 - (1 - [allele frequency])2.
| Univariate model | Multivariate model 1 | Multivariate model 2 | |||||||
|---|---|---|---|---|---|---|---|---|---|
| HR | 95% CI | P | HR | 95% CI | P | HR | 95% CI | P | |
| Age ≥40 y | 4.00 | 1.90–8.40 | .00026 | 4.87 | 2.16–11.0 | .00014 | 4.73 | 2.10–10.7 | .00018 |
| HLA-B*14:02 genotype | 2.83 | 1.32–6.10 | .0077 | 2.47 | 1.01–6.05 | .048 | |||
| HLA loss | 3.68 | 1.77–7.66 | .00050 | 2.70 | 1.20–6.08 | .017 | |||
| Combined HLA risk† | 4.44 | 2.04–9.68 | .00018 | 4.26 | 1.02–9.48 | .00038 | |||
Table 3. Fine-Gray proportional hazard regression for high-risk clonal evolution
†Presence of HLA loss or HLA-B*14:02 genotype.
This activity is intended for hematologists, immunologists, oncologists, internists, and other clinicians caring for patients with immune aplastic anemia (AA).
The goal of this activity is to describe the clinical significance of HLA alleles and their loss in patients with immune AA, including HLA-A, HLA-B, HLA-C, HLA-DRB1, and HLA-DQB1 allele frequencies, somatic loss of HLA class I alleles, and correlations of HLA alleles and HLA loss with clinical presentation and outcome after immunosuppressive therapy (IST) in 544 patients with immune AA.
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Immune aplastic anemia (AA) features somatic loss of HLA class I allele expression on bone marrow cells, consistent with a mechanism of escape from T-cell–mediated destruction of hematopoietic stem and progenitor cells. The clinical significance of HLA abnormalities has not been well characterized. We examined the somatic loss of HLA class I alleles and correlated HLA loss and mutation-associated HLA genotypes with clinical presentation and outcomes after immunosuppressive therapy in 544 AA patients. HLA class I allele loss was detected in 92 (22%) of the 412 patients tested, in whom there were 393 somatic HLA gene mutations and 40 instances of loss of heterozygosity. Most frequently affected was HLA-B*14:02, followed by HLA-A*02:01, HLA-B*40:02, HLA-B*08:01, and HLA-B*07:02. HLA-B*14:02, HLA-B*40:02, and HLA-B*07:02 were also overrepresented in AA. High-risk clonal evolution was correlated with HLA loss, HLA-B*14:02 genotype, and older age, which yielded a valid prediction model. In 2 patients, we traced monosomy 7 clonal evolution from preexisting clones harboring somatic mutations in HLA-A*02:01 and HLA-B*40:02. Loss of HLA-B*40:02 correlated with higher blood counts. HLA-B*07:02 and HLA-B*40:01 genotypes and their loss correlated with late-onset of AA. Our results suggest the presence of specific immune mechanisms of molecular pathogenesis with clinical implications. HLA genotyping and screening for HLA loss may be of value in the management of immune AA. This study was registered at clinicaltrials.gov as NCT00001964, NCT00061360, NCT00195624, NCT00260689, NCT00944749, NCT01193283, and NCT01623167.
Immune aplastic anemia (AA) is caused by T cells that destroy hematopoietic stem cells (HSCs), and marrow failure is successfully treated with hematopoietic cell transplantation (HCT) or immunosuppressive therapy (IST).[1] Eltrombopag (EPAG) combined with IST yielded higher hematologic responses and survival compared with IST alone,[2] but long-term outcomes such as relapse and clonal evolution remain clinically problematic and biologically not well understood.
The immune pathophysiology of AA has been, in part, inferred from frequent somatic loss of HLA class I alleles. Increased frequency of some HLA alleles has been reported in AA patients of various ethnicities,[3–14] and has been confirmed in a recent genome-wide association study.[15] Somatic loss of HLA class I alleles may result from copy-neutral chromosome 6p loss of heterozygosity (6p LOH)[11,16,17] or acquired inactivating HLA gene mutations.[18,19] A limited set of HLA-A and HLA-B alleles are more likely to acquire somatic mutations;[18,19] a T-cell line specific for a missing HLA class I allele has been isolated from an AA patient.[20] Loss in a recurrently mutated HLA allele may characterize a specific immune pathogenesis and associated clinical manifestations. Previous studies suggested better IST responses and survival in patients with HLA loss[11,18,21] and poor outcomes, including frequent clonal evolution, in patients who harbored HLA alleles related to somatic mutations, irrespective of somatic loss of an HLA allele.[19]
Clonality is common in AA.[22] Paroxysmal nocturnal hemoglobinuria (PNH)-clones, cells deficient in glycosylphosphatidylinositol (GPI)-anchored proteins due to acquired PIGA mutations, are most frequent. PNH is closely related to immune marrow failure, and the GPI anchor itself may be a target of immune attack.[23,24] Somatic mutations are also present in genes recurrently mutated in myelodysplastic syndromes or acute myeloid leukemia (AML), especially DNMT3A, ASXL1, and BCOR.[17] However, the allelic burden of these clones in AA are usually small, clones remain stable for years, and affected cells infrequently drive evolution to myeloid neoplasms, which are usually characterized by complete or partial loss of chromosome 7.[1,25,26] Of all clonal associations, the mechanism of HLA loss is most clearly related to escape from immune cell destruction.
Our aim was to clarify and enlarge on the clinical significance of HLA class I allele loss and recurrently mutated genotypes in a large cohort of patients with immune AA.
