MHC Class I Chain-Related Gene A (MICA) Donor-Recipient Mismatches and MICA-129 Polymorphism in Unrelated Donor Hematopoietic Cell Transplantations Has No Impact on Outcomes in Acute Lymphoblastic Leukemia, Acute Myeloid Leukemia, or Myelodysplastic Syndrome: A Center for International Blood and Marrow Transplant Research Study

Abstract

Single-center studies have previously reported associations of MHC Class I Chain-Related Gene A (MICA) polymorphisms and donor-recipient MICA mismatching with graft-versus-host disease (GVHD) after unrelated donor hematopoietic cell transplantation (HCT). In this study, we investigated the association of MICA polymorphism (MICA-129, MM versus MV versus VV) and MICA mismatches after HCT with 10/10 HLA–matched (n = 552) or 9/10 (n = 161) unrelated donors. Included were adult patients with a first unrelated bone marrow or peripheral blood HCT for acute lymphoblastic leukemia, acute myeloid leukemia, or myelodysplastic syndrome that were reported to the Center for International Blood and Marrow Transplant Research between 1999 and 2011. Our results showed that neither MICA mismatch nor MICA-129 polymorphism were associated with any transplantation outcome (P < .01), with the exception of a higher relapse in recipients of MICA-mismatched HLA 10/10 donors (hazard ratio [HR], 1.7; P = .003). There was a suggestion of association between MICA mismatches and a higher risk of acute GVHD grades II to IV (HR, 1.4; P = .013) There were no significant interactions between MICA mismatches and HLA matching (9/10 versus 10/10). In conclusion, the findings in this cohort did not confirm prior studies reporting that MICA polymorphism and MICA mismatches were associated with HCT outcomes.

Natural Killer Group 2, Member D/NKG2D Ligands in Hematopoietic Cell Transplantation

“…Other studies have specifically analyzed the influence of the MICA gene by three different approaches: (i) focused analysis of the genotype of a single polymorphism at amino acid position 129 in patients (12, 15), (ii) matching of donors and patients genotypes at the same position; 129 (14), and (iii) matching of donor and patients at the MICA allele level (13, 16, 30, 31). …”

“…In the case of heterozygote carriers, the beneficial effect was indeed attributed to the subgroup of patients not treated with ATG, indicating that such a faster activation may not matter if a full CD8 + T cell repertoire is present. Finally, a third publication by Askar et al reported that neither the patient’s nor the donor’s genotype at position 129 had an impact on survival or GVHD (30). The authors could only detect an association between donor MICA-129 non-Val/Val genotypes and slower platelet engraftment (HR = 1.4; 95% CI: 1.109–1.985; P  = 0.02).…”

“…The increased risk of GVHD was mirrored by a lower risk of relapse (HR = 0.50; 95% CI: 0.43–0.59; P  < 0.001), indicating a possible GVL effect. A few weeks later in 2016, Askar and coworkers, however, published contradictory results using a cohort of 713 patients and their unrelated HLA-matched 10/10 ( n  = 552) or 9/10 ( n  = 161) donors (30). They showed an absence of MICA mismatch effect on all major clinical outcomes apart an unexpected significantly higher incidence of relapse in MICA -mismatched vs. -matched patients (HR = 1.7; 95% CI: 1.2–2.4; P  = 0.003).…”

Which factors influence the development of GVHD in HLA-matched or mismatched transplants?

“…These results suggest that when HLA-A, B, C, DRB1 or DQB1-mismatched donors are available, additional testing of DRB3/4/5 may help to lower risks. Most recently, mismatching for the non-classical class I gene, MICA, has been shown to impact GVHD and survival in some [6,7], but not other, studies [8]. …”

Genetic Association of Hematopoietic Stem Cell Transplantation Outcome beyond Histocompatibility Genes

“…Matching of donor and recipient for MICA alleles (68–71) and specifically for the MICA-129 , polymorphism (72) has been found to be beneficial in HSCT, although not in all studies (73, 74). The effect of MICA matching appears hardly explainable solely by the avoidance of potential miHAg and further points toward an important biological function of MICA after HSCT.…”