MHC Class I Chain-Related Gene a (MICA) Donor-Recipient Mismatches and MICA-129 Polymorphism in Unrelated Donor Hematopoietic Stem Cell Transplants (HSCT) for Hematological Malignancies: A CIBMTR Study

Background: Previous reports from single centers suggested that MICA polymorphism and donor/recipient MICA mismatches are associated with chronic graft versus host disease (GVHD) and acute GVHD (respectively) after unrelated donor HSCT. MICA is both a transplantation antigen and a ligand recognized by the activating receptor NKG2D expressed by NK, NKT, CD8+ and TCRγδ+ T cells.  Allelic variants of MICA due to a single amino acid substitution at position 129 result in significant differences in NKG2D binding.  MICA alleles with a methionine (M) or valine (V) have been classified as having strong or weak binding affinity for NKG2D, respectively. 

 

Methods: We studied the association of MICA polymorphism (MICA-129) and MICA mismatches with unrelated donor HSCT with 10/10 HLA match (n=552 pairs) or 9/10 (HLA-B mismatch only, n=161 pairs), reported to the CIBMTR between 2000 and 2011. Included were adult patients who had undergone a first unrelated bone marrow or peripheral blood HSCT for ALL, AML, or MDS. Pre-transplant samples were obtained from the NMDP Research Repository.  MICA typing was performed using rSSOP (One Lambda Thermo Fisher, Canoga Park, CA). Study outcomes included overall survival, disease-free survival, treatment-related mortality, relapse, acute graft vs. host disease (GVHD), chronic GVHD, and engraftment. Variables considered in multivariate analyses included patient, disease and transplant characteristics. A p value < 0.01 for the main effect was considered significant.

 

Results: Of the recipients 101 were MICA-129 MM (14%), 363 MV (52%), and 239 VV (34%). Of the donors 106 were MICA-129 MM (15%), 375 MV (53%), and 229 VV (32%). 27% of the pairs were MICA mismatched, 9 pairs had double (one 10/10 and eight 9/10) and 182 had single mismatches (83 10/10 and 99 9/10). At 0.01 significance level, there was no association between any outcome and MICA mismatch or MICA-129 polymorphism, with the exception of an unexpected finding of significantly higher relapse in association with MICA mismatches in 10/10 patients (HR 1.7, 95% CI 1.2-2.4, p= 0.003) but not in 9/10 patients. There was a suggestion that MICA mismatches were associated with a higher risk of aGVHD grades II-IV (HR 1.4, 95% CI 1.1-1.9, p= 0.013) but not grades III-IV and with higher risk of cGVHD (HR 1.8, 95% CI: 1.0-3.1, p value 0.04). There were no significant interactions between MICA mismatches and HLA matching (9/10 vs. 10/10). There was also a suggestion of an association between donor MICA-129 non-VV genotypes and slower platelet engraftment with HR 1.4 (95% CI 1.109-1.985, p= 0.02).

 

Conclusions: In this cohort neither MICA-129 polymorphism nor MICA mismatches were associated with HSCT outcomes at a level that reached the predetermined level of statistical significance. This registry analysis in patients with ALL, AML and MDS was discordant with prior reports of single center studies of patients with mixed diagnoses.