Donor-Recipient Mismatches in MHC Class I Chain-Related Gene a (MICA) in Unrelated Donor (UD) Transplantation
Authors: De Lima Marcos , Rodrigues Morgani , Cano Pedro , Stastny Peter , Liu Ping , Wei Wei , Pesoa Susana , Patah Poliana , Shpall Elizabeth , Giralt Sergio , Rondon Gabriela , Korbling Martin , De Padua Silva Leandro , Champlin Richard , Fernandez-Vina Marcelo 
Published: April 2020

MICA is a highly polymorphic locus located in the Class III region of the HLA system in the short arm of chromosome 6. The products of MICA can elicit humoral allo-recognition and are the ligands of the NKG2-D receptors of natural killer cells. MICA is involved in chronic and possibly acute graft rejection in kidney transplantation. The impact of mismatches in MICA has not been examined systematically in bone marrow transplantation. We hypothesized that donor-recipient MICA mismatches may influence graft-versus-host disease (GVHD) and relapse rates after UD hematopoietic stem cell transplantation (HSCT), and tested this hypothesis in a cohort comprised of all patients with myeloid leukemias transplanted in our institution from January, 2002 to December, 2007 (n=238).

Methods: Typing of each of the classical human leukocyte antigen (HLA) and MICA loci was performed by amplification with locus-specific primers of genomic DNA by PCR followed by nucleotide sequencing. For the assignment of MICA alleles, the polymorphisms in exons 2, 3, 4, and 5 were evaluated. Matching grade is described in the GVH direction. Outcomes were acute (a) GVHD incidence, and aGVHD-free survival (time dependent variable, with development of aGVHD as the event), and relapse-free survival (RFS), both estimated by the Kaplan Meier method. Cox proportional hazards regression model was used to estimate the influence of HLA match degree, patient, disease, and transplant-related characteristics on outcomes. Median age was 50 years (range, 18–74; 24% over age 59). Diagnosis were AML/high-risk MDS in 82% (n=195) and CML in 18% (n=43). 42% (n=100) of the patients were in remission (CR) at HSCT. Preparative regimens were ablative in 59% (n=141), and contained ATG, fludarabine and IV busulfan in respectively 96%, 90% and 70% of the HSCT. GVHD prophylaxis was tacrolimus and mini-methotrexate-based in all HSCT. Stem cell source was bone marrow (BM) in 72% (n=172) and peripheral blood (PB) in 28% (n=66) of HSCT. 78 patients have relapsed (34%) and 133 have died (56%).

Results. 169 pairs were matched in HLA A, B, C, DRB1, and DQB1 (10/10; 71%); 69 (29%) were &lt;10/10 matches, of which 60 were 9/10 (78% of the mismatches were in HLA class I). One or two HLA-DPB1 mismatches were present in 48% and 25% of the patients, respectively. MICA one or two mismatches were present in 22 pairs (9%). Grade (gd) II–IV and III–IV aGVHD rates for patients with MICA mismatches were 80% and 30%, respectively, versus 40% and 14% for those with no MICA mismatches. Effect of MICA on aGVHD was similar among 10/10 and &lt;10/10 patients. RFS at 52 weeks post HSCT was 0.58 (95%CI 0.5–0.66) versus 0.77 (95%CI 0.59–1) for patients without and with MICA mismatches (P=0.5). Multivariate models are shown in the table.

Conclusion: MICA mismatches independently increased the incidence of grade II–IV aGVHD.

Multivariate Models for grade II-IV acute GVHD and relapse-free survival (RFS)

Variable Incidence Univariate P value Multivariate P, HR and 95% CI Grade II-IV aGVHD Fludarabine-based regimen(yes vs no) 39% vs 72% P=0.0009 0.02; HR 0.51 (0.29–0.9) DPB1 mismatches (0/1 vs 2) 38% vs 52% P=0.06 0.03; HR 0.59 (0.37–0.94) Ablative conditioning (no vs yes) 31% vs 48% P=0.001 0.05; HR 0.65 (0.43–0.99) MICA mismatches (yes vs no) 80% vs 38% P=0.0002 0.002; HR 2.33 (1.37–3.98) RFS Rate at 52 weeks 95%CI Univariate P Multivariate P, HR and 95% CI DPB1 (0 vs 1 vs 2) 0.54(0.42, 0.68) P=0.09 0.03; HR 1.65 (1.051–2.6) 0.55(0.45, 0.67) 0.7(0.58, 0.84) CR at HSCT (yes vs no) 0.78(0.69, 0.87) P&lt;0.0001 &lt;0.0001; HR 0.308 (0.18–0.52) 0.44(0.36, 0.55) (P and HR for aGVHD-free survival) HR: hazard ratio; CI: confidence interval