Authors:
D. Fuerst (Ulm, DE)
C. Neuchel (Ulm, DE)
D. Niederwieser (Leipzig, DE)
D. Bunjes (Ulm, DE)
M. Gramatzki (Kiel, DE)
E. Wagner (Mainz, DE)
G. Wulf (Göttingen, DE)
B. Glass (Hamburg, DE)
M. Pfreundschuh (Homburg, DE)
H. Einsele (Würzburg, DE)
R. Arnold (Berlin, DE)
G. Stuhler (Wiesbaden, DE)
K. Schaefer-Eckart (Nuremberg, DE)
S. Freitag (Rostock, DE)
J. Casper (Oldenburg, DE)
M. Kaufmann (Stuttgart, DE)
M. Wattad (Essen-Werden, DE)
B. Hertenstein (Bremen, DE)
S. Klein (Mannheim, DE)
M. Ringhoffer (Karlsruhe, DE)
D. Mytilineos (Ulm, DE)
C. Tsamadou (Ulm, DE)
C. Mueller (Ulm, DE)
H. Schrezenmeier (Ulm, DE)
J. Mytilineos (Ulm, DE)
MICA (MHC class I polypeptide-related sequence A) is a non-classical HLA-molecule activating NK-cells, γδ-T-cells and NKT-cells via the NKG2D receptor. MICA incompatibilities have been associated with an increased GvHD incidence and the MICA-129 (met/val) dimorphism has been shown to influence NKG2D signaling in unrelated hematopoietic stem cell transplantation (uHSCT). We analyzed the effect of MICA-Allele and MICA-129 matching on the outcome of uHSCT. We sequenced 3262 patients and their respective donors. All patients and donors were high-resolution HLA-typed and matched for 10/10 (n=2107), 9/10 (n=946) or 8/10 (n=209) HLA-alleles. Within each HLA match group, cases matched and mismatched for MICA-Alleles/MICA-129 were analyzed for the endpoints of overall survival (OS), disease free survival (DFS), non-relapse mortality (NRM), relapse-incidence (RI) and GvHD. Mismatches at the MICA locus as well as MICA-129 increased with the number of HLA mismatches (MICA mismatched 10/10: 7.8%, n=164; 9/10: 23.2%, n=219; 8/10: 39.2%, n=82; MICA-129 mismatched: 10/10 3.3%, n=69; 9/10: 11.5%, n=109; 8/10: 16.3%, n=34). Adverse OS was observed in the 10/10 and 8/10 match group if MICA-129 was mismatched (10/10: HR 1.64, CI 1.18-2.30, p=0.003, 8/10: HR 1.72, CI 1.06-2.80, p=0.027). MICA-129 mismatches correlated with a significantly worse outcome for DFS in the 10/10 and 8/10 HLA match group (10/10 HR: 1.46, CI 1.07-1.98, p=0.016, 8/10: HR 1.76, CI 1.11-2.79, p=0.016). Higher rates of aGvHD were seen in MICA-129 mismatched cases. Our results in this extended cohort indicate that MICA-129 matching is relevant in uHSCT. Prospective typing of patients and donors in unrelated donor search may identify mismatches for MICA-129 and compatible donor selection may improve outcome for this small but high-risk subgroup.