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Matching for the MICA-129 polymorphism is beneficial in unrelated hematopoietic stem cell transplantation

Daniel Fuerst, Christine Neuchel, Dietger Niederwieser, Donald Bunjes, Martin Gramatzki, Eva Wagner, Gerald Wulf, Bertram Glass, Michael Pfreundschuh, Hermann Einsele, Renate Arnold, Gernot Stuhler, Kerstin Schaefer-Eckart, Sebastian Freitag, Jochen Casper, Martin Kaufmann, Mohammed Wattad, Bernd Hertenstein, Stefan Klein, Mark Ringhoffer, Daphne Mytilineos, Chrysanthi Tsamadou, Carlheinz Mueller, Hubert Schrezenmeier and Joannis Mytilineos

Key points

  • MICA-129 matching improves survival in unrelated hematopoietic stem cell transplantation.

  • MICA-129 mismatches were observed in 6.7 % of all transplant patients.

Abstract

MICA (MHC class I polypeptide-related sequence A) is a highly polymorphic ligand of the activating NKG2D receptor on NK-cells, γδ-T-cells and NKT-cells. 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 investigated the effect of MICA-matching on survival after uHSCT. We sequenced 2172 patients and their respective donors for MICA. All patients and donors were high-resolution HLA-typed and matched for 10/10 (n=1379), 9/10 (n=636) or 8/10 (n=157) HLA-alleles. Within each HLA match group, cases matched and mismatched for MICA and MICA-129 were analyzed for the endpoints 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: 9.2%, n=127; 9/10: 22.3%, n=142; 8/10: 38.2%, n=60; MICA-129 mismatched: 10/10 3.9%, n=54; 9/10: 10.2%, n=65; 8/10: 17.2%, n=27). Adverse OS was observed in the 10/10 match group if MICA-129 was mismatched (10/10: HR 1.77, CI 1.22-2.57, p=0.003). MICA-129 mismatches correlated with a significantly worse outcome for DFS in the 10/10 HLA match group (HR: 1.77, CI 1.26-2.50, p=0.001). Higher rates of aGvHD were seen in MICA-129 mismatched cases. Our results 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.

  • Submitted May 13, 2016.
  • Accepted October 22, 2016.