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Haploidentical hematopoietic transplantation from KIR ligand-mismatched donors with activating KIRs reduces non-relapse mortality

Antonella Mancusi, Loredana Ruggeri, Elena Urbani, Antonio Pierini, Maria Speranza Massei, Alessandra Carotti, Adelmo Terenzi, Franca Falzetti, Antonella Tosti, Fabiana Topini, Silvia Bozza, Luigina Romani, Rita Tognellini, Martin Stern, Franco Aversa, Massimo F. Martelli and Andrea Velardi

Key points

  • Haploidentical transplantation from KIR ligand-mismatched donors with activating KIRs reduces non-relapse mortality and improves survival.

  • Activating KIR genetics should be considered when selecting donors for T-cell depleted haploidentical hematopoietic transplantation.

Abstract

As activating Killer Cell Immunoglobulin-like Receptors (KIRs) are heterogeneously expressed in the population, we investigated the role of donor activating KIRs in haploidentical hematopoietic transplants for acute leukemia. Transplants were grouped according to presence versus absence of KIR ligand mismatches in the graft-versus-host direction (i.e., of donor-versus-recipient Natural Killer (NK) cell alloreactivity). In the absence of donor-versus-recipient NK cell alloreactivity, donor activating KIRs had no effects on outcomes. In the 69 transplant pairs with donor-versus-recipient NK cell alloreactivity, multivariate analyses showed transplantation from donors with KIR2DS1 and/or KIR3DS1 was associated with reduced risk of non-relapse mortality, largely infection-related (KIR2DS1 present versus absent: HR: 0.25, P=.01; KIR3DS1 present versus absent: HR: 0.18, P=.006) and better event-free survival (KIR2DS1 present versus absent: HR: 0.31, P=.011; KIR3DS1 present versus absent: HR: 0.30, P=.008). Transplantation from donors with KIR2DS1 and/or KIR3DS1 was also associated with a 50% reduction in infection rate (P=.003). In vitro analyses showed KIR2DS1 binding to its HLA-C2 ligand up-regulated inflammatory cytokine production by alloreactive NK cells in response to infectious challenges (Aspergillus fumigatus). As ~40% of donors able to exert donor-versus-recipient NK cell alloreactivity carry KIR2DS1 and/or KIR3DS1, searching for them may become a feasible, additional criterion in donor selection.

  • Submitted September 8, 2014.
  • Accepted March 2, 2015.