Abstract
This retrospective analysis studied the impact of natural killer (NK) alloreactivity based on the missing ligand model, for a cohort of recipients undergoing haemopoietic stem cell transplant without T-cell depletion from HLA full-matched sibling donors. All patients received a uniform myeloablative conditioning regimen and prophylaxis for GVHD. A total of 151 patients were studied, including 62 patients with AML or myelodysplastic syndrome, 42 patients with ALL and 47 patients with CML. We found that 81% of patients had at least one missing KIR-ligand (KIR-L), and HLA-C1 allogroup homozygosity is present in 70% of patients. From multivariate analysis, we observed that the only consistently significant factor that was associated with superior survival was disease stage. Missing KIR-L, whether considering HLA-Bw and HLA-C alleles, without or with HLA-A ligands or narrowing to only HLA-C alleles alone to classify the number of missing KIR-L, did not have any impact on OS or relapse-free survival. This negative finding implies that as the KIR-L composition of recipient is not important in this matched non-T-depleted setting, further immunotherapeutic measures involving adoptive NK cell infusions have to be explored to exploit the benefit of NK alloreactivity for such transplants.
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References
Ruggeri L, Capanni M, Urbani E, Perruccio K, Shlomchik WD, Tosti A et al. Effectiveness of donor natural killer cell alloreactivity in mismatched hematopoietic transplants. Science 2002; 295: 2097–2100.
Aversa F, Terenzi A, Tabilio A, Falzetti F, Carotti A, Ballanti S et al. Full haplotype-mismatched hematopoietic stem-cell transplantation: a phase II study in patients with acute leukemia at high risk of relapse. J Clin Oncol 2005; 23: 3447–3454.
Leung W, Iyengar R, Turner V, Lang P, Bader P, Conn P et al. Determinants of antileukemia effects of allogeneic NK cells. J Immunol 2004; 172: 644–650.
Ruggeri L, Mancusi A, Capanni M, Urbani E, Carotti A, Aloisi T et al. Donor natural killer cell allorecognition of missing self in haploidentical hematopoietic transplantation for acute myeloid leukemia: challenging its predictive value. Blood 2007; 110: 433–440.
Willemze R, Rodrigues CA, Labopin M, Sanz G, Michel G, Socie G et al. KIR-ligand incompatibility in the graft-versus-host direction improves outcomes after umbilical cord blood transplantation for acute leukemia. Leukemia 2009; 23: 492–500.
Giebel S, Locatelli F, Lamparelli T, Velardi A, Davies S, Frumento G et al. Survival advantage with KIR ligand incompatibility in hematopoietic stem cell transplantation from unrelated donors. Blood 2003; 102: 814–819.
Bornhauser M, Schwerdtfeger R, Martin H, Frank KH, Theuser C, Ehninger G . Role of KIR ligand incompatibility in hematopoietic stem cell transplantation using unrelated donors. Blood 2004; 103: 2860–2861.
Davies SM, Ruggieri L, DeFor T, Wagner JE, Weisdorf DJ, Miller JS et al. Evaluation of KIR ligand incompatibility in mismatched unrelated donor hematopoietic transplants. Killer immunoglobulin-like receptor. Blood 2002; 100: 3825–3827.
Hsu KC, Keever-Taylor CA, Wilton A, Pinto C, Heller G, Arkun K et al. Improved outcome in HLA-identical sibling hematopoietic stem-cell transplantation for acute myelogenous leukemia predicted by KIR and HLA genotypes. Blood 2005; 105: 4878–4884.
Leung W, Handgretinger R, Iyengar R, Turner V, Holladay MS, Hale GA . Inhibitory KIR-HLA receptor-ligand mismatch in autologous haematopoietic stem cell transplantation for solid tumour and lymphoma. Br J Cancer 2007; 97: 539–542.
Stern M, Paulussen M, Rischewski J, Tichelli A, Gratwohl A . Missing ligand model in autologous stem cell transplantation. Br J Cancer 2008; 98: 852–853.
Sobecks RM, Ball EJ, Maciejewski JP, Rybicki LA, Brown S, Kalaycio M et al. Survival of AML patients receiving HLA-matched sibling donor allogeneic bone marrow transplantation correlates with HLA-Cw ligand groups for killer immunoglobulin-like receptors. Bone Marrow Transplant 2007; 39: 417–424.
Clausen J, Wolf D, Petzer AL, Gunsilius E, Schumacher P, Kircher B et al. Impact of natural killer cell dose and donor killer-cell immunoglobulin-like receptor (KIR) genotype on outcome following human leucocyte antigen-identical haematopoietic stem cell transplantation. Clin Exp Immunol 2007; 148: 520–528.
Hsu KC, Gooley T, Malkki M, Pinto-Agnello C, Dupont B, Bignon JD et al. KIR ligands and prediction of relapse after unrelated donor hematopoietic cell transplantation for hematologic malignancy. Biol Blood Marrow Transplant 2006; 12: 828–836.
Miller JS, Cooley S, Parham P, Farag SS, Verneris MR, McQueen KL et al. Missing KIR ligands are associated with less relapse and increased graft-versus-host disease (GVHD) following unrelated donor allogeneic HCT. Blood 2007; 109: 5058–5061.
Cook MA, Milligan DW, Fegan CD, Darbyshire PJ, Mahendra P, Craddock CF et al. The impact of donor KIR and patient HLA-C genotypes on outcome following HLA-identical sibling hematopoietic stem cell transplantation for myeloid leukemia. Blood 2004; 103: 1521–1526.
Ruggeri L, Capanni M, Mancusi A, Urbani E, Perruccio K, Burchielli E et al. Alloreactive natural killer cells in mismatched hematopoietic stem cell transplantation. Blood Cells Mol Dis 2004; 33: 216–221.
Stern M, Ruggeri L, Capanni M, Mancusi A, Velardi A . Human leukocyte antigens A23, A24, and A32 but not A25 are ligands for KIR3DL1. Blood 2008; 112: 708–710.
Beelen DW, Quabeck K, Kaiser B, Wiefelsputz J, Scheulen ME, Graeven U et al. Six weeks of continuous intravenous cyclosporine and short-course methotrexate as prophylaxis for acute graft-versus-host disease after allogeneic bone marrow transplantation. Transplantation 1990; 50: 421–427.
Cooley S, McCullar V, Wangen R, Bergemann TL, Spellman S, Weisdorf DJ et al. KIR reconstitution is altered by T cells in the graft and correlates with clinical outcomes after unrelated donor transplantation. Blood 2005; 106: 4370–4376.
Lowe EJ, Turner V, Handgretinger R, Horwitz EM, Benaim E, Hale GA et al. T-cell alloreactivity dominates natural killer cell alloreactivity in minimally T-cell-depleted HLA-non-identical paediatric bone marrow transplantation. Br J Haematol 2003; 123: 323–326.
Chklovskaia E, Nowbakht P, Nissen C, Gratwohl A, Bargetzi M, Wodnar-Filipowicz A . Reconstitution of dendritic and natural killer-cell subsets after allogeneic stem cell transplantation: effects of endogenous flt3 ligand. Blood 2004; 103: 3860–3868.
Yu J, Venstrom JM, Liu XR, Pring J, Hasan RS, O’Reilly RJ et al. Breaking tolerance to self, circulating natural killer cells expressing inhibitory KIR for non-self HLA exhibit effector function after T cell-depleted allogeneic hematopoietic cell transplantation. Blood 2009; 113: 3875–3884.
Alici E, Sutlu T, Bjorkstrand B, Gilljam M, Stellan B, Nahi H et al. Autologous antitumor activity by NK cells expanded from myeloma patients using GMP-compliant components. Blood 2008; 111: 3155–3162.
Berg M, Lundqvist A, McCoy Jr P, Samsel L, Fan Y, Tawab A et al. Clinical-grade ex vivo-expanded human natural killer cells up-regulate activating receptors and death receptor ligands and have enhanced cytolytic activity against tumor cells. Cytotherapy 2009; 11: 341–355.
Acknowledgements
We thank Ms Joan Seet (HLA laboratory), Dr Perumal Premalatha and Ms Zhang Xuehui (Haematology Research) for their assistance in the provision of data. We also express our gratitude to all nursing and paramedical staff in the Department of Haematology for their contribution towards the transplant program. This project is supported by a grant from the SingHealth Research Foundation SRF#113/05.
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Linn, Y., Phang, C., Lim, T. et al. Effect of missing killer-immunoglobulin-like receptor ligand in recipients undergoing HLA full matched, non-T-depleted sibling donor transplantation: a single institution experience of 151 Asian patients. Bone Marrow Transplant 45, 1031–1037 (2010). https://doi.org/10.1038/bmt.2009.303
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DOI: https://doi.org/10.1038/bmt.2009.303
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