KIR-ligand incompatibility in the graft-versus-host direction improves outcomes after umbilical cord blood transplantation for acute leukemia

R Willemze, C A Rodrigues, M Labopin, G Sanz, G Michel, G Socié, B Rio, A Sirvent, M Renaud, L Madero, M Mohty, C Ferra, F Garnier, P Loiseau, J Garcia, L Lecchi, G Kögler, Y Beguin, C Navarrete, T Devos, I Ionescu, K Boudjedir, A-L Herr, E Gluckman, V Rocha, Eurocord-Netcord and Acute Leukaemia Working Party of the EBMT, R Willemze, C A Rodrigues, M Labopin, G Sanz, G Michel, G Socié, B Rio, A Sirvent, M Renaud, L Madero, M Mohty, C Ferra, F Garnier, P Loiseau, J Garcia, L Lecchi, G Kögler, Y Beguin, C Navarrete, T Devos, I Ionescu, K Boudjedir, A-L Herr, E Gluckman, V Rocha, Eurocord-Netcord and Acute Leukaemia Working Party of the EBMT

Abstract

Donor killer cell immunoglobulin-like receptor (KIR)-ligand incompatibility is associated with decreased relapse incidence (RI) and improved leukemia-free survival (LFS) after haploidentical and HLA-mismatched unrelated hematopoietic stem cell transplantation. We assessed outcomes of 218 patients with acute myeloid leukemia (AML n=94) or acute lymphoblastic leukemia (n=124) in complete remission (CR) who had received a single-unit unrelated cord blood transplant (UCBT) from a KIR-ligand-compatible or -incompatible donor. Grafts were HLA-A, -B or -DRB1 matched (n=21) or mismatched (n=197). Patients and donors were categorized according to their degree of KIR-ligand compatibility in the graft-versus-host direction by determining whether or not they expressed HLA-C group 1 or 2, HLA-Bw4 or HLA-A3/-A11. Both HLA-C/-B KIR-ligand- and HLA-A-A3/-A11 KIR-ligand-incompatible UCBT showed a trend to improved LFS (P=0.09 and P=0.13, respectively). Sixty-nine donor-patient pairs were HLA-A, -B or -C KIR-ligand incompatible and 149 compatible. KIR-ligand-incompatible UCBT showed improved LFS (hazards ratio=2.05, P=0.0016) and overall survival (OS) (hazards ratio=2.0, P=0.004) and decreased RI (hazards ratio=0.53, P=0.05). These results were more evident for AML transplant recipients (2-year LFS and RI with or without KIR-ligand incompatibility 73 versus 38% (P=0.012), and 5 versus 36% (P=0.005), respectively). UCBT for acute leukemia in CR from KIR-ligand-incompatible donors is associated with decreased RI and improved LFS and OS.

Figures

Figure 1
Figure 1
(a) Estimated leukemia-free survival in patients with Kir-ligand-compatible (_______) (n=149) or -incompatible (- - - - - - -) donors (n=69), after UCBT for acute leukemia in CR. (b) Estimated overall survival in patients with Kir-ligand-compatible (_______) (n=149) or -incompatible (- - - - - - -) donors (n=69), after UCBT for acute leukemia in CR. (c) Cumulative incidence of relapse in patients with Kir-ligand-compatible (______) (n=149) or -incompatible (- - - - - - - -) donors (n=69), after UCBT for acute leukemia in CR. CR, complete remission; UCBT, unrelated cord blood transplant.
Figure 2
Figure 2
(a) Estimated leukemia-free survival in AML patients in CR with Kir-ligand-compatible (_______) (n=68) or -incompatible (- - - - - - -) donors (n=26), after UCBT. (b) Estimated leukemia-free survival in ALL patients in CR with Kir-ligand-compatible (_______) (n=81) or -incompatible (- - - - - - -) donors (n=43), after UCBT. AML, acute myeloid leukemia; CR, complete remission; UCBT, unrelated cord blood transplant.

References

    1. Falkenburg JHF, Marijt WAF, Heemskerk MH, Willemze R. Minor histocompatibility antigens as target of graft-versus-leukemia reactions. Curr Opin Hematol. 2002;9:497–502. doi: 10.1097/00062752-200211000-00005.
    1. Kolb HJ, Schattenberg A, Goldman JM. Graft-versus-leukemia effect of donor lymphocyte transfusions in marrow grafted patients. Blood. 1995;86:2041–2050.
    1. Farag SS, Fehninger TA, Ruggeri L, Velardi A, Caligiuri MA. Natural killer cell receptors: new biology and insights into the graft-versus-leukemia effect. Blood. 2002;100:1935–1947. doi: 10.1182/blood-2002-02-0350.
    1. Moretta L, Moretta A. Killer immunoglobulin-like receptors. Curr Opin Immunol. 2004;16:626–633. doi: 10.1016/j.coi.2004.07.010.
    1. Parham P. MHC class I molecules and KIRs in human history, health and survival. Nat Rev Immunol. 2005;5:201–214. doi: 10.1038/nri1570.
    1. Hansasuta P, Dong T, Thananchai H, Weekes M, Willberg C, Aldemir H. Recognition of HLA-A3 and HLA-A11 by KIR3DL2 is peptide-specific. Eur J Immunol. 2004;34:1673–1679. doi: 10.1002/eji.200425089.
    1. Ruggeri L, Capanni M, Casucci M, Volpi I, Tosti A, Perruccio K. Role of natural killer cell alloreactivity in HLA-mismatched hematopoietic stem cell transplantation. Blood. 1999;94:333–339.
    1. Ruggeri L, Capanni M, Urbani E, Perruccio K, Shlomchik WD, Tosti A. Effectiveness of donor natural killer alloreactivity in mismatched haematopoietic transplants. Science. 2002;295:2097–2100. doi: 10.1126/science.1068440.
    1. Ruggeri L, Mancusi A, Capanni M, Urbani E, Carotti A, Aloisi T. Donor natural killer cell allorecognition of missing self in haploidentical hematopoieitc transplantation for acute myeloid leukemia: challenging its predictive value. Blood. 2007;110:433–440. doi: 10.1182/blood-2006-07-038687.
    1. Giebel S, Locatelli F, Lamparelli T, Velardi A, Davies S, Frumento G. Survival advantage with KIR ligand incompatibility in hematopoietic stem cell transplantation from unrelated donors. Blood. 2003;102:814–819. doi: 10.1182/blood-2003-01-0091.
    1. Beelen DW, Ottinger HD, Ferencik S, Elmaagacli AH, Peceny R, Trenschel R. Genotypic inhibitory killer immunoglobulin-like receptor ligand incompatibility enhances the long-term antileukemic effect of unmodified allogeneic hematopoietic stem cell transplantation in patients with myeloid leukemias. Blood. 2005;105:2594–2600. doi: 10.1182/blood-2004-04-1441.
    1. Hsu K, Keever-Taylor CA, Wilton A, Pinto C, Heller G, Arkun K. 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. doi: 10.1182/blood-2004-12-4825.
    1. Davies SM, Ruggieri L, DeFor T, Wagner JE, Weisdorf DJ, Miller JC. Evaluation of KIR ligand incompatibility in mismatched unrelated donor hematopoietic transplants. Blood. 2002;100:3825–3827. doi: 10.1182/blood-2002-04-1197.
    1. Farag SS, Bacigalupo A, Eapen M, Hurley C, Dupont B, Caligiuri MA. The effect of KIR ligand incompatibility on the outcome of unrelated donor transplantation: a report from the center for international blood and bone marrow transplant research, the European blood and bone marrow transplant registry, and the Dutch registry. Biol Blood Marrow Transplant. 2006;12:876–884. doi: 10.1016/j.bbmt.2006.05.007.
    1. Bornhauser M, Schwerdtfeger R, Marin 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. doi: 10.1182/blood-2003-11-3893.
    1. Cook MA, Milligan DW, Fegan CD, Darbyshire PJ, Mahendra P, Craddock CF. 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. doi: 10.1182/blood-2003-02-0438.
    1. Sun JY, Dagis A, Gaidulis L, Miller MM, Rodriquez R, Parker P. Detrimental effect of natural killer cell alloreactivity in T-replete hematopoietic stem cell transplantation for leukaemia patients. Biol Blood Marrow Transplant. 2007;13:197–205. doi: 10.1016/j.bbmt.2006.09.009.
    1. Gluckman E, Rocha V. History of the clinical use of umbilical cord blood hematopoietic cells. Cytotherapy. 2005;7:219–227. doi: 10.1080/14653240510027136.
    1. Rocha V, Labopin M, Sanz G, Arcese W, Schwerdtfeger R, Bosi A. Transplants of umbilical-cord blood or bone marrow from unrelated donors in adults with acute leukemia. N Engl J Med. 2004;351:2276–2285. doi: 10.1056/NEJMoa041469.
    1. Gluckman E, Rocha V. Donor selection for unrelated cord blood transplants. Curr Opin Immunol. 2006;18:565–570. doi: 10.1016/j.coi.2006.07.014.
    1. Eapen M, Rubinstein P, Zhang MJ, Stevens C, Kurtzberg J, Scaradavou A. Outcomes of transplantation of unrelated donor umbilical cord blood and bone marrow in children with acute leukaemia: a comparison study. The Lancet. 2007;369:1947–1954. doi: 10.1016/S0140-6736(07)60915-5.
    1. Ruggeri L, Capanni M, Mancusi A, Urbani E, Perroccio K, Burcgielli E. Alloreactive natural killer cells in mismatched hematopoietic stem cell transplantation. Blood Cells Mol Dis. 2004;33:216–221. doi: 10.1016/j.bcmd.2004.08.005.
    1. Przepiorka D, Weisdorf D, Martin P, Klingemann HG, Beatty P, Hows J. 1994 Consensus Conference on Acute GvHD Grading. Bone Marrow Transplant. 1995;15:825–828.
    1. Shulman HM, Sullivan KM, Weiden PL, McDonald GB, Striker GE, Sale GE. Chronic graft-versus-host syndrome in man. A long-term clinicopathologic study of 20 Seattle patients. Am J Med. 1980;69:204–217. doi: 10.1016/0002-9343(80)90380-0.
    1. Gooley TA, Leisenring W, Crowley J, Storer BE. Estimation of failure probabilities in the presence of competing risks: new representations of old estimators. Stat Med. 1999;18:695–706. doi: 10.1002/(SICI)1097-0258(19990330)18:6<695::AID-SIM60>;2-O.
    1. Gray RJ. A class of K-sample tests for comparing the cumulative incidence of a competing risk. Ann Stat. 1988;116:1141–1154. doi: 10.1214/aos/1176350951.
    1. Fine JP, Gray RJ. A proportional hazards model for subdistribution of a competing risk. J Am Stat Assoc. 1999;94:496–509. doi: 10.1080/01621459.1999.10474144.
    1. Gagne K, Brizard G, Gueglio B, Milpied N, Herry P, Bonneville F. Relevance of KIR gene polymorphisms in bone marrow transplantation outcome. Hum Immunol. 2002;63:271–280. doi: 10.1016/S0198-8859(02)00373-7.
    1. Leung W, Iyengar R, Triplett B, Turner V, Behm FG, Holladay MS. Comparison of killer Ig-like receptor genotyping and phenotyping for selection of allogeneic blood stem cell donors. J Immunol. 2005;174:6540–6545. doi: 10.4049/jimmunol.174.10.6540.
    1. Leung W, Iyengar R, Turner V, Lang P, Bader P, Conn P. Determinants of antileukemia effects of allogeneic NK cells. J Immunol. 2004;172:644–650. doi: 10.4049/jimmunol.172.1.644.
    1. Lowe EJ, Turner V, Handgretinger R, Horwitz EM, Benaim E, Hale GA. 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. doi: 10.1046/j.1365-2141.2003.04604.x.
    1. Kloosterboer FM, van Luxemburg-Heijs SA, Willemze R, Falkenburg JH. Similar potential to become activated and proliferate but differential kinetics and profiles of cytokine production of umbilical cord blood T cells and adult blood naive and memory T cells. Hum Immunol. 2006;67:874–883. doi: 10.1016/j.humimm.2006.02.040.
    1. Szabolcs P, Niedzwiecki D. Immune reconstitution after unrelated cord blood transplantation. Cytotherapy. 2007;9:111–122. doi: 10.1080/14653240701231014.
    1. Cooley S, McCullar V, Wangen R, Bergemann TL, Spellman S, Weisdorf DJ. KIR reconstitution is altered by T cells in the graft and correlates with clinical outcomes after unrelated donor transplantation. Blood. 2005;106:4370–4376. doi: 10.1182/blood-2005-04-1644.
    1. Miller JS, Cooley S, Parham P, Farag SS, Verneris MR, McQueen KL. 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. doi: 10.1182/blood-2007-01-065383.
    1. Hsu K, Gooley T, Malkki M, Pinto-Agnello C, Dupont B, Bignon JD. KIR ligands and prediction of relapse after unrelated donor hematopoietic cell transplantation for hematologic malignancy. Biol Blood Marrow Transplant. 2006;12:828–836. doi: 10.1016/j.bbmt.2006.04.008.
    1. Kröger N, Binder T, Zabelina T, Wolschke C, Schieder H, Renges H. Low number of donor activating killer immunoglobulin-like receptors (KIR) genes but not KIR-ligand mismatch prevents relapse and improves disease-free survival in leukemia patients after in vivo T-cell depleted unrelated stem cell transplantation. Transplantation. 2006;82:1024–1030. doi: 10.1097/01.tp.0000235859.24513.43.
    1. Yabe T, Matsuo K, Hirayasu K, Kashiwase K, Kawamura-Ishii S, Tanaka H. Japan Marrow Donor Program. Donor killer immunoglobulin-like receptor (KIR) genotype-patient cognate KIR ligand combination and antithymocyte globulin preadministration are critical factors in outcome of HLA-C-KIR ligand-mismatched T cell-replete unrelated bone marrow transplantation. Biol Blood Marrow Transplant. 2008;14:75–87. doi: 10.1016/j.bbmt.2007.09.012.
    1. Elmaagacli AH, Ottinger H, Koldehoff M, Peceny R, Steckel NK, Trenschel R. Reduced risk for molecular disease in patients with chronic myeloid leukemia after transplantation from a KIR-mismatched donor. Transplantation. 2005;79:1741–1747. doi: 10.1097/01.TP.0000164500.16052.3C.
    1. Kröger N, Shaw B, Iacobelli S, Zabelina T, Peggs K, Shimoni A. Comparison between antithymocyte globulin and alemtuzumab and the possible impact of KIR-ligand mismatch after dose-reduced conditioning and unrelated stem cell transplantation in patients with multiple myeloma. Br J Haematol. 2005;129:631–643. doi: 10.1111/j.1365-2141.2005.05513.x.
    1. Dawson MA, Spencer A. Successful use of haploidentical stem-cell transplantation with KIR mismatch as initial therapy for poor-risk myelodysplastic syndrome. J Clin Oncol. 2005;23:4473–4474. doi: 10.1200/JCO.2005.01.3581.
    1. Anfossi N, André P, Guia S, Falk CS, Roetynck S, Stewart CA. Human NK cell education by inhibitory receptors for MHC class I. Immunity. 2006;2:331–342. doi: 10.1016/j.immuni.2006.06.013.

Source: PubMed

Спонсоры и соавторы

Заболевания

Медикаментозные вмешательства

Подписаться