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Altered effect of killer immunoglobulin-like receptor–ligand mismatch by graft versus host disease prophylaxis in cord blood transplantation

Bone Marrow Transplantation volume 56, pages 3059–3067 (2021)Cite this article

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Abstract

The role of killer immunoglobulin-like receptor–ligand mismatch (KIR–ligand mismatch) between donors and recipients undergoing cord blood transplantation (CBT) is controversial. If each immunosuppressant differently affects natural killer (NK) cell function, the effect of KIR–ligand mismatch may be altered depending on the type of graft versus host disease (GVHD) prophylaxis. To verify this hypothesis, the difference in the effect of KIR–ligand mismatch was retrospectively assessed between patients who received CBT for acute leukemia, myelodysplastic syndrome, or chronic myeloid leukemia, as well as GVHD prophylaxis comprising tacrolimus plus methotrexate (MTX) or mycophenolate mofetil (MMF). In the MMF group (n = 1363), KIR–ligand mismatch augmented the incidence of non-relapse mortality (NRM; hazard ratio [HR], 1.40; P = 0.008), which worsened overall survival (OS; HR, 1.30, P = 0.0077). In the analysis of each KIR–ligand mismatch type, HLA-C2 mismatch had a favorable effect on relapse incidence (HR, 0.56; P = 0.0043) and OS (HR, 0.72; P = 0.037) only in the MTX group. In the MMF group, HLA-A3/A11 mismatch worsened NRM (HR, 1.93; P < 0.001) and OS (HR, 1.48; P = 0.014). These results imply that the effects of KIR–ligand mismatch differ with the type of GVHD prophylaxis and that assessing the KIR–ligand mismatch status is important for CBT.

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Fig. 1: Effect of KIR–ligand mismatch on CBT outcomes in patients who received tacrolimus plus MTX or tacrolimus plus MMF as GVHD prophylaxis.
Fig. 2: Multivariate analysis of the effect of a KIR–ligand mismatch on the incidence of relapse, aGVHD III–IV, cGVHD, NRM, and OS in patients undergoing CBT who received tacrolimus plus MTX or tacrolimus plus MMF for GVHD prophylaxis.
Fig. 3: Multivariate analysis of the effect of HLA-C2, -Bw4, and -A3/A11 mismatch on relapse and non-relapse mortality in patients undergoing CBT who received tacrolimus plus MTX or tacrolimus plus MMF as GVHD prophylaxis.
Fig. 4: Effect of HLA-C2, -Bw4, and -A3/A11 mismatch on overall survival following CBT in patients who received tacrolimus plus MTX or tacrolimus plus MMF as GVHD prophylaxis.
Fig. 5: Multivariate analysis of the effect of HLA-C2, -Bw4, and -A3/A11 mismatch on overall survival following CBT in patients who received tacrolimus plus MTX or tacrolimus plus MMF as GVHD prophylaxis.
Fig. 6: Impact of HLA-C2 and -A3/A11 mismatch on overall survival in patients with acute myeloid leukemia receiving CBT and tacrolimus plus MTX or tacrolimus plus MMF as GVHD prophylaxis.

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References

  1. Leung W. Use of NK cell activity in cure by transplant. Br J Haematol. 2011;155:14–29.

    Article  CAS  Google Scholar 

  2. Ruggeri L, Capanni M, Casucci M, Volpi I, Tosti A, Perruccio K, et al. Role of natural killer cell alloreactivity in HLA-mismatched hematopoietic stem cell transplantation. Blood. 1999;94:333–9.

    Article  CAS  Google Scholar 

  3. 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;102:814–9.

    Article  CAS  Google Scholar 

  4. Morishima Y, Yabe T, Matsuo K, Kashiwase K, Inoko H, Saji H, et al. Effects of HLA allele and killer immunoglobulin-like receptor ligand matching on clinical outcome in leukemia patients undergoing transplantation with T-cell-replete marrow from an unrelated donor. Biol Blood Marrow Transplant. 2007;13:315–28.

    Article  CAS  Google Scholar 

  5. Yabe T, Matsuo K, Hirayasu K, Kashiwase K, Kawamura-Ishii S, Tanaka H, et al. 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 transplantatio. Biol Blood Marrow Transplant. 2008;14:75–87.

    Article  Google Scholar 

  6. Willemze R, Rodrigues CA, Labopin M, Sanz G, Michel G, Socié 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.

    Article  CAS  Google Scholar 

  7. Brunstein CG, Wagner JE, Weisdorf DJ, Cooley S, Noreen H, Barker JN, et al. Negative effect of KIR alloreactivity in recipients of umbilical cord blood transplant depends on transplantation conditioning intensity. Blood. 2009;113:5628–34.

    Article  CAS  Google Scholar 

  8. Tanaka J, Morishima Y, Takahashi Y, Yabe T, Oba K, Takahashi S, et al. Effects of KIR ligand incompatibility on clinical outcomes of umbilical cord blood transplantation without ATG for acute leukemia in complete remission. Blood Cancer J. 2013;3:e164.

    Article  CAS  Google Scholar 

  9. Rocha V, Ruggeri A, Spellman S, Wang T, Sobecks R, Locatelli F, et al. Killer cell immunoglobulin-like receptor-ligand matching and outcomes after unrelated cord blood transplantation in acute myeloid leukemia. Biol Blood Marrow Transplant. 2016;22:1284–9.

    Article  CAS  Google Scholar 

  10. Yokoyama H, Kanda J, Kawahara Y, Uchida N, Tanaka M, Takahashi S, et al. Reduced leukemia relapse through cytomegalovirus reactivation in killer cell immunoglobulin-like receptor-ligand-mismatched cord blood transplantation. Bone Marrow Transplant. 2021;56:1352–63.

    Article  CAS  Google Scholar 

  11. Wang H, Grzywacz B, Sukovich D, McCullar V, Cao Q, Lee AB, et al. The unexpected effect of cyclosporin A on CD56+CD16- and CD56+CD16+ natural killer cell subpopulations. Blood. 2007;110:1530–9.

    Article  CAS  Google Scholar 

  12. Ohata K, Espinoza JL, Lu X, Kondo Y, Nakao S. Mycophenolic acid inhibits natural killer cell proliferation and cytotoxic function: a possible disadvantage of including mycophenolate mofetil in the graft-versus-host disease prophylaxis regimen. Biol Blood Marrow Transplant. 2011;17:205–13.

    Article  CAS  Google Scholar 

  13. Atsuta Y, Suzuki R, Yoshimi A, Gondo H, Tanaka J, Hiraoka A, et al. Unification of hematopoietic stem cell transplantation registries in Japan and establishment of the TRUMP System. Int J Hematol. 2007;86:269–74.

    Article  Google Scholar 

  14. Atsuta Y. Introduction of Transplant Registry Unified Management Program 2 (TRUMP2): scripts for TRUMP data analyses, part I (variables other than HLA-related data). Int J Hematol. 2016;103:3–10.

    Article  Google Scholar 

  15. Kanda J. Scripts for TRUMP data analyses. Part II (HLA-related data): statistical analyses specific for hematopoietic stem cell transplantation. Int J Hematol. 2016;103:11–9.

    Article  CAS  Google Scholar 

  16. Bacigalupo A, Ballen K, Rizzo D, Giralt S, Lazarus H, Ho V, et al. Defining the intensity of conditioning regimens: working definitions. Biol Blood Marrow Transplant. 2009;15:1628–33.

    Article  Google Scholar 

  17. Kanda Y. Investigation of the freely available easy-to-use software ‘EZR’ for medical statistics. Bone Marrow Transplant. 2013;48:452–8.

    Article  CAS  Google Scholar 

  18. 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;295:2097–100.

    Article  CAS  Google Scholar 

  19. Farag SS, Bacigalupo A, Eapen M, Hurley C, Dupont B, Caligiuri MA, et al. The effect of KIR ligand incompatibility on the outcome of unrelated donor transplantation: a report from the center for international blood and marrow transplant research, the European blood and marrow transplant registry, and the Dutch registry. Biol Blood Marrow Transplant. 2006;12:876–84.

    Article  CAS  Google Scholar 

  20. Hsu KC, Gooley T, Malkki M, Pinto-Agnello C, Dupont B, Bignon J-D, et al. KIR ligands and prediction of relapse after unrelated donor hematopoietic cell transplantation for hematologic malignancy. Biol Blood Marrow Transplant. 2006;12:828–36.

    Article  CAS  Google Scholar 

  21. 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;100:3825–7.

    Article  CAS  Google Scholar 

  22. Beelen DW, Ottinger HD, Ferencik S, Elmaagacli AH, Peceny R, Trenschel R, et al. 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;105:2594–600.

    Article  CAS  Google Scholar 

  23. Sivula J, Volin L, Porkka K, Vettenranta K, Itälä M, Partanen J, et al. Killer-cell immunoglobulin-like receptor ligand compatibility in the outcome of Finnish unrelated donor hematopoietic stem cell transplantation. Transpl Immunol. 2007;18:62–6.

    Article  CAS  Google Scholar 

  24. Terakura S, Kuwatsuka Y, Yamasaki S, Wake A, Kanda J, Inamoto Y, et al. GvHD prophylaxis after single-unit reduced intensity conditioning cord blood transplantation in adults with acute leukemia. Bone Marrow Transplant. 2017;52:1261–7.

    Article  CAS  Google Scholar 

  25. Terakura S, Wake A, Inamoto Y, Murata M, Sakai R, Yamaguchi T, et al. Exploratory research for optimal GvHD prophylaxis after single unit CBT in adults: short-term methotrexate reduced the incidence of severe GvHD more than mycophenolate mofetil. Bone Marrow Transplant. 2017;52:423–30.

    Article  CAS  Google Scholar 

  26. 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;123:323–6.

    Article  Google Scholar 

  27. 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;106:4370–6.

    Article  CAS  Google Scholar 

  28. Nguyen S, Achour A, Souchet L, Vigouroux S, Chevallier P, Furst S, et al. Clinical impact of NK-cell reconstitution after reduced intensity conditioned unrelated cord blood transplantation in patients with acute myeloid leukemia: analysis of a prospective phase II multicenter trial on behalf of the Société Française de Greffe d. Bone Marrow Transplant. 2017;52:1428–35.

    Article  CAS  Google Scholar 

  29. Dekojová T, Houdová L, Fatka J, Pitule P, Ostašov P, Caputo VS, et al. Dynamic changes of inhibitory killer-immunoglobulin-like receptors on NK cells after allogeneic hematopoietic stem cell transplantation: an initial study. J Clin Med. 2020;9:E3502.

    Article  Google Scholar 

  30. Zhao XY, Yu XX, Xu ZL, Cao XH, Huo MR, Zhao XS, et al. Donor and host coexpressing KIR ligands promote NK education after allogeneic hematopoietic stem cell transplantation. Blood Adv. 2019;3:4312–25.

    Article  Google Scholar 

  31. Gumperz JE, Valiante NM, Parham P, Lanier LL, Tyan D. Heterogeneous phenotypes of expression of the NKB1 natural killer cell class I receptor among individuals of different human histocompatibility leukocyte antigens types appear genetically regulated, but not linked to major histocompatibililty complex haplotype. J Exp Med. 1996;183:1817–27.

    Article  CAS  Google Scholar 

  32. Gardiner CM, Guethlein LA, Shilling HG, Pando M, Carr WH, Rajalingam R, et al. Different NK cell surface phenotypes defined by the DX9 antibody are due to KIR3DL1 gene polymorphism. J Immunol. 2001;166:2992–3001.

    Article  CAS  Google Scholar 

  33. Boudreau JE, Mulrooney TJ, Le Luduec J-B, Barker E, Hsu KC. KIR3DL1 and HLA-B density and binding calibrate NK education and response to HIV. J Immunol. 2016;196:3398–410.

    Article  CAS  Google Scholar 

  34. Boudreau JE, Giglio F, Gooley TA, Stevenson PA, Le Luduec J-B, Shaffer BC, et al. KIR3DL1/HLA-B subtypes govern acute myelogenous leukemia relapse after hematopoietic cell transplantation. J Clin Oncol. 2017;35:2268–78.

    Article  CAS  Google Scholar 

  35. Petersdorf EW, Carrington M, O’hUigin C, Bengtsson M, De Santis D, Dubois V, et al. Role of HLA-B exon 1 in graft-versus-host disease after unrelated haemopoietic cell transplantation: a retrospective cohort study. Lancet Haematol. 2020;7:e50–e60.

    Article  Google Scholar 

  36. Petersdorf EW, Gooley T, Volt F, Kenzey C, Madrigal A, McKallor C, et al. Use of the HLA-B leader to optimize cord-blood transplantation. Haematologica. 2020; https://doi.org/10.3324/haematol.2020.264424.

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Acknowledgements

The authors would like to thank all the physicians and data managers who provided valuable data available from the Japanese Society for Transplantation and Cellular Therapy. The authors would also like to thank the staff at the Japanese Data Center for Hematopoietic Cell Transplantation for their contributions.

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Authors and Affiliations

  1. Department of Hematology and Rheumatology, Tohoku University Graduate School of Medicine, Sendai, Japan

    Hisayuki Yokoyama

  2. Department of Pediatrics, Mie University Graduate School of Medicine, Tsu, Japan

    Masahiro Hirayama

  3. Department of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan

    Yoshiyuki Takahashi

  4. Department of Hematology, Federation of National Public Service Personnel Mutual Aid Associations, Toranomon Hospital, Tokyo, Japan

    Naoyuki Uchida

  5. Department of Hematology, Kanagawa Cancer Center, Yokohama, Japan

    Masatsugu Tanaka

  6. Department of Hematology/Oncology, Tokai University School of Medicine, Isehara, Japan

    Makoto Onizuka

  7. Department of Hematology, Japanese Red Cross Nagoya First Hospital, Nagoya, Japan

    Yukiyasu Ozawa

  8. Hematology Division, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital, Tokyo, Japan

    Daishi Onai

  9. Department of Hematology, National Hospital Organization Sendai Medical Center, Sendai, Japan

    Yuna Katsuoka

  10. Department of Hematology, Federation of National Public Service Personnel Mutual Aid Associations, Toranomon Hospital, Kajigaya, Japan

    Atsushi Wake

  11. Department of Hematology and Oncology, Anjo Kosei Hospital, Anjo, Japan

    Masashi Sawa

  12. Department of Hematology, Nagano Red Cross Hospital, Nagano, Japan

    Hikaru Kobayashi

  13. Department of Hematology, University of Tsukuba Hospital, Tsukuba, Japan

    Yumiko Maruyama

  14. Department of Hematology and Oncology, Konan Kosei Hospital, Konan, Japan

    Kazutaka Ozeki

  15. Preparation Department, Japanese Red Cross Kinki Block Blood Center, Osaka, Japan

    Takafumi Kimura

  16. Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Japan

    Junya Kanda

  17. Hematopoietic Stem Cell Transplantation Division, National Cancer Center Hospital, Tokyo, Japan

    Takahiro Fukuda

  18. Japanese Data Center for Hematopoietic Cell Transplantation, Nagoya, Japan

    Yoshiko Atsuta

  19. Department of Healthcare Administration, Nagoya University Graduate School of Medicine, Nagoya, Japan

    Yoshiko Atsuta

  20. Department of Hematology and Oncology, Nagoya University Graduate School of Medicine, Nagoya, Japan

    Seitaro Terakura

  21. Division of Endocrinology, Diabetes and Metabolism, Hematology, Rheumatology (Second Department of Internal Medicine), Graduate School of Medicine, University of the Ryukyus, Nishihara, Japan

    Satoko Morishima

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  1. Hisayuki Yokoyama
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Contributions

HY, MH, YT, ST, and SM designed the study. NU, MT, MO, YO, DO, YK, AW, MS, HK, YM, and KO collected the data. TK, JK, TF, and YA managed the data. HY, MH, YT, ST, and SM analyzed and interpreted the data. HY wrote the first draft of the manuscript. ST and SM were responsible for the GvHD Working Group and HLA Working Group of JSHCT. All the authors reviewed and revised the manuscript.

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Correspondence to Hisayuki Yokoyama.

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Yokoyama, H., Hirayama, M., Takahashi, Y. et al. Altered effect of killer immunoglobulin-like receptor–ligand mismatch by graft versus host disease prophylaxis in cord blood transplantation. Bone Marrow Transplant 56, 3059–3067 (2021). https://doi.org/10.1038/s41409-021-01469-6

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