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Improved outcomes of single-unit cord blood transplantation for acute myeloid leukemia by killer immunoglobulin-like receptor 2DL1-ligand mismatch

Bone Marrow Transplantation volume 57, pages 1171–1179 (2022)Cite this article

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Abstract

The impact of the killer immunoglobulin-like receptor (KIR)-ligand mismatch between donor and recipient in hematopoietic stem cell transplantation is controversial. Recently, it has been suggested that their effect on cord blood transplantation (CBT) differs among types of mismatched KIR–ligand and graft-versus-host disease (GVHD) prophylaxis. To investigate their role in acute myeloid leukemia (AML), mismatch of KIR2DL1, KIR3DL1, and KIR3DL2-ligand (HLA-C2, Bw4, and A3/11) were retrospectively assessed in patients undergoing CBT with GVHD prophylaxis comprising a calcineurin inhibitor plus methotrexate (CNI/MTX) or mycophenolate mofetil (CNI/MMF). In patients who received CNI/MTX, a favorable effect of KIR-ligand mismatch on relapse was noted in HLA-C2 mismatched cases (24.8% at 3 years post-CBT [no HLA-C2 mismatch, n = 1602] vs. 15.4% [HLA-C2 mismatch, n = 161], P = 0.0116). In this group, overall survival (OS) was also superior (68.2%, P = 0.0083) compared to the other group (55.0%). Multivariate analysis results supported these findings (hazard ratio [HR] 0.61 for relapse, P = 0.017 and HR 0.72 for OS, P = 0.016). However, the KIR-ligand mismatch effect was not observed in patients with KIR-ligand mismatch types other than HLA-C2 and those using CNI/MMF for GVHD prophylaxis. These results suggest that HLA-C2 mismatch in CBT using CNI/MTX as GVHD prophylaxis may improve the outcomes of patients with AML.

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Fig. 1: Effect of HLA-C2 mismatch on CBT outcomes in patients who received CNI plus MTX or CNI plus MMF as GVHD prophylaxis.
Fig. 2: Multivariate analysis of the effect of KIR–ligand mismatch types on relapse incidence, NRM, and OS in patients undergoing CBT who received calcineurin inhibitor (CNI) plus MTX or CNI plus MMF as GVHD prophylaxis.
Fig. 3: Multivariate analysis of the effect of KIR–ligand mismatch types on the incidence of aGVHD II–IV, aGVHD III–IV, and cGVHD in patients undergoing CBT who received calcineurin inhibitor (CNI) plus MTX or CNI plus MMF as GVHD prophylaxis.
Fig. 4: Effect of KIR-ligand mismatch on neutrophil engraftment following CBT in patients who received calcineurin inhibitor plus MTX or MMF as GVHD prophylaxis.
Fig. 5: Effect of HLA-C2 mismatch on GRFS in patients who received CNI plus MTX as GVHD prophylaxis and the differences in the effects on OS and GRFS.
Fig. 6: Multivariate analysis of the effect of the HLA-C2 mismatch on OS and GRFS in patients undergoing CBT who received calcineurin inhibitor (CNI) plus MTX.

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Data availability

The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.

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. 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.

    Article  CAS  Google Scholar 

  4. 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 

  5. 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 

  6. 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;105:2594–2600.

    Article  CAS  Google Scholar 

  7. 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 Transpl. 2006;12:876–84.

    Article  CAS  Google Scholar 

  8. 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 Transpl. 2006;12:828–36.

    Article  CAS  Google Scholar 

  9. 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 Transpl. 2007;13:315–28.

    Article  CAS  Google Scholar 

  10. 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;18:62–66.

    Article  CAS  Google Scholar 

  11. 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 transplantation. Biol Blood Marrow Transpl. 2008;14:75–87.

    Article  Google Scholar 

  12. 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 

  13. 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 

  14. 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 

  15. 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 Transpl. 2016;22:1284–9.

    Article  CAS  Google Scholar 

  16. Yokoyama H, Hirayama M, Takahashi Y, Uchida N, Tanaka M, Onizuka M, et al. Altered effect of killer immunoglobulin-like receptor-ligand mismatch by graft versus host disease prophylaxis in cord blood transplantation. Bone Marrow Transpl. 2021;56:3059–67.

    Article  CAS  Google Scholar 

  17. 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 Transpl. 2021;56:1352–63.

    Article  CAS  Google Scholar 

  18. 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 

  19. 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 

  20. Kanda J. Scripts for TRUMP data analyses. part II (HLA-related data): statistical analyses specific for hematopoietic stem cell transplantation. Int J Hematol. 2016;103:11–19.

    Article  CAS  Google Scholar 

  21. 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 Transpl. 2009;15:1628–33.

    Article  Google Scholar 

  22. Ruggeri A, Labopin M, Ciceri F, Mohty M, Nagler A. Definition of GvHD-free, relapse-free survival for registry-based studies: an ALWP-EBMT analysis on patients with AML in remission. Bone Marrow Transpl. 2016;51:610–1.

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  24. Martínez-Losada C, Martín C, Gonzalez R, Manzanares B, García-Torres E, Herrera C. Patients lacking a KIR-ligand of HLA Group C1 or C2 have a better outcome after umbilical cord blood transplantation. Front Immunol. 2017;8:810.

    Article  Google Scholar 

  25. Sekine T, Marin D, Cao K, Li L, Mehta P, Shaim H, et al. Specific combinations of donor and recipient KIR-HLA genotypes predict for large differences in outcome after cord blood transplantation. Blood. 2016;128:297–312.

    Article  CAS  Google Scholar 

  26. Yawata M, Yawata N, Draghi M, Little AM, Partheniou F, Parham P. Roles for HLA and KIR polymorphisms in natural killer cell repertoire selection and modulation of effector function. J Exp Med. 2006;203:633–45.

    Article  CAS  Google Scholar 

  27. Yokoyama H, Morishima Y, Fuji S, Uchida N, Takahashi S, Onizuka M, et al. Impact of HLA Allele Mismatch at HLA-A, -B, -C, and -DRB1 in Single Cord Blood Transplantation. Biol Blood Marrow Transpl. 2020;26:519–28.

    Article  CAS  Google Scholar 

  28. 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 Transpl. 2017;52:423–30.

    Article  CAS  Google Scholar 

  29. 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 Transpl. 2017;52:1261–7.

    Article  CAS  Google Scholar 

  30. 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 

  31. 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 

  32. 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 Transpl. 2011;17:205–13.

    Article  CAS  Google Scholar 

  33. Scott BL, Pasquini MC, Fei M, Fraser R, Wu J, Devine SM, et al. Myeloablative versus Reduced-Intensity Conditioning for hematopoietic Cell Transplantation in Acute myelogenous leukemia and Myelodysplastic Syndromes-Long-Term Follow-Up of the BMT CTN 0901 Clinical. Trial Transpl Cell Ther. 2021;27:483.e1–483.e6.

    Google Scholar 

  34. Yoshimura K, Yano I, Yamamoto T, Kondo T, Kawanishi M, Isomoto Y, et al. Pharmacokinetic and pharmacodynamic markers of mycophenolic acid associated with effective prophylaxis for acute graft-versus-host disease and neutrophil engraftment in cord blood transplant patients. Biol Blood Marrow Transpl. 2018;24:1441–8.

    Article  CAS  Google Scholar 

  35. Terakura S, Kuwatsuka Y, Sugita J, Takahashi S, Ozawa Y, Ozeki K, et al. Effect of methotrexate dose in graft-versus-host disease prophylaxis after single-unit cord blood transplantation in adult acute myeloid leukemia. Int J Hematol. 2021;113:840–50.

    Article  CAS  Google Scholar 

  36. 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 

  37. 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 

  38. Bari R, Rujkijyanont P, Sullivan E, Kang G, Turner V, Gan K, et al. Effect of donor KIR2DL1 allelic polymorphism on the outcome of pediatric allogeneic hematopoietic stem-cell transplantation. J Clin Oncol. 2013;31:3782–90.

    Article  CAS  Google Scholar 

  39. Boudreau JE, Giglio F, Gooley TA, Stevenson PA, Le Luduec JB, 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 

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Acknowledgements

The authors would like to thank all the physicians and data managers who provided valuable data 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. This work was supported by JSPS KAKENHI Grant Number JP21K08363.

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Authors and Affiliations

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

    Hisayuki Yokoyama

  2. Department of Cancer Immunology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway

    Minoru Kanaya

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

    Tomoki Iemura & Tadakazu Kondo

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

    Masahiro Hirayama

  5. Department of Internal Medicine, Kyushu University Beppu Hospital, Beppu, Japan

    Satoshi Yamasaki

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

    Naoyuki Uchida

  7. Division of Clinical Precision Research Platform, the Institute of Medical Science, the University of Tokyo, Tokyo, Japan

    Satoshi Takahashi

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

    Masatsugu Tanaka

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

    Makoto Onizuka

  10. Department of Hematology, Japanese Red Cross Aichi Medical Center Nagoya Daiichi Hospital, Nagoya, Japan

    Yukiyasu Ozawa

  11. Department of Transfusion Medicine, Tokyo Metropolitan Tama Medical Center, Tokyo, Japan

    Yasuji Kozai

  12. Department of Hematology, Hamanomachi Hospital, Fukuoka, Japan

    Tetsuya Eto

  13. Department of Hematology, Kitakyushu City Hospital Organization, Kitakyushu Municipal Medical Center, Kitakyushu, Japan

    Yasuhiro Sugio

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

    Atsushi Hamamura

  15. Department of Hematology, National Hospital Organization Kumamoto Medical Center, Kumamoto, Japan

    Toshiro Kawakita

  16. Division of Hematology-Oncology, Japanese Red Cross Society Narita Hospital, Narita, Japan

    Nobuyuki Aotsuka

  17. Leukemia Research Center, Saiseikai Maebashi Hospital, Maebashi, Japan

    Satoru Takada

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

    Atsushi Wake

  19. Preparation Department, Japanese Red Cross Kinki Block Blood Center, Ibaraki, Japan

    Takafumi Kimura

  20. Department of Hematology and Oncology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan

    Tatsuo Ichinohe

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

    Yoshiko Atsuta

  22. Department of Registry Science for Transplant and Cellular Therapy, Aichi Medical University School of Medicine, Nagoya, Japan

    Yoshiko Atsuta

  23. Department of Hematology and Cell Therapy, Aichi Cancer Center, Nagoya, Japan

    Masamitsu Yanada

  24. 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

H.Y., M.K., T.I., M.H., S.Y., T.K., M.Y., and S.M. designed the study. N.U., S.T., M.T., M.O., Y.O., Y.K., T.E., Y.S., A.H., T.K., N.A., S.T., and A.W. collected data. T.K., T.I., and Y.A. managed the data collection. H.Y., M.K., T.I., M.H., S.Y., T.K., M.Y., and S.M. analyzed and interpreted the data. H.Y. wrote the first draft of the manuscript. M.Y. and S.M. were responsible for the Adult AML Working Group and HLA Working Group of the JSTCT. All authors have reviewed and revised the manuscript.

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Correspondence to Hisayuki Yokoyama.

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Yokoyama, H., Kanaya, M., Iemura, T. et al. Improved outcomes of single-unit cord blood transplantation for acute myeloid leukemia by killer immunoglobulin-like receptor 2DL1-ligand mismatch. Bone Marrow Transplant 57, 1171–1179 (2022). https://doi.org/10.1038/s41409-022-01700-y

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