Review Article | Published:

Prevention of relapse after allogeneic hematopoietic cell transplantation by donor and cell source selection

Bone Marrow Transplantation (2018) | Download Citation


Allogeneic hematopoietic cell transplantation (HCT) is the most established form of cancer immunotherapy and has been successfully applied for the treatment and cure of otherwise lethal neoplastic blood disorders. Cancer immune surveillance is mediated to a large extent by alloreactive T and natural killer (NK) cells recognizing genetic differences between patient and donor. Profound insights into the biology of these effector cells has been obtained over recent years and used for the development of innovative strategies for intelligent donor selection, aiming for improved graft-versus-leukemia effect without unmanageable graft-versus-host disease. The cellular composition of the stem cell source plays a major role in modulating these effects. This review summarizes the current state-of the-art of donor selection according to HLA, NK alloreactivity and stem cell source.

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  1. 1.

    Passweg JR, Baldomero H, Bader P, Bonini C, Duarte RF, Dufour C, et al. Use of haploidentical stem cell transplantation continues to increase: the 2015 European Society for Blood and Marrow Transplant activity survey report. Bone Marrow Transplant. 2017;52:811–7.

  2. 2.

    D’Souza A, Lee S, Zhu X, Pasquini M. Current use and trends in hematopoietic cell transplantation in the United States. Biol Blood Marrow Transplant. 2017;23:1417–21.

  3. 3.

    Soiffer RJ, Kim HT, McGuirk J, Horwitz ME, Johnston L, Patnaik MM, et al. Prospective, randomized, double-blind, phase III clinical trial of anti-T-lymphocyte globulin to assess impact on chronic graft-versus-host disease-free survival in patients undergoing HLA-matched unrelated myeloablative hematopoietic cell transplantation. J Clin Oncol. 2017;35:4003–11.

  4. 4.

    Robinson J, Halliwell JA, Hayhurst JD, Flicek P, Parham P, Marsh SG. TheIPD and IMGT/HLA database: allele variant databases. Nucleic Acids Res. 2015;43:D423–431. (Database issue)

  5. 5.

    van Rood JJ, van Leeuwen A, Persijn GG, Lansbergen Q, Goulmy E, Termijtelen A, et al. Role of the HLA system in transplantation. HLA compatibility in clinical transplantation. Transplant Proc. 1977;9:459–67.

  6. 6.

    Petersdorf EW. In celebration of Ruggero Ceppellini: HLA in transplantation. HLA. 2017;89:71–76.

  7. 7.

    Kanakry CG, Fuchs EJ, Luznik L. Modern approaches to HLA-haploidentical blood or marrow transplantation. Nat Rev Clin Oncol. 2016;13:10–24.

  8. 8.

    Apperley J, Niederwieser D, Huang XJ, Nagler A, Fuchs E, Szer J, et al. Haploidentical hematopoietic stem cell transplantation: a global overview comparing Asia, the European Union, and the United States. Biol Blood Marrow Transplant. 2016;22:23–26.

  9. 9.

    Altaf SY, Apperley JF, Olavarria E. Matched unrelated donor transplants-State of the art in the 21st century. Semin Hematol. 2016;53:221–9.

  10. 10.

    Rocha V. Umbilical cord blood cells from unrelated donor as an alternative source of hematopoietic stem cells for transplantation in children and adults. Semin Hematol. 2016;53:237–45.

  11. 11.

    Gragert L, Eapen M, Williams E, Freeman J, Spellman S, Baitty R, et al. HLA match likelihoods for hematopoietic stem-cell grafts in the U.S. registry. N Engl J Med. 2014;371:339–48.

  12. 12.

    Buck K, Wadsworth K, Setterholm M, Maiers M, Confer D, Hartzman R, et al. High-resolution match rate of 7/8 and 9/10 or better for the match unrelated donor registry. Biol Blood Marrow Transplant. 2016;22:759–63.

  13. 13.

    Archbold JK, Macdonald WA, Burrows SR, Rossjohn J, McCluskey J. T-cell allorecognition: a case of mistaken identity or deja vu? Trends Immunol. 2008;29:220–6.

  14. 14.

    Lakkis FG, Lechler RI. Origin and biology of the allogeneic response. Cold Spring Harb Perspect Med. 2013.

  15. 15.

    Afzali B, Lechler RI, Hernandez-Fuentes MP. Allorecognition and the alloresponse: clinical implications. Tissue Antigens. 2007;69:545–56.

  16. 16.

    Falkenburg JH, Jedema I. Allo-reactive T cells for the treatment of hematological malignancies. Mol Oncol. 2015;9:1894–903.

  17. 17.

    Griffioen M, van Bergen CA, Falkenburg JH. Autosomal minor histocompatibility antigens: how genetic variants create diversity in immune targets. Front Immunol. 2016;7:100

  18. 18.

    Spierings E. Minor histocompatibility antigens: past, present, and future. Tissue Antigens. 2014;84:374–360.

  19. 19.

    Bleakley M, Heimfeld S, Loeb KR, Jones LA, Chaney C, Seropian S, et al. Outcomes of acute leukemia patients transplanted with naive T cell-depleted stem cell grafts. J Clin Invest. 2015;125:2677–89.

  20. 20.

    Li Pira G, Di Cecca S, Montanari M, Moretta L, Manca F. Specific removal of alloreactive T-cells to prevent GvHD in hemopoietic stem cell transplantation: rationale, strategies and perspectives. Blood Rev. 2016;30:297–307.

  21. 21.

    Keever-Taylor CA, Passweg J, Kawanishi Y, Casper J, Flomenberg N, Baxter-Lowe LA. Association of donor-derived host-reactive cytolytic and helper T cells with outcome following alternative donor T cell-depleted bone marrow transplantation. Bone Marrow Transplant. 1997;19:1001–9.

  22. 22.

    Irschick EU, Hladik F, Niederwieser D, Nussbaumer W, Holler E, Kaminski E, et al. Studies on the mechanism of tolerance or graft-versus-host disease in allogeneic bone marrow recipients at the level of cytotoxic T-cell precursor frequencies. Blood. 1992;79:1622–8.

  23. 23.

    Fleischhauer K, Beelen DW. HLA mismatching as a strategy to reduce relapse after alternative donor transplantation. Semin Hematol. 2016;53:57–64.

  24. 24.

    Lee SJ, Klein J, Haagenson M, Baxter-Lowe LA, Confer DL, Eapen M, et al. High-resolution donor-recipient HLA matching contributes to the success of unrelated donor marrow transplantation. Blood. 2007;110:4576–83.

  25. 25.

    Furst D, Muller C, Vucinic V, Bunjes D, Herr W, Gramatzki M, et al. High-resolution HLA matching in hematopoietic stem cell transplantation: a retrospective collaborative analysis. Blood. 2013;122:3220–9.

  26. 26.

    Pidala J, Lee SJ, Ahn KW, Spellman S, Wang HL, Aljurf M, et al. Nonpermissive HLA-DPB1 mismatch increases mortality after myeloablative unrelated allogeneic hematopoietic cell transplantation. Blood. 2014;124:2596–606.

  27. 27.

    Gratwohl A, Sureda A, Cornelissen J, Apperley J, Dreger P, Duarte R, et al. Alloreactivity: the Janus-face of hematopoietic stem cell transplantation. Leukemia. 2017;31:1752-9.

  28. 28.

    Kollman C, Spellman SR, Zhang MJ, Hassebroek A, Anasetti C, Antin JH, et al. The effect of donor characteristics on survival after unrelated donor transplantation for hematologic malignancy. Blood. 2016;127:260–7.

  29. 29.

    Morishima Y, Kashiwase K, Matsuo K, Azuma F, Morishima S, Onizuka M, et al. Biological significance of HLA locus matching in unrelated donor bone marrow transplantation. Blood. 2015;125:1189–97.

  30. 30.

    Shaw BE, Gooley TA, Malkki M, Madrigal JA, Begovich AB, Horowitz MM, et al. The importance of HLA-DPB1 in unrelated donor hematopoietic cell transplantation. Blood. 2007;110:4560–6.

  31. 31.

    Petersdorf EW, Gooley TA, Malkki M, Bacigalupo AP, Cesbron A, Du Toit E, et al. HLA-C expression levels define permissible mismatches in hematopoietic cell transplantation. Blood. 2014;124:3996–4003.

  32. 32.

    Petersdorf EW, Malkki M, O’HUigin C, Carrington M, Gooley T, Haagenson MD, et al. High HLA-DP expression and graft-versus-host disease. N Engl J Med. 2015;373:599–609.

  33. 33.

    Edinger M, Hoffmann P, Ermann J, Drago K, Fathman CG, Strober S, et al. CD4+ CD25+ regulatory T cells preserve graft-versus-tumor activity while inhibiting graft-versus-host disease after bone marrow transplantation. Nat Med. 2003;9:1144–50.

  34. 34.

    van Bergen CA, van Luxemburg-Heijs SA, de Wreede LC, Eefting M, von dem Borne PA, van Balen P, et al. Selective graft-versus-leukemia depends on magnitude and diversity of the alloreactive T cell response. J Clin Invest. 2017;127:517–29.

  35. 35.

    Zino E, Frumento G, Marktel S, Sormani MP, Ficara F, Di Terlizzi S, et al. A T-cell epitope encoded by a subset of HLA-DPB1 alleles determines nonpermissive mismatches for hematologic stem cell transplantation. Blood. 2004;103:1417–24.

  36. 36.

    Crocchiolo R, Zino E, Vago L, Oneto R, Bruno B, Pollichieni S, et al. Nonpermissive HLA-DPB1 disparity is a significant independent risk factor for mortality after unrelated hematopoietic stem cell transplantation. Blood. 2009;114:1437–44.

  37. 37.

    Fleischhauer K, Shaw BE, Gooley T, Malkki M, Bardy P, Bignon JD, et al. Effect of T-cell-epitope matching at HLA-DPB1 in recipients of unrelated-donor haemopoietic-cell transplantation: a retrospective study. Lancet Oncol. 2012;13:366–74.

  38. 38.

    Crivello P, Zito L, Sizzano F, Zino E, Maiers M, Mulder A, et al. The impact of amino acid variability on alloreactivity defines a functional distance predictive of permissive HLA-DPB1 mismatches in hematopoietic stem cell transplantation. Biol Blood Marrow Transplant. 2015;21:233–41.

  39. 39.

    Crivello P, Heinold A, Rebmann V, Ottinger HD, Horn PA, Beelen DW, et al. Functional distance between recipient and donor HLA-DPB1 determines nonpermissive mismatches in unrelated HCT. Blood. 2016;128:120–9.

  40. 40.

    McCurdy SR, Fuchs EJ. Selecting the best haploidentical donor. Semin Hematol. 2016;53:246–51.

  41. 41.

    Barker JN, Kurtzberg J, Ballen K, Boo M, Brunstein C, Cutler C, et al. Optimal practices in unrelated donor cord blood transplantation for hematologic malignancies. Biol Blood Marrow Transplant. 2017.

  42. 42.

    Horowitz MM, Gale RP, Sondel PM, Goldman JM, Kersey J, Kolb HJ, et al. Graft-versus-leukemia reactions after bone marrow transplantation. Blood. 1990;75:555–62.

  43. 43.

    Kiessling R, Klein E, Wigzell H. “Natural” killer cells in the mouse. I. Cytotoxic cells with specificity for mouse Moloney leukemia cells. Specificity and distribution according to genotype. Eur J Immunol. 1975;5:112–7.

  44. 44.

    Karre K, Ljunggren HG, Piontek G, Kiessling R. Selective rejection of H-2-deficient lymphoma variants suggests alternative immune defence strategy. Nature. 1986;319:675–8.

  45. 45.

    Hsu KC, Liu XR, Selvakumar A, Mickelson E, O’Reilly RJ, Dupont B. Killer Ig-like receptor haplotype analysis by gene content: evidence for genomic diversity with a minimum of six basic framework haplotypes, each with multiple subsets. J Immunol. 2002;169:5118–29.

  46. 46.

    Uhrberg M, Valiante NM, Shum BP, Shilling HG, Lienert-Weidenbach K, Corliss B, et al. Human diversity in killer cell inhibitory receptor genes. Immunity. 1997;7:753–63.

  47. 47.

    Jiang W, Johnson C, Jayaraman J, Simecek N, Noble J, Moffatt MF, et al. Copy number variation leads to considerable diversity for B but not A haplotypes of the human KIR genes encoding NK cell receptors. Genome Res. 2012;22:1845–54.

  48. 48.

    Wagtmann N, Rajagopalan S, Winter CC, Peruzzi M, Long EO. Killer cell inhibitory receptors specific for HLA-C and HLA-B identified by direct binding and by functional transfer. Immunity. 1995;3:801–9.

  49. 49.

    Anfossi N, Andre P, Guia S, Falk CS, Roetynck S, Stewart CA, et al. Human NK cell education by inhibitory receptors for MHC class I. Immunity. 2006;25:331–42.

  50. 50.

    Yu J, Heller G, Chewning J, Kim S, Yokoyama WM, Hsu KC. Hierarchy of the human natural killer cell response is determined by class and quantity of inhibitory receptors for self-HLA-B and HLA-C ligands. J Immunol. 2007;179:5977–89.

  51. 51.

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

  52. 52.

    Boudreau JE, Liu XR, Zhao Z, Zhang A, Shultz LD, Greiner DL, et al. Cell-extrinsic MHC class I molecule engagement augments human NK cell education programmed by cell-intrinsic MHC class I. Immunity. 2016;45:280–91.

  53. 53.

    Fernandez NC, Treiner E, Vance RE, Jamieson AM, Lemieux S, Raulet DH. A subset of natural killer cells achieves self-tolerance without expressing inhibitory receptors specific for self-MHC molecules. Blood. 2005;105:4416–23.

  54. 54.

    Kim S, Poursine-Laurent J, Truscott SM, Lybarger L, Song YJ, Yang L, et al. Licensing of natural killer cells by host major histocompatibility complex class I molecules. Nature. 2005;436:709–13.

  55. 55.

    Garcia-Beltran WF, Holzemer A, Martrus G, Chung AW, Pacheco Y, Simoneau CR, et al. Open conformers of HLA-F are high-affinity ligands of the activating NK-cell receptor KIR3DS1. Nat Immunol. 2016;17:1067–74.

  56. 56.

    Chewning JH, Gudme CN, Hsu KC, Selvakumar A, Dupont B. KIR2DS1-positive NK cells mediate alloresponse against the C2 HLA-KIR ligand group in vitro. J Immunol. 2007;179:854–68.

  57. 57.

    Fauriat C, Ivarsson MA, Ljunggren HG, Malmberg KJ, Michaelsson J. Education of human natural killer cells by activating killer cell immunoglobulin-like receptors. Blood. 2010;115:1166–74.

  58. 58.

    Dupont B, Hsu KC. Inhibitory killer Ig-like receptor genes and human leukocyte antigen class I ligands in haematopoietic stem cell transplantation. Curr Opin Immunol. 2004;16:634–43.

  59. 59.

    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.

  60. 60.

    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.

  61. 61.

    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;110:433–40.

  62. 62.

    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.

  63. 63.

    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.

  64. 64.

    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;105:4878–84.

  65. 65.

    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;12:828–36.

  66. 66.

    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;109:5058–61.

  67. 67.

    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;113:3875–84.

  68. 68.

    Venstrom JM, Gooley TA, Spellman S, Pring J, Malkki M, Dupont B, et al. Donor activating KIR3DS1 is associated with decreased acute GVHD in unrelated allogeneic hematopoietic stem cell transplantation. Blood. 2010;115:3162–5.

  69. 69.

    Mancusi A, Ruggeri L, Urbani E, Pierini A, Massei MS, Carotti A, et al. Haploidentical hematopoietic transplantation from KIR ligand-mismatched donors with activating KIRs reduces nonrelapse mortality. Blood. 2015;125:3173–82.

  70. 70.

    Cooley S, Trachtenberg E, Bergemann TL, Saeteurn K, Klein J, Le CT, et al. Donors with group B KIR haplotypes improve relapse-free survival after unrelated hematopoietic cell transplantation for acute myelogenous leukemia. Blood. 2009;113:726–32.

  71. 71.

    Cooley S, Weisdorf DJ, Guethlein LA, Klein JP, Wang T, Le CT, et al. Donor selection for natural killer cell receptor genes leads to superior survival after unrelated transplantation for acute myelogenous leukemia. Blood. 2010;116:2411–9.

  72. 72.

    Venstrom JM, Pittari G, Gooley TA, Chewning JH, Spellman S, Haagenson M, et al. HLA-C-dependent prevention of leukemia relapse by donor activating KIR2DS1. N Engl J Med. 2012;367:805–16.

  73. 73.

    Cooley S, Weisdorf DJ, Guethlein LA, Klein JP, Wang T, Marsh SG, et al. Donor killer cell Ig-like receptor B haplotypes, recipient HLA-C1, and HLA-C mismatch enhance the clinical benefit of unrelated transplantation for acute myelogenous leukemia. J Immunol. 2014;192:4592–4600.

  74. 74.

    Parham P, Norman PJ, Abi-Rached L, Guethlein LA. Variable NK cell receptors exemplified by human KIR3DL1/S1. J Immunol. 2011;187:11–19.

  75. 75.

    Saunders PM, Pymm P, Pietra G, Hughes VA, Hitchen C, O’Connor GM, et al. Killer cell immunoglobulin-like receptor 3DL1 polymorphism defines distinct hierarchies of HLA class I recognition. J Exp Med. 2016;213:791–807.

  76. 76.

    Boudreau JE, Giglio F, Gooley TA, Stevenson PA, Le Luduec JB, Shaffer BC, Rajalingam R, Hou L, Hurley CK, Noreen H, Reed EF, Yu N, Vierra-Green C, Haagenson MD, Malkki M, Petersdorf EW, Spellman S, Hsu KC. KIR3DL1/HLA-B subtypes govern AML relapse after hematopoietic cell transplantation. J Clin Oncol. 2017;35:2268–78. In Press

  77. 77.

    Ordonez D, Moraru M, Gomez-Lozano N, Cisneros E, Vilches C. KIR typing by non-sequencing methods: polymerase-chain reaction with sequence-specific primers. Methods Mol Biol. 2012;882:415–30.

  78. 78.

    Boudreau JE, Le Luduec JB, Hsu KC. Development of a novel multiplex PCR assay to detect functional subtypes of KIR3DL1 alleles. PLoS ONE. 2014;9:e99543

  79. 79.

    Norman PJ, Hollenbach JA, Nemat-Gorgani N, Marin WM, Norberg SJ, Ashouri E, et al. Defining KIR and HLA class I genotypes at highest resolution via high-throughput sequencing. Am J Hum Genet. 2016;99:375–91.

  80. 80.

    Pidala J, Anasetti C, Kharfan-Dabaja MA, Cutler C, Sheldon A, Djulbegovic B. Decision analysis of peripheral blood versus bone marrow hematopoietic stem cells for allogeneic hematopoietic cell transplantation. Biol Blood Marrow Transplant. 2009;15:1415–21.

  81. 81.

    Hassan HT, Stockschlader M, Schleimer B, Kruger W, Zander AR. Comparison of the content and subpopulations of CD3 and CD34 positive cells in bone marrow harvests and G-CSF-mobilized peripheral blood leukapheresis products from healthy adult donors. Transpl Immunol. 1996;4:319–23.

  82. 82.

    Chevallier P, Robillard N, Illiaquer M, Esbelin J, Mohty M, Bodin-Bressollette C, et al. Characterization of various blood and graft sources: a prospective series. Transfusion. 2013;53:2020–6.

  83. 83.

    Holtick U, Albrecht M, Chemnitz JM, Theurich S, Shimabukuro-Vornhagen A, Skoetz N, et al. Comparison of bone marrow versus peripheral blood allogeneic hematopoietic stem cell transplantation for hematological malignancies in adults–a systematic review and meta-analysis. Crit Rev Oncol Hematol. 2015;94:179–88.

  84. 84.

    Anasetti C, Logan BR, Lee SJ, Waller EK, Weisdorf DJ, Wingard JR, et al. Peripheral-blood stem cells versus bone marrow from unrelated donors. N Engl J Med. 2012;367:1487–96.

  85. 85.

    Eapen M. Unrelated donor transplantation: peripheral blood or bone marrow--does it matter? Best Pract Res Clin Haematol. 2014;27:278–82.

  86. 86.

    Nagler A, Labopin M, Shimoni A, Niederwieser D, Mufti GJ, Zander AR, et al. Mobilized peripheral blood stem cells compared with bone marrow as the stem cell source for unrelated donor allogeneic transplantation with reduced-intensity conditioning in patients with acute myeloid leukemia in complete remission: an analysis from the Acute Leukemia Working Party of the European Group for Blood and Marrow Transplantation. Biol Blood Marrow Transplant. 2012;18:1422–9.

  87. 87.

    Nagler A, Labopin M, Shimoni A, Mufti GJ, Cornelissen JJ, Blaise D, et al. Mobilized peripheral blood stem cells compared with bone marrow from HLA-identical siblings for reduced-intensity conditioning transplantation in acute myeloid leukemia in complete remission: a retrospective analysis from the Acute Leukemia Working Party of EBMT. Eur J Haematol. 2012;89:206–13.

  88. 88.

    Bradstock K, Bilmon I, Kwan J, Blyth E, Micklethwaite K, Huang G, et al. Influence of stem cell source on outcomes of allogeneic reduced-intensity conditioning therapy transplants using haploidentical related donors. Biol Blood Marrow Transplant. 2015;21:1641–5.

  89. 89.

    Castagna L, Crocchiolo R, Furst S, Bramanti S, El Cheikh J, Sarina B, et al. Bone marrow compared with peripheral blood stem cells for haploidentical transplantation with a nonmyeloablative conditioning regimen and post-transplantation cyclophosphamide. Biol Blood Marrow Transplant. 2014;20:724–9.

  90. 90.

    Armand P, Kim HT, Logan BR, Wang Z, Alyea EP, Kalaycio ME, et al. Validation and refinement of the disease risk index for allogeneic stem cell transplantation. Blood. 2014;123:3664–71.

  91. 91.

    Wagner JE Jr., Eapen M, Carter S, Wang Y, Schultz KR, Wall DA, et al. One-unit versus two-unit cord-blood transplantation for hematologic cancers. N Engl J Med. 2014;371:1685–94.

  92. 92.

    Shi-Xia X, Xian-Hua T, Xiang-Feng T. Unrelated umbilical cord blood transplantation and unrelated bone marrow transplantation in children with hematological disease: a meta-analysis. Pediatr Transplant. 2009;13:278–84.

  93. 93.

    Eapen M, Rocha V, Sanz G, Scaradavou A, Zhang MJ, Arcese W, et al. Effect of graft source on unrelated donor haemopoietic stem-cell transplantation in adults with acute leukaemia: a retrospective analysis. Lancet Oncol. 2010;11:653–60.

  94. 94.

    Marks DI, Woo KA, Zhong X, Appelbaum FR, Bachanova V, Barker JN, et al. Unrelated umbilical cord blood transplant for adult acute lymphoblastic leukemia in first and second complete remission: a comparison with allografts from adult unrelated donors. Haematologica. 2014;99:322–8.

  95. 95.

    Brunstein CG, Eapen M, Ahn KW, Appelbaum FR, Ballen KK, Champlin RE, et al. Reduced-intensity conditioning transplantation in acute leukemia: the effect of source of unrelated donor stem cells on outcomes. Blood. 2012;119:5591–8.

  96. 96.

    Rodrigues CA, Rocha V, Dreger P, Brunstein C, Sengeloev H, Finke J, et al. Alternative donor hematopoietic stem cell transplantation for mature lymphoid malignancies after reduced-intensity conditioning regimen: similar outcomes with umbilical cord blood and unrelated donor peripheral blood. Haematologica. 2014;99:370–7.

  97. 97.

    Robin M, Ruggeri A, Labopin M, Niederwieser D, Tabrizi R, Sanz G, et al. Comparison of unrelated cord blood and peripheral blood stem cell transplantation in adults with myelodysplastic syndrome after reduced-intensity conditioning regimen: a collaborative study from Eurocord (Cord blood Committee of Cellular Therapy & Immunobiology Working Party of EBMT) and Chronic Malignancies Working Party. Biol Blood Marrow Transplant. 2015;21:489–95.

  98. 98.

    Milano F, Gooley T, Wood B, Woolfrey A, Flowers ME, Doney K, et al. Cord-blood transplantation in patients with minimal residual disease. N Engl J Med. 2016;375:944–53.

  99. 99.

    Verneris MR, Brunstein CG, Barker J, MacMillan ML, DeFor T, McKenna DH, et al. Relapse risk after umbilical cord blood transplantation: enhanced graft-versus-leukemia effect in recipients of 2 units. Blood. 2009;114:4293–9.

  100. 100.

    Labopin M, Ruggeri A, Gorin NC, Gluckman E, Blaise D, Mannone L, et al. Cost-effectiveness and clinical outcomes of double versus single cord blood transplantation in adults with acute leukemia in France. Haematologica. 2014;99:535–40.

  101. 101.

    Ruggeri A, Sanz G, Bittencourt H, Sanz J, Rambaldi A, Volt F, et al. Comparison of outcomes after single or double cord blood transplantation in adults with acute leukemia using different types of myeloablative conditioning regimen, a retrospective study on behalf of Eurocord and the Acute Leukemia Working Party of EBMT. Leukemia. 2014;28:779–86.

  102. 102.

    Tsang KS, Leung AW, Lee V, Cheng FW, Shing MM, Pong HN, et al. Indiscernible benefit of double-unit umbilical cord blood transplantation in children: a single-center experience from Hong Kong. Cell Transplant. 2016;25:1277–86.

  103. 103.

    Shaffer BC, Le Luduec JB, Forlenza C, Jakubowski AA, Perales MA, Young JW, et al. Phase II study of haploidentical natural killer cell infusion for treatment of relapsed or persistent myeloid malignancies following allogeneic hematopoietic cell transplantation. Biol Blood Marrow Transplant. 2016;22:705–9.

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This work was supported by grants from the Deutsche José Carreras Leukämie Stiftung (DJCLS R 15/02 and DJCLS 01R/2017), the European Commission Transcan JTC2012 (Cancer12-045-HLALOSS), the Dr. Werner Jackstädt Stiftung, Germany and the Joseph Senker Stiftung, Germany to KF and from NIH U01 AI069197, P01 CA23766, R01 HL129472, and Leukemia & Lymphoma Society to KCH.

Author contributions

KF, KCH and BES wrote the manuscript and created the Figures and Tables relevant to the parts on HLA, NK alloreactivity and stem cell source, respectively.

Author information

Author notes

  1. These authors contributed equally: Katharina Fleischhauer, Katharine C. Hsu, Bronwen E. Shaw.


  1. Institute for Experimental Cellular Therapy, University Hospital Essen, Essen, Germany

    • Katharina Fleischhauer
  2. German Cancer Consortium, Heidelberg, Germany

    • Katharina Fleischhauer
  3. Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA

    • Katharine C. Hsu
  4. Immunology Program, Sloan Kettering Institute, New York, NY, USA

    • Katharine C. Hsu
  5. Department of Medicine, Weill Cornell Medical College, New York, NY, USA

    • Katharine C. Hsu
  6. Center for International Blood and Marrow Transplant Research (CIBMTR), Froedtert & the Medical College of Wisconsin, Milwaukee, WI, USA

    • Bronwen E. Shaw


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The authors declare that they have no conflict of interest.

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Correspondence to Katharina Fleischhauer or Katharine C. Hsu or Bronwen E. Shaw.

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