Review Article | Published:

Selected biological issues affecting relapse after stem cell transplantation: role of T-cell impairment, NK cells and intrinsic tumor resistance

Bone Marrow Transplantationvolume 53pages949959 (2018) | Download Citation


The graft vs. leukemia (GvL) effect as a method of preventing relapse is well described after allogeneic hematopoietic cell transplantation (HCT), but the mechanisms to this effect and how tumor sometimes develops resistance to GvL are just beginning to be understood. This article reviews and expands upon data presented at the Third International Workshop on Biology, Prevention and Treatment of Relapse after Stem Cell Transplantation held in Hamburg, Germany, in November 2016. We first discuss in detail the role that T-cell impairment early after HCT plays in relapse by looking at data from T cell-depleted approaches as well as the clear role that early T-cell recovery has shown in improving outcomes. We then review key findings regarding the role of specific KIR donor/recipient pairings that contribute to relapse prevention after HCT for several tumor types. Finally, we discuss a unique mouse model following the development of tumor resistance to GvL. Detailed molecular characterization of events marking the development of tumor resistance to the immunotherapy of GvL may help in developing future strategies to overcome immune escape.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Additional information

Marcel van den Brink, Markus Uhrberg, Lorenz Jahn, John F. DiPersio and Michael A. Pulsipher contributed equally to this work.


  1. 1.

    Goldman JM, Gale RP, Horowitz MM, Biggs JC, Champlin RE, Gluckman E, et al. Bone marrow transplantation for chronic myelogenous leukemia in chronic phase. Increased risk for relapse associated with T-cell depletion. Ann Intern Med. 1988;108:806–14.

  2. 2.

    Martin PJ, Clift RA, Fisher LD, Buckner CD, Hansen JA, Appelbaum FR, et al. HLA-identical marrow transplantation during accelerated-phase chronic myelogenous leukemia: analysis of survival and remission duration. Blood. 1988;72:1978–84.

  3. 3.

    Marmont AM, Horowitz MM, Gale RP, Sobocinski K, Ash RC, van Bekkum DW, et al. T-cell depletion of HLA-identical transplants in leukemia. Blood. 1991;78:2120–30.

  4. 4.

    Drobyski WR, Ash RC, Casper JT, McAuliffe T, Horowitz MM, Lawton C, et al. Effect of T-cell depletion as graft-versus-host disease prophylaxis on engraftment, relapse, and disease-free survival in unrelated marrow transplantation for chronic myelogenous leukemia. Blood. 1994;83:1980–7.

  5. 5.

    Young JW, Papadopoulos EB, Cunningham I, Castro-Malaspina H, Flomenberg N, Carabasi MH, et al. T-cell-depleted allogeneic bone marrow transplantation in adults with acute nonlymphocytic leukemia in first remission. Blood. 1992;79:3380–7.

  6. 6.

    Soiffer RJ, Fairclough D, Robertson M, Alyea E, Anderson K, Freedman A, et al. CD6-depleted allogeneic bone marrow transplantation for acute leukemia in first complete remission. Blood. 1997;89:3039–47.

  7. 7.

    Papadopoulos EB, Carabasi MH, Castro-Malaspina H, Childs BH, Mackinnon S, Boulad F, et al. T-cell-depleted allogeneic bone marrow transplantation as postremission therapy for acute myelogenous leukemia: freedom from relapse in the absence of graft-versus-host disease. Blood. 1998;91:1083–90.

  8. 8.

    Aversa F, Terenzi A, Carotti A, Felicini R, Jacucci R, Zei T, et al. Improved outcome with T-cell-depleted bone marrow transplantation for acute leukemia. J Clin Oncol. 1999;17:1545–50.

  9. 9.

    Wagner JE, Thompson JS, Carter SL, Kernan NA. Effect of graft-versus-host disease prophylaxis on 3-year disease-free survival in recipients of unrelated donor bone marrow (T-cell Depletion Trial): a multi-centre, randomised phase II–III trial. Lancet. 2005;366:733–41.

  10. 10.

    Devine SM, Carter S, Soiffer RJ, Pasquini MC, Hari PN, Stein A, et al. Low risk of chronic graft-versus-host disease and relapse associated with T cell-depleted peripheral blood stem cell transplantation for acute myelogenous leukemia in first remission: results of the blood and marrow transplant clinical trials network protocol 0303. Biol Blood Marrow Transplant. 2011;17:1343–51.

  11. 11.

    Pasquini MC, Devine S, Mendizabal A, Baden LR, Wingard JR, Lazarus HM, et al. Comparative outcomes of donor graft CD34+selection and immune suppressive therapy as graft-versus-host disease prophylaxis for patients with acute myeloid leukemia in complete remission undergoing HLA-matched sibling allogeneic hematopoietic cell transplantation. J Clin Oncol. 2012;30:3194–201.

  12. 12.

    Bayraktar UD, de Lima M, Saliba RM, Maloy M, Castro-Malaspina HR, Chen J, et al. Ex vivo T cell-depleted versus unmodified allografts in patients with acute myeloid leukemia in first complete remission. Biol Blood Marrow Transplant. 2013;19:898–903.

  13. 13.

    Barba P, Hilden P, Devlin SM, Maloy M, Dierov D, Nieves J, et al. Ex vivo CD34+-selected T cell-depleted peripheral blood stem cell grafts for allogeneic hematopoietic stem cell transplantation in acute leukemia and myelodysplastic syndrome is associated with low incidence of acute and chronic graft-versus-host disease and high treatment response. Biol Blood Marrow Transplant. 2017;23:452–8.

  14. 14.

    Hobbs GS, Perales MA. Effects of T-cell depletion on allogeneic hematopoietic stem cell transplantation outcomes in AML patients. J Clin Med. 2015;4:488–503.

  15. 15.

    Chakrabarti S, Brown J, Guttridge M, Pamphilon DH, Lankester A, Marks DI. Early lymphocyte recovery is an important determinant of outcome following allogeneic transplantation with CD34+selected graft and limited T-cell addback. Bone Marrow Transplant. 2003;32:23–30.

  16. 16.

    Powles R, Singhal S, Treleaven J, Kulkarni S, Horton C, Mehta J. Identification of patients who may benefit from prophylactic immunotherapy after bone marrow transplantation for acute myeloid leukemia on the basis of lymphocyte recovery early after transplantation. Blood. 1998;91:3481–6.

  17. 17.

    Kim DH, Kim JG, Sohn SK, Sung WJ, Suh JS, Lee KS, et al. Clinical impact of early absolute lymphocyte count after allogeneic stem cell transplantation. Br J Haematol. 2004;125:217–24.

  18. 18.

    Savani BN, Mielke S, Rezvani K, Montero A, Yong AS, Wish L, et al. Absolute lymphocyte count on day 30 is a surrogate for robust hematopoietic recovery and strongly predicts outcome after T cell-depleted allogeneic stem cell transplantation. Biol Blood Marrow Transplant. 2007;13:1216–23.

  19. 19.

    Bayraktar UD, Milton DR, Guindani M, Rondon G, Chen J, Al-Atrash G, et al. Optimal threshold and time of absolute lymphocyte count assessment for outcome prediction after bone marrow transplantation. Biol Blood Marrow Transplant. 2016;22:505–13.

  20. 20.

    Mielcarek M, Furlong T, O’Donnell PV, Storer BE, McCune JS, Storb R, et al. Posttransplantation cyclophosphamide for prevention of graft-versus-host disease after HLA-matched mobilized blood cell transplantation. Blood. 2016;127:1502–8.

  21. 21.

    Kanakry CG, O’Donnell PV, Furlong T, de Lima MJ, Wei W, Medeot M, et al. Multi-institutional study of post-transplantation cyclophosphamide as single-agent graft-versus-host disease prophylaxis after allogeneic bone marrow transplantation using myeloablative busulfan and fludarabine conditioning. J Clin Oncol. 2014;32:3497–505.

  22. 22.

    Luznik L, Bolanos-Meade J, Zahurak M, Chen AR, Smith BD, Brodsky R, et al. High-dose cyclophosphamide as single-agent, short-course prophylaxis of graft-versus-host disease. Blood. 2010;115:3224–30.

  23. 23.

    Lang P, Feuchtinger T, Teltschik HM, Schwinger W, Schlegel P, Pfeiffer M, et al. Improved immune recovery after transplantation of TCRalphabeta/CD19-depleted allografts from haploidentical donors in pediatric patients. Bone Marrow Transplant. 2015;50:S6–10.

  24. 24.

    Maschan M, Shelikhova L, Ilushina M, Kurnikova E, Boyakova E, Balashov D, et al. TCR-alpha/beta and CD19 depletion and treosulfan-based conditioning regimen in unrelated and haploidentical transplantation in children with acute myeloid leukemia. Bone Marrow Transplant. 2016;51:668–74.

  25. 25.

    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.

  26. 26.

    Kim DH, Sohn SK, Won DI, Lee NY, Suh JS, Lee KB. Rapid helper T-cell recovery above 200 x 10 6/l at 3 months correlates to successful transplant outcomes after allogeneic stem cell transplantation. Bone Marrow Transplant. 2006;37:1119–28.

  27. 27.

    Berger M, Figari O, Bruno B, Raiola A, Dominietto A, Fiorone M, et al. Lymphocyte subsets recovery following allogeneic bone marrow transplantation (BMT): CD4+cell count and transplant-related mortality. Bone Marrow Transplant. 2008;41:55–62.

  28. 28.

    Goldberg JD, Zheng J, Ratan R, Small TN, Lai KC, Boulad F. et al. Early recovery of T-cell function predicts improved survival after T-cell depleted allogeneic transplant. Leuk Lymphoma. 2017;58:1859–71.

  29. 29.

    Merindol N, Champagne MA, Duval M, Soudeyns H. CD8(+) T-cell reconstitution in recipients of umbilical cord blood transplantation and characteristics associated with leukemic relapse. Blood. 2011;118:4480–8.

  30. 30.

    Heijst JW, Ceberio I, Lipuma LB, Samilo DW, Wasilewski GD, Gonzales AM. Quantitative assessment of T cell repertoire recovery after hematopoietic stem cell transplantation. Nat Med. 2013;19:372–7.

  31. 31.

    Yew PY, Alachkar H, Yamaguchi R, Kiyotani K, Fang H, Yap KL, et al. Quantitative characterization of T-cell repertoire in allogeneic hematopoietic stem cell transplant recipients. Bone Marrow Transplant. 2015;50:1227–34.

  32. 32.

    Zvyagin IV, Mamedov IZ, Tatarinova OV, Komech EA, Kurnikova EE, Boyakova EV, et al. Tracking T-cell immune reconstitution after TCRalphabeta/CD19-depleted hematopoietic cells transplantation in children. Leukemia. 2017;31:1145–53.

  33. 33.

    Ravens S, Schultze-Florey C, Raha S, Sandrock I, Drenker M, Oberdorfer L, et al. Human gammadelta T cells are quickly reconstituted after stem-cell transplantation and show adaptive clonal expansion in response to viral infection. Nat Immunol. 2017;18:393–401.

  34. 34.

    Small TN, Papadopoulos EB, Boulad F, Black P, Castro-Malaspina H, Childs BH, et al. Comparison of immune reconstitution after unrelated and related T-cell-depleted bone marrow transplantation: effect of patient age and donor leukocyte infusions. Blood. 1999;93:467–80.

  35. 35.

    Maury S, Mary JY, Rabian C, Schwarzinger M, Toubert A, Scieux C, et al. Prolonged immune deficiency following allogeneic stem cell transplantation: risk factors and complications in adult patients. Br J Haematol. 2001;115:630–41.

  36. 36.

    Keever-Taylor CA, Wagner JE, Kernan NA, Small TN, Carter SL, Thompson JS, et al. Comparison of immune recovery in recipients of unmanipulated vs T-cell-depleted grafts from unrelated donors in a multicenter randomized phase II-III trial (T-cell depletion trial). Bone Marrow Transplant. 2010;45:587–9.

  37. 37.

    Kanda J, Chiou LW, Szabolcs P, Sempowski GD, Rizzieri DA, Long GD, et al. Immune recovery in adult patients after myeloablative dual umbilical cord blood, matched sibling, and matched unrelated donor hematopoietic cell transplantation. Biol Blood Marrow Transplant. 2012;18:1664–76.

  38. 38.

    Castillo N, Garcia-Cadenas I, Barba P, Canals C, Diaz-Heredia C, Martino R, et al. Early and long-term impaired T lymphocyte immune reconstitution after cord blood transplantation with antithymocyte globulin. Biol Blood Marrow Transplant. 2017;23:491–7.

  39. 39.

    Kanakry CG, Coffey DG, Towlerton AM, Vulic A, Storer BE, Chou J. et al. Origin and evolution of the T cell repertoire after posttransplantation cyclophosphamide. JCI Insight. 2016;1:pii: e86252

  40. 40.

    Douek DC, McFarland RD, Keiser PH, Gage EA, Massey JM, Haynes BF, et al. Changes in thymic function with age and during the treatment of HIV infection. Nature. 1998;396:690–5.

  41. 41.

    Ringhoffer S, Rojewski M, Dohner H, Bunjes D, Ringhoffer M. T-cell reconstitution after allogeneic stem cell transplantation: assessment by measurement of the sjTREC/betaTREC ratio and thymic naive T cells. Haematologica. 2013;98:1600–8.

  42. 42.

    Lewin SR, Heller G, Zhang L, Rodrigues E, Skulsky E, van den Brink MR, et al. Direct evidence for new T-cell generation by patients after either T-cell-depleted or unmodified allogeneic hematopoietic stem cell transplantations. Blood. 2002;100:2235–42.

  43. 43.

    Weinberg K, Blazar BR, Wagner JE, Agura E, Hill BJ, Smogorzewska M, et al. Factors affecting thymic function after allogeneic hematopoietic stem cell transplantation. Blood. 2001;97:1458–66.

  44. 44.

    Alpdogan O, Muriglan SJ, Eng JM, Willis LM, Greenberg AS, Kappel BJ, et al. IL-7 enhances peripheral T cell reconstitution after allogeneic hematopoietic stem cell transplantation. J Clin Invest. 2003;112:1095–107.

  45. 45.

    Perales MA, Goldberg JD, Yuan J, Koehne G, Lechner L, Papadopoulos EB, et al. Recombinant human interleukin-7 (CYT107) promotes T-cell recovery after allogeneic stem cell transplantation. Blood. 2012;120:4882–91.

  46. 46.

    Chaudhry MS, Velardi E, Dudakov JA, van den Brink MR. Thymus: the next (re)generation. Immunol Rev. 2016;271:56–71.

  47. 47.

    Ault KA, Antin JH, Ginsburg D, Orkin SH, Rappeport JM, Keohan ML, et al. Phenotype of recovering lymphoid cell populations after marrow transplantation. J Exp Med. 1985;161:1483–502.

  48. 48.

    Lamb LS Jr., Gee AP, Henslee-Downey PJ, Geier SS, Hazlett L, Pati AR, et al. Phenotypic and functional reconstitution of peripheral blood lymphocytes following T cell-depleted bone marrow transplantation from partially mismatched related donors. Bone Marrow Transplant. 1998;21:461–71.

  49. 49.

    Nguyen S, Dhedin N, Vernant JP, Kuentz M, Al Jijakli A, Rouas-Freiss N, et al. NK-cell reconstitution after haploidentical hematopoietic stem-cell transplantations: immaturity of NK cells and inhibitory effect of NKG2A override GvL effect. Blood. 2005;105:4135–42.

  50. 50.

    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.

  51. 51.

    Valiante NM, Uhrberg M, Shilling HG, Lienert-Weidenbach K, Arnett KL, D’Andrea A, et al. Functionally and structurally distinct NK cell receptor repertoires in the peripheral blood of two human donors. Immunity. 1997;7:739–51.

  52. 52.

    Manser AR, Weinhold S, Uhrberg M. Human KIR repertoires: shaped by genetic diversity and evolution. Immunol Rev. 2015;267:178–96.

  53. 53.

    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.

  54. 54.

    Oevermann L, Michaelis SU, Mezger M, Lang P, Toporski J, Bertaina A, et al. KIR B haplotype donors confer a reduced risk for relapse after haploidentical transplantation in children with ALL. Blood. 2014;124:2744–2747.

  55. 55.

    Kroger N, Zabelina T, Berger J, Duske H, Klyuchnikov E, Binder T, et al. Donor KIR haplotype B improves progression-free and overall survival after allogeneic hematopoietic stem cell transplantation for multiple myeloma. Leukemia. 2011;25:1657–61.

  56. 56.

    Bachanova V, Weisdorf DJ, Wang T, Marsh SG, Trachtenberg E, Haagenson MD, et al. Donor KIR B genotype improves progression-free survival of non-Hodgkin lymphoma patients receiving unrelated donor transplantation. Biol Blood Marrow Transplant. 2016;22:1602–7.

  57. 57.

    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.

  58. 58.

    Moesta AK, Graef T, Abi-Rached L, Older Aguilar AM, Guethlein LA, Parham P. Humans differ from other hominids in lacking an activating NK cell receptor that recognizes the C1 epitope of MHC class I. J Immunol. 2010;185:4233–7.

  59. 59.

    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.

  60. 60.

    Uhrberg M. The KIR gene family: life in the fast lane of evolution. Eur J Immunol. 2005;35:10–15.

  61. 61.

    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;192:4592–600.

  62. 62.

    Winter CC, Gumperz JE, Parham P, Long EO, Wagtmann N. Direct binding and functional transfer of NK cell inhibitory receptors reveal novel patterns of HLA-C allotype recognition. J Immunol. 1998;161:571–7.

  63. 63.

    Hilton HG, Guethlein LA, Goyos A, Nemat-Gorgani N, Bushnell DA, Norman PJ, et al. Polymorphic HLA-C receptors balance the functional characteristics of KIR haplotypes. J Immunol. 2015;195:3160–70.

  64. 64.

    Giebel S, Locatelli F, Wojnar J, Velardi A, Mina T, Giorgiani G, et al. Homozygosity for human leucocyte antigen-C ligands of KIR2DL1 is associated with increased risk of relapse after human leucocyte antigen-C-matched unrelated donor haematopoietic stem cell transplantation. Br J Haematol. 2005;131:483–6.

  65. 65.

    Fischer JC, Ottinger H, Ferencik S, Sribar M, Punzel M, Beelen DW, et al. Relevance of C1 and C2 epitopes for hemopoietic stem cell transplantation: role for sequential acquisition of HLA-C-specific inhibitory killer Ig-like receptor. J Immunol. 2007;178:3918–23.

  66. 66.

    Fischer JC, Uhrberg M. Prevention of leukemia relapse by donor activating KIR2DS1. N Engl J Med. 2012;367:2054–5. author reply 2055

  67. 67.

    Neuchel C, Furst D, Niederwieser D, Bunjes D, Tsamadou C, Wulf G, et al. Impact of donor activating KIR genes on HSCT outcome in C1-ligand negative myeloid disease patients transplanted with unrelated donors-a retrospective study. PLoS ONE. 2017;12:e0169512

  68. 68.

    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.

  69. 69.

    Babor F, Manser AR, Fischer JC, Scherenschlich N, Enczmann J, Chazara O, et al. KIR ligand C2 is associated with increased susceptibility to childhood ALL and confers an elevated risk for late relapse. Blood. 2014;124:2248–51.

  70. 70.

    Babor F, Fischer JC, Uhrberg M. The role of KIR genes and ligands in leukemia surveillance. Front Immunol. 2013;4:27

  71. 71.

    Miller JS, McCullar V. Human natural killer cells with polyclonal lectin and immunoglobulinlike receptors develop from single hematopoietic stem cells with preferential expression of NKG2A and KIR2DL2/L3/S2. Blood. 2001;98:705–13.

  72. 72.

    Shilling HG, McQueen KL, Cheng NW, Shizuru JA, Negrin RS, Parham P. Reconstitution of NK cell receptor repertoire following HLA-matched hematopoietic cell transplantation. Blood. 2003;101:3730–40.

  73. 73.

    Stern M, de Angelis C, Urban E, Mancusi A, Aversa F, Velardi A. et al. Natural killer-cell KIR repertoire reconstitution after haploidentical SCT. Bone Marrow Transplant. 2010;45:1607–10.

  74. 74.

    Haas P, Loiseau P, Tamouza R, Cayuela JM, Moins-Teisserenc H, Busson M, et al. NK-cell education is shaped by donor HLA genotype after unrelated allogeneic hematopoietic stem cell transplantation. Blood. 2011;117:1021–9.

  75. 75.

    Reusing SB, Manser AR, Enczmann J, Mulder A, Claas FH, Carrington M, et al. Selective downregulation of HLA-C and HLA-E in childhood acute lymphoblastic leukaemia. Br J Haematol. 2016;174:477–80.

  76. 76.

    Schonberg K, Sribar M, Enczmann J, Fischer JC, Uhrberg M. Analyses of HLA-C-specific KIR repertoires in donors with group A and B haplotypes suggest a ligand-instructed model of NK cell receptor acquisition. Blood. 2011;117:98–107.

  77. 77.

    Moesta AK, Norman PJ, Yawata M, Yawata N, Gleimer M, Parham P. Synergistic polymorphism at two positions distal to the ligand-binding site makes KIR2DL2 a stronger receptor for HLA-C than KIR2DL3. J Immunol. 2008;180:3969–79.

  78. 78.

    Gupta V, Tallman MS, Weisdorf DJ. Allogeneic hematopoietic cell transplantation for adults with acute myeloid leukemia: myths, controversies, and unknowns. Blood. 2011;117:2307–18.

  79. 79.

    Stein EM, Tallman MS. Emerging therapeutic drugs for AML. Blood. 2016;127:71–8.

  80. 80.

    Thol F, Schlenk RF, Heuser M, Ganser A. How I treat refractory and early relapsed acute myeloid leukemia. Blood. 2015;126:319–27.

  81. 81.

    Bleakley M, Riddell SR. Exploiting T cells specific for human minor histocompatibility antigens for therapy of leukemia. Immunol Cell Biol. 2011;89:396–407.

  82. 82.

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

  83. 83.

    Bejanyan N, Weisdorf DJ, Logan BR, Wang HL, Devine SM, de Lima M, et al. Survival of patients with acute myeloid leukemia relapsing after allogeneic hematopoietic cell transplantation: a center for international blood and marrow transplant research study. Biol Blood Marrow Transplant. 2015;21:454–9.

  84. 84.

    Bacher U, Haferlach T, Alpermann T, Zenger M, Kroger N, Beelen DW, et al. Comparison of cytogenetic clonal evolution patterns following allogeneic hematopoietic transplantation versus conventional treatment in patients at relapse of AML. Biol Blood Marrow Transplant. 2010;16:1649–57.

  85. 85.

    Schmidt-Hieber M, Blau IW, Richter G, Turkmen S, Bommer C, Thiel G, et al. Cytogenetic studies in acute leukemia patients relapsing after allogeneic stem cell transplantation. Cancer Genet Cytogenet. 2010;198:135–43.

  86. 86.

    Waterhouse M, Pfeifer D, Pantic M, Emmerich F, Bertz H, Finke J. Genome-wide profiling in AML patients relapsing after allogeneic hematopoietic cell transplantation. Biol Blood Marrow Transplant. 2011;17:1450–1459.e1.

  87. 87.

    Ding L, Ley TJ, Larson DE, Miller CA, Koboldt DC, Welch JS, et al. Clonal evolution in relapsed acute myeloid leukaemia revealed by whole-genome sequencing. Nature. 2012;481:506–10.

  88. 88.

    Farrar JE, Schuback HL, Ries RE, Wai D, Hampton OA, Trevino LR, et al. Genomic profiling of pediatric acute myeloid leukemia reveals a changing mutational landscape from disease diagnosis to relapse. Cancer Res. 2016;76:2197–205.

  89. 89.

    Hirsch P, Zhang Y, Tang R, Joulin V, Boutroux H, Pronier E, et al. Genetic hierarchy and temporal variegation in the clonal history of acute myeloid leukaemia. Nat Commun. 2016;7:12475

  90. 90.

    Kronke J, Bullinger L, Teleanu V, Tschurtz F, Gaidzik VI, Kuhn MW, et al. Clonal evolution in relapsed NPM1-mutated acute myeloid leukemia. Blood. 2013;122:100–8.

  91. 91.

    Sood R, Hansen NF, Donovan FX, Carrington B, Bucci D, Maskeri B, et al. Somatic mutational landscape of AML with inv(16) or t(8;21) identifies patterns of clonal evolution in relapse leukemia. Leukemia. 2016;30:501–4.

  92. 92.

    Della Porta MG, Galli A, Bacigalupo A, Zibellini S, Bernardi M, Rizzo E et al. Clinical effects of driver somatic mutations on the outcomes of patients with myelodysplastic syndromes treated with allogeneic hematopoietic stem-cell transplantation. J Clin Oncol 2016;34:3627–37.

  93. 93.

    Luskin MR, Carroll M, Lieberman D, Morrissette JJD, Zhao J, Crisalli L, et al. Clinical utility of next-generation sequencing for oncogenic mutations in patients with acute myeloid leukemia undergoing allogeneic stem cell transplantation. Biol Blood Marrow Transplant. 2016;22:1961–7.

  94. 94.

    Quek L, Fergudon P, Metzner M, Ahmed I, Kennedy A, Garnett C, et al. Mutational analysis of disease relapse in patients allografted for acute myeloid leukemia. Blood Adv. 2016;1:193–204.

  95. 95.

    Stolzel F, Hackmann K, Kuithan F, Mohr B, Fussel M, Oelschlagel U, et al. Clonal evolution including partial loss of human leukocyte antigen genes favoring extramedullary acute myeloid leukemia relapse after matched related allogeneic hematopoietic stem cell transplantation. Transplantation. 2012;93:744–9.

  96. 96.

    Vago L, Perna SK, Zanussi M, Mazzi B, Barlassina C, Stanghellini MT, et al. Loss of mismatched HLA in leukemia after stem-cell transplantation. New Engl J Med. 2009;361:478–88.

  97. 97.

    Hamdi A, Cao K, Poon LM, Aung F, Kornblau S, Fernandez Vina MA, et al. Are changes in HLA Ags responsible for leukemia relapse after HLA-matched allogeneic hematopoietic SCT? Bone Marrow Transplant. 2015;50:411–3.

  98. 98.

    Cole CB, Verdoni AM, Ketkar S, Leight ER, Russler-Germain DA, Lamprecht TL, et al. PML-RARA requires DNA methyltransferase 3A to initiate acute promyelocytic leukemia. J Clin Invest. 2016;126:85–98.

  99. 99.

    Westervelt P, Lane AA, Pollock JL, Oldfather K, Holt MS, Zimonjic DB, et al. High-penetrance mouse model of acute promyelocytic leukemia with very low levels of PML-RARalpha expression. Blood. 2003;102:1857–65.

Download references


The work of MvdB was supported by the National Institutes of Health award numbers R01-HL069929 (MvdB), R01-AI101406 (MvdB), P01-CA023766 (RJ O’Reilly) and Project 4 of P01-CA023766 (MvdB). Support was also received from The Lymphoma Foundation, The Susan and Peter Solomon Divisional Genomics Program, Cycle for Survival and P30 CA008748 MSK Cancer Center Support Grant/Core Grant. The work of MU was supported by the Deutsche Krebshilfe e.V. (project 110351) and the research commission of the Medical faculty of the Heinrich Heine University. The work of LJ was supported by the European Molecular Biology Organization (EMBO; ALTF 431-2017) and the MSK Sawiris Foundation Myeloma and Transplant Research Award. The work of MAP was supported by 2UG1HL069254-17 (NHLBI/NCI), R01 CA181050 (NCI), R34HL133384 (NHLBI) and U01AI126612 (NIAID), and by the Johnny Crisstopher Children’s Charitable Foundation St. Baldrick’s Consortium Grant.

Author information

Author notes


    1. Center of Cell Engineering, Memorial Sloan Kettering Cancer Center, New York, NY, USA

      • Marcel van den Brink
    2. Institute for Transplantation Diagnostics and Cell Therapeutics, University Clinic Düsseldorf, Düsseldorf, Germany

      • Markus Uhrberg
    3. Department of Medicine and Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA

      • Lorenz Jahn
    4. Department of Medicine, Division of Oncology, Washington University School of Medicine, St. Louis, MO, USA

      • John F. DiPersio
    5. Children’s Center for Cancer and Blood Diseases, Children’s Hospital Los Angeles, Los Angeles, CA, USA

      • Michael A. Pulsipher


    1. Search for Marcel van den Brink in:

    2. Search for Markus Uhrberg in:

    3. Search for Lorenz Jahn in:

    4. Search for John F. DiPersio in:

    5. Search for Michael A. Pulsipher in:

    Conflict of interest

    Marcel van den Brink: current: research support: Seres; past 2 years: consultant for Jazz Pharmaceuticals, Novartis, Regeneron, Flagship Ventures, Boehringer Ingelheim, Merck and Evelo. John F DiPersio: stock/equity/founder: Magenta, Boston; honorarium: Celgene, Macrogenics; consultant for Zymeworks, Incyte and Celgene. Michael A Pulsipher: advisory board: Novartis, Adaptive, Chimerix and CLS Behring; educational meetings for Jazz, Medac and Amgen.

    Corresponding author

    Correspondence to Michael A. Pulsipher.

    About this article

    Publication history