Prevention and Treatment of Relapse After HLA-Haploidentical Hematopoietic Cell Transplantation

  • Sameh Gaballa
  • Syed A. Abutalib
  • Stefan O. CiureaEmail author
Part of the Advances and Controversies in Hematopoietic Transplantation and Cell Therapy book series (ACHTCT)


Recent advances in HLA-haploidentical hematopoietic cell transplantation have been associated with significant reduction in treatment-related mortality; however, disease relapse remains the most common cause of treatment failure as with any other type of allogeneic transplant. While, in general, etiology of relapses after haploidentical transplantation may overlap with other types of allogeneic transplants, unique relapse mechanism with loss of heterozygosity (LOH) is only observed after haploidentical transplantation. Haploidentical transplants may offer augmented graft-versus-tumor (GvT) effect owing to its unique treatment platform, HLA disparity, and in certain situations enhanced natural killer (NK) cell alloreactivity. Preemptive infusions of modified donor lymphocytes, NK cells, or chimeric antigen receptor (CAR) T-cells after haploidentical transplantation are interesting areas of ongoing research to prevent and treat relapses and will also be the focus of this review chapter.


Relapse Prevention Donor lymphocyte Infusion Suicide gene Cell therapy Conditioning 


  1. 1.
    Ciurea SO, Bayraktar UD. “No donor”? Consider a haploidentical transplant. Blood Rev. 2015;29(2):63–70.CrossRefGoogle Scholar
  2. 2.
    Beatty PG, Clift RA, Mickelson EM, Nisperos BB, Flournoy N, Martin PJ, et al. Marrow transplantation from related donors other than HLA-identical siblings. N Engl J Med. 1985;313(13):765–71.CrossRefGoogle Scholar
  3. 3.
    Clift RA, Hansen JA, Thomas ED, Buckner CD, Sanders JE, Mickelson EM, et al. Marrow transplantation from donors other than HLA-identical siblings. Transplantation. 1979;28(3):235–42.CrossRefGoogle Scholar
  4. 4.
    Powles RL, Morgenstern GR, Kay HE, McElwain TJ, Clink HM, Dady PJ, et al. Mismatched family donors for bone-marrow transplantation as treatment for acute leukaemia. Lancet. 1983;1(8325):612–5.CrossRefGoogle Scholar
  5. 5.
    Ball LM, Lankester AC, Bredius RG, Fibbe WE, van Tol MJ, Egeler RM. Graft dysfunction and delayed immune reconstitution following haploidentical peripheral blood hematopoietic stem cell transplantation. Bone Marrow Transplant. 2005;35(Suppl 1):S35–8.CrossRefGoogle Scholar
  6. 6.
    Rizzieri DA, Koh LP, Long GD, Gasparetto C, Sullivan KM, Horwitz M, et al. Partially matched, nonmyeloablative allogeneic transplantation: clinical outcomes and immune reconstitution. J Clin Oncol. 2007;25(6):690–7.CrossRefGoogle Scholar
  7. 7.
    Mehta J, Singhal S, Gee AP, Chiang KY, Godder K, Rhee Fv F, et al. Bone marrow transplantation from partially HLA-mismatched family donors for acute leukemia: single-center experience of 201 patients. Bone Marrow Transplant. 2004;33(4):389–96.CrossRefGoogle Scholar
  8. 8.
    Aversa F, Tabilio A, Velardi A, Cunningham I, Terenzi A, Falzetti F, et al. Treatment of high-risk acute leukemia with T-cell-depleted stem cells from related donors with one fully mismatched HLA haplotype. N Engl J Med. 1998;339(17):1186–93.CrossRefGoogle Scholar
  9. 9.
    Santos GW, Owens AH. Production of graft-versus-host disease in the rat and its treatment with cytotoxic agents. Nature. 1966;210(5032):139–40.CrossRefGoogle Scholar
  10. 10.
    Luznik L, O'Donnell PV, Symons HJ, Chen AR, Leffell MS, Zahurak M, et al. HLA-haploidentical bone marrow transplantation for hematologic malignancies using nonmyeloablative conditioning and high-dose, posttransplantation cyclophosphamide. Biol Blood Marrow Transplant. 2008;14(6):641–50.CrossRefGoogle Scholar
  11. 11.
    Jones RJ, Barber JP, Vala MS, Collector MI, Kaufmann SH, Ludeman SM, et al. Assessment of aldehyde dehydrogenase in viable cells. Blood. 1995;85(10):2742–6.PubMedGoogle Scholar
  12. 12.
    Ciurea SO, Mulanovich V, Saliba RM, Bayraktar UD, Jiang Y, Bassett R, et al. Improved early outcomes using a T cell replete graft compared with T cell depleted haploidentical hematopoietic stem cell transplantation. Biol Blood Marrow Transplant. 2012;18(12):1835–44.CrossRefGoogle Scholar
  13. 13.
    Ciurea SO, Zhang MJ, Bacigalupo AA, Bashey A, Appelbaum FR, Aljitawi OS, et al. Haploidentical transplant with posttransplant cyclophosphamide vs matched unrelated donor transplant for acute myeloid leukemia. Blood. 2015;126(8):1033–40.CrossRefGoogle Scholar
  14. 14.
    Di Stasi A, Milton DR, Poon LM, Hamdi A, Rondon G, Chen J, et al. Similar transplantation outcomes for acute myeloid leukemia and myelodysplastic syndrome patients with haploidentical versus 10/10 human leukocyte antigen-matched unrelated and related donors. Biol Blood Marrow Transplant. 2014;20(12):1975–81.CrossRefGoogle Scholar
  15. 15.
    Bashey A, Zhang X, Sizemore CA, Manion K, Brown S, Holland HK, et al. T-cell-replete HLA-haploidentical hematopoietic transplantation for hematologic malignancies using post-transplantation cyclophosphamide results in outcomes equivalent to those of contemporaneous HLA-matched related and unrelated donor transplantation. J Clin Oncol. 2013;31(10):1310–6.CrossRefGoogle Scholar
  16. 16.
    Gaballa S, Palmisiano N, Alpdogan O, Carabasi M, Filicko-O’Hara J, Kasner M, et al. A two-step haploidentical versus a two-step matched related allogeneic myeloablative peripheral blood stem cell transplantation. Biol Blood Marrow Transplant. 2016;22(1):141–8.CrossRefGoogle Scholar
  17. 17.
    Kanate AS, Mussetti A, Kharfan-Dabaja MA, Ahn KW, DiGilio A, Beitinjaneh A, et al. Reduced-intensity transplantation for lymphomas using haploidentical related donors vs HLA-matched unrelated donors. Blood. 2016;127(7):938–47.CrossRefGoogle Scholar
  18. 18.
    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(4):339–48.CrossRefGoogle Scholar
  19. 19.
    Gaballa S, Ge I, El Fakih RO, Brammer JE, Wang SA, Lee DA, et al. Results of a two-arm phase II clinical trial using post-transplantation cyclophosphamide for prevention of graft-versus-host disease in haploidentical and mismatched unrelated donors hematopoietic stem-cell transplantation. Blood. 2015;126(23):152.Google Scholar
  20. 20.
    Solomon SR, Sizemore CA, Sanacore M, Zhang X, Brown S, Holland HK, et al. Haploidentical transplantation using T cell replete peripheral blood stem cells and myeloablative conditioning in patients with high-risk hematologic malignancies who lack conventional donors is well tolerated and produces excellent relapse-free survival: results of a prospective phase II trial. Biol Blood Marrow Transplant. 2012;18(12):1859–66.CrossRefGoogle Scholar
  21. 21.
    Grosso D, Gaballa S, Alpdogan O, Carabasi M, Filicko-O’Hara J, Kasner M, et al. A 2-step approach to myeloablative haploidentical transplantation: low non-relapse mortality and high survival confirmed in patients with early stage disease. Biol Blood Marrow Transplant. 2015;21(4):646–52.CrossRefGoogle Scholar
  22. 22.
    Shabbir-Moosajee M, Lombardi L, Ciurea SO. An overview of conditioning regimens for haploidentical stem cell transplantation with post-transplantation cyclophosphamide. Am J Hematol. 2015;90(6):541–8.CrossRefGoogle Scholar
  23. 23.
    Raj K, Pagliuca A, Bradstock K, Noriega V, Potter V, Streetly M, et al. Peripheral blood hematopoietic stem cells for transplantation of hematological diseases from related, haploidentical donors after reduced-intensity conditioning. Biol Blood Marrow Transplant. 2014;20(6):890–5.CrossRefGoogle Scholar
  24. 24.
    Solomon SR, Sizemore CA, Sanacore M, Zhang X, Brown S, Holland HK, et al. Total body irradiation-based myeloablative haploidentical stem cell transplantation is a safe and effective alternative to unrelated donor transplantation in patients without matched sibling donors. Biol Blood Marrow Transplant. 2015;21(7):1299–307.CrossRefGoogle Scholar
  25. 25.
    Gaballa S, Ge I, El Fakih R, Brammer JE, Kongtim P, Tomuleasa C, et al. Results of a 2-arm, phase 2 clinical trial using post-transplantation cyclophosphamide for the prevention of graft-versus-host disease in haploidentical donor and mismatched unrelated donor hematopoietic stem cell transplantation. Cancer. 2016;122(21):3316–26.CrossRefGoogle Scholar
  26. 26.
    Raiola AM, Dominietto A, Ghiso A, Di Grazia C, Lamparelli T, Gualandi F, et al. Unmanipulated haploidentical bone marrow transplantation and posttransplantation cyclophosphamide for hematologic malignancies after myeloablative conditioning. Biol Blood Marrow Transplant. 2013;19(1):117–22.CrossRefGoogle Scholar
  27. 27.
    Wang Y, Liu DH, LP X, Liu KY, Chen H, Chen YH, et al. Haploidentical/mismatched hematopoietic stem cell transplantation without in vitro T cell depletion for T cell acute lymphoblastic leukemia. Biol Blood Marrow Transplant. 2012;18(5):716–21.CrossRefGoogle Scholar
  28. 28.
    Brunstein CG, Fuchs EJ, Carter SL, Karanes C, Costa LJ, Wu J, et al. Alternative donor transplantation after reduced intensity conditioning: results of parallel phase 2 trials using partially HLA-mismatched related bone marrow or unrelated double umbilical cord blood grafts. Blood. 2011;118(2):282–8.CrossRefGoogle Scholar
  29. 29.
    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(16):1487–96.CrossRefGoogle Scholar
  30. 30.
    Kongtim P, Di Stasi A, Rondon G, Chen J, Adekola K, Popat U, et al. Can a female donor for a male recipient decrease the relapse rate for patients with acute myeloid leukemia treated with allogeneic hematopoietic stem cell transplantation? Biol Blood Marrow Transplant. 2015;21(4):713–9.CrossRefGoogle Scholar
  31. 31.
    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(5562):2097–100.CrossRefGoogle Scholar
  32. 32.
    Gagne K, Brizard G, Gueglio B, Milpied N, Herry P, Bonneville F, et al. Relevance of KIR gene polymorphisms in bone marrow transplantation outcome. Hum Immunol. 2002;63(4):271–80.CrossRefGoogle Scholar
  33. 33.
    Huang XJ, Zhao XY, Liu DH, Liu KY, Deleterious XLP. effects of KIR ligand incompatibility on clinical outcomes in haploidentical hematopoietic stem cell transplantation without in vitro T-cell depletion. Leukemia. 2007;21(4):848–51.CrossRefGoogle Scholar
  34. 34.
    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(3):726–32.CrossRefGoogle Scholar
  35. 35.
    Sivori S, Carlomagno S, Falco M, Romeo E, Moretta L, Moretta A. Natural killer cells expressing the KIR2DS1-activating receptor efficiently kill T-cell blasts and dendritic cells: implications in haploidentical HSCT. Blood. 2011;117(16):4284–92.CrossRefGoogle Scholar
  36. 36.
    Chen DF, Prasad VK, Broadwater G, Reinsmoen NL, DeOliveira A, Clark A, et al. Differential impact of inhibitory and activating Killer Ig-Like Receptors (KIR) on high-risk patients with myeloid and lymphoid malignancies undergoing reduced intensity transplantation from haploidentical related donors. Bone Marrow Transplant. 2012;47(6):817–23.CrossRefGoogle Scholar
  37. 37.
    Ciurea SO, Champlin RE. Donor selection in T cell-replete haploidentical hematopoietic stem cell transplantation: knowns, unknowns, and controversies. Biol Blood Marrow Transplant. 2013;19(2):180–4.CrossRefGoogle Scholar
  38. 38.
    Lee DA, Denman CJ, Rondon G, Woodworth G, Chen J, Fisher T, et al. Haploidentical natural killer cells infused before allogeneic stem cell transplantation for myeloid malignancies: a phase I trial. Biol Blood Marrow Transplant. 2016;22(7):1290–8.CrossRefGoogle Scholar
  39. 39.
    Goodyear OC, Dennis M, Jilani NY, Loke J, Siddique S, Ryan G, et al. Azacitidine augments expansion of regulatory T cells after allogeneic stem cell transplantation in patients with acute myeloid leukemia (AML). Blood. 2012;119(14):3361–9.CrossRefGoogle Scholar
  40. 40.
    de Lima M, Giralt S, Thall PF, de Padua Silva L, Jones RB, Komanduri K, et al. Maintenance therapy with low-dose azacitidine after allogeneic hematopoietic stem cell transplantation for recurrent acute myelogenous leukemia or myelodysplastic syndrome: a dose and schedule finding study. Cancer. 2010;116(23):5420–31.CrossRefGoogle Scholar
  41. 41.
    Younes A, Gopal AK, Smith SE, Ansell SM, Rosenblatt JD, Savage KJ, et al. Results of a pivotal phase II study of brentuximab vedotin for patients with relapsed or refractory Hodgkin’s lymphoma. J Clin Oncol. 2012;30(18):2183–9.CrossRefGoogle Scholar
  42. 42.
    Chen R, Palmer JM, Tsai NC, Thomas SH, Siddiqi T, Popplewell L, et al. Brentuximab vedotin is associated with improved progression-free survival after allogeneic transplantation for Hodgkin lymphoma. Biol Blood Marrow Transplant. 2014;20(11):1864–8.CrossRefGoogle Scholar
  43. 43.
    Kanakry JA, Gocke CD, Bolanos-Meade J, Gladstone DE, Swinnen LJ, Blackford AL, et al. Phase II study of nonmyeloablative allogeneic bone marrow transplantation for B cell lymphoma with post-transplantation rituximab and donor selection based first on non-HLA factors. Biol Blood Marrow Transplant. 2015;21(12):2115–22.CrossRefGoogle Scholar
  44. 44.
    Chen H, Liu KY, LP X, Liu DH, Chen YH, Zhao XY, et al. Administration of imatinib after allogeneic hematopoietic stem cell transplantation may improve disease-free survival for patients with Philadelphia chromosome-positive acute lymphobla stic leukemia. J Hematol Oncol. 2012;5:29.CrossRefGoogle Scholar
  45. 45.
    Sun J, Wang Z, Luo Y, Tan Y, Allan DS, Huang H. Prolonged survival with imatinib mesylate combined with chemotherapy and allogeneic stem cell transplantation in de novo Ph+ acute myeloid leukemia. Acta Haematol. 2012;127(3):143–8.CrossRefGoogle Scholar
  46. 46.
    Teng CL, JT Y, Chen HC, Hwang WL. Maintenance therapy with dasatinib after allogeneic hematopoietic stem cell transplantation in Philadelphia chromosome-positive acute lymphoblastic leukemia. Ann Hematol. 2013;92(8):1137–9.CrossRefGoogle Scholar
  47. 47.
    Klyuchnikov E, Kroger N, Brummendorf TH, Wiedemann B, Zander AR, Bacher U. Current status and perspectives of tyrosine kinase inhibitor treatment in the posttransplant period in patients with chronic myelogenous leukemia (CML). Biol Blood Marrow Transplant. 2010;16(3):301–10.CrossRefGoogle Scholar
  48. 48.
    Olavarria E, Siddique S, Griffiths MJ, Avery S, Byrne JL, Piper KP, et al. Posttransplantation imatinib as a strategy to postpone the requirement for immunotherapy in patients undergoing reduced-intensity allografts for chronic myeloid leukemia. Blood. 2007;110(13):4614–7.CrossRefGoogle Scholar
  49. 49.
    Weisser M, Tischer J, Schnittger S, Schoch C, Ledderose G, Kolb HJ. A comparison of donor lymphocyte infusions or imatinib mesylate for patients with chronic myelogenous leukemia who have relapsed after allogeneic stem cell transplantation. Haematologica. 2006;91(5):663–6. Epub 2006 Apr 19PubMedGoogle Scholar
  50. 50.
    Sammons SL, Pratz KW, Smith BD, Karp JE, Emadi A. Sorafenib is tolerable and improves clinical outcomes in patients with FLT3-ITD acute myeloid leukemia prior to stem cell transplant and after relapse post-transplant. Am J Hematol. 2014;89(9):936–8.CrossRefGoogle Scholar
  51. 51.
    Chen YB, Li S, Lane AA, Connolly C, Del Rio C, Valles B, et al. Phase I trial of maintenance sorafenib after allogeneic hematopoietic stem cell transplantation for fms-like tyrosine kinase 3 internal tandem duplication acute myeloid leukemia. Biol Blood Marrow Transplant. 2014;20(12):2042–8.CrossRefGoogle Scholar
  52. 52.
    Stone RM, Mandrekar S, Sanford BL, Geyer S, Bloomfield CD, Dohner K, et al. The multi-kinase inhibitor midostaurin (M) prolongs survival compared with placebo (P) in combination with daunorubicin (D)/cytarabine (C) induction (ind), high-dose C consolidation (consol), and as maintenance (maint) therapy in newly diagnosed acute my…. Blood. 2015;126(23):6.Google Scholar
  53. 53.
    Gaballa S, Saliba R, Oran B, Brammer JE, Chen J, Rondon G, et al. Minimal residual disease by PCR testing is a significant predictor of disease relapse in patients with FLT3 positive AML after hematopoietic stem cell transplantation. Biol Blood Marrow Transplant. 2015;21(2):S81–S2.CrossRefGoogle Scholar
  54. 54.
    Kongtim P, Lee DA, Cooper LJ, Kebriaei P, Champlin RE, Ciurea SO. Haploidentical hematopoietic stem cell transplantation as a platform for post-transplantation cellular therapy. Biol Blood Marrow Transplant. 2015;21(10):1714–20.CrossRefGoogle Scholar
  55. 55.
    Dazzi F, Szydlo RM, Craddock C, Cross NC, Kaeda J, Chase A, et al. Comparison of single-dose and escalating-dose regimens of donor lymphocyte infusion for relapse after allografting for chronic myeloid leukemia. Blood. 2000;95(1):67–71.PubMedGoogle Scholar
  56. 56.
    Zeidan AM, Forde PM, Symons H, Chen A, Smith BD, Pratz K, et al. HLA-haploidentical donor lymphocyte infusions for patients with relapsed hematologic malignancies after related HLA-haploidentical bone marrow transplantation. Biol Blood Marrow Transplant. 2014;20(3):314–8.CrossRefGoogle Scholar
  57. 57.
    Ghiso A, Raiola AM, Gualandi F, Dominietto A, Varaldo R, Van Lint MT, et al. DLI after haploidentical BMT with post-transplant CY. Bone Marrow Transplant. 2015;50(1):56–61.CrossRefGoogle Scholar
  58. 58.
    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(3):411–3.CrossRefGoogle Scholar
  59. 59.
    Vago L, Perna SK, Zanussi M, Mazzi B, Barlassina C, Stanghellini MT, et al. Loss of mismatched HLA in leukemia after stem-cell transplantation. N Engl J Med. 2009;361(5):478–88.CrossRefGoogle Scholar
  60. 60.
    Villalobos IB, Takahashi Y, Akatsuka Y, Muramatsu H, Nishio N, Hama A, et al. Relapse of leukemia with loss of mismatched HLA resulting from uniparental disomy after haploidentical hematopoietic stem cell transplantation. Blood. 2010;115(15):3158–61.CrossRefGoogle Scholar
  61. 61.
    Grosso D, Colombe B, Wang Z-X, Carabasi M, Alpdogan O, Filicko-O’Hara J, et al. Detection of acquired uniparental disomy (aUPD) with HLA typing and microarray analysis after t cell-containing haploidentical (HI) hematopoietic stem cell transplantation (HSCT). Blood. 2015;126(23):3165.Google Scholar
  62. 62.
    Zheng P, Sarma S, Guo Y, Liu Y. Two mechanisms for tumor evasion of preexisting cytotoxic T-cell responses: lessons from recurrent tumors. Cancer Res. 1999;59(14):3461–7.PubMedGoogle Scholar
  63. 63.
    Garcia-Lora A, Algarra I, Gaforio JJ, Ruiz-Cabello F, Garrido F. Immunoselection by T lymphocytes generates repeated MHC class I-deficient metastatic tumor variants. Int J Cancer. 2001;91(1):109–19.CrossRefGoogle Scholar
  64. 64.
    Ciceri F, Bonini C, Stanghellini MT, Bondanza A, Traversari C, Salomoni M, et al. Infusion of suicide-gene-engineered donor lymphocytes after family haploidentical haemopoietic stem-cell transplantation for leukaemia (the TK007 trial): a non-randomised phase I-II study. Lancet Oncol. 2009;10(5):489–500.CrossRefGoogle Scholar
  65. 65.
    Di Stasi A, Tey SK, Dotti G, Fujita Y, Kennedy-Nasser A, Martinez C, et al. Inducible apoptosis as a safety switch for adoptive cell therapy. N Engl J Med. 2011;365(18):1673–83.CrossRefGoogle Scholar
  66. 66.
    Locatelli F, Merli P, Li Pira G, Bertaina V, Lucarelli B, Brescia LP, et al. Clinical outcome after adoptive infusion of BPX-501 cells (donor T cells transduced with iC9 suicide gene) in children given alpha/beta T-cell depleted HLA-haploidentical hematopoietic stem cell transplantation (haplo-HSCT): preliminary results of a phas…. Blood. 2015;126(23):1931.Google Scholar
  67. 67.
    Maude SL, Frey N, Shaw PA, Aplenc R, Barrett DM, Bunin NJ, et al. Chimeric antigen receptor T cells for sustained remissions in leukemia. N Engl J Med. 2014;371(16):1507–17.CrossRefGoogle Scholar
  68. 68.
    Kebriaei P, Singh H, Huls MH, Figliola MJ, Bassett R, Olivares S, et al. Phase I trials using Sleeping Beauty to generate CD19-specific CAR T cells. J Clin Invest. 2016;126(9):3363–76.CrossRefGoogle Scholar
  69. 69.
    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(1):333–9.PubMedGoogle Scholar
  70. 70.
    Miller JS, Soignier Y, Panoskaltsis-Mortari A, McNearney SA, Yun GH, Fautsch SK, et al. Successful adoptive transfer and in vivo expansion of human haploidentical NK cells in patients with cancer. Blood. 2005;105(8):3051–7.CrossRefGoogle Scholar
  71. 71.
    Tonn T, Schwabe D, Klingemann HG, Becker S, Esser R, Koehl U, et al. Treatment of patients with advanced cancer with the natural killer cell line NK-92. Cytotherapy. 2013;15(12):1563–70.CrossRefGoogle Scholar
  72. 72.
    Spanholtz J, Preijers F, Tordoir M, Trilsbeek C, Paardekooper J, de Witte T, et al. Clinical-grade generation of active NK cells from cord blood hematopoietic progenitor cells for immunotherapy using a closed-system culture process. PLoS One. 2011;6(6):e20740.CrossRefGoogle Scholar
  73. 73.
    Denman CJ, Senyukov VV, Somanchi SS, Phatarpekar PV, Kopp LM, Johnson JL, et al. Membrane-bound IL-21 promotes sustained ex vivo proliferation of human natural killer cells. PLoS One. 2012;7(1):e30264.CrossRefGoogle Scholar
  74. 74.
    McEwen-Smith RM, Salio M, Cerundolo V. The regulatory role of invariant NKT cells in tumor immunity. Cancer Immunol Res. 2015;3(5):425–35.CrossRefGoogle Scholar
  75. 75.
    Malard F, Labopin M, Chevallier P, Guillaume T, Duquesne A, Rialland F, et al. Larger number of invariant natural killer T cells in PBSC allografts is associated with improved GVHD-free, progression-free survival. Blood. 2016.
  76. 76.
    Vivier E, Tomasello E, Baratin M, Walzer T, Ugolini S. Functions of natural killer cells. Nat Immunol. 2008;9(5):503–10.CrossRefGoogle Scholar
  77. 77.
    Shaw BE, Mufti GJ, Mackinnon S, Cavenagh JD, Pearce RM, Towlson KE, et al. Outcome of second allogeneic transplants using reduced-intensity conditioning following relapse of haematological malignancy after an initial allogeneic transplant. Bone Marrow Transplant. 2008;42(12):783–9.CrossRefGoogle Scholar
  78. 78.
    Tischer J, Engel N, Fritsch S, Prevalsek D, Hubmann M, Schulz C, et al. Second haematopoietic SCT using HLA-haploidentical donors in patients with relapse of acute leukaemia after a first allogeneic transplantation. Bone Marrow Transplant. 2014;49(7):895–901.CrossRefGoogle Scholar
  79. 79.
    Kako S, Izutsu K, Oshima K, Sato H, Kanda Y, Motokura T, et al. Regression of the tumor after withdrawal of cyclosporine in relapsed extranodal natural killer/T cell lymphoma following allogeneic hematopoietic stem cell transplantation. Am J Hematol. 2007;82(10):937–9.CrossRefGoogle Scholar
  80. 80.
    Elmaagacli AH, Beelen DW, Trenn G, Schmidt O, Nahler M, Schaefer UW. Induction of a graft-versus-leukemia reaction by cyclosporin A withdrawal as immunotherapy for leukemia relapsing after allogeneic bone marrow transplantation. Bone Marrow Transplant. 1999;23(8):771–7.CrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  • Sameh Gaballa
    • 1
  • Syed A. Abutalib
    • 2
  • Stefan O. Ciurea
    • 3
    Email author
  1. 1.Division of Hematological Malignancies and Stem Cell Transplantation, Department of Medical OncologyThomas Jefferson University HospitalPhiladelphiaUSA
  2. 2.Department of Hematology and Hematopoietic Cell TransplantationCancer Treatment Centers of AmericaZionUSA
  3. 3.Department of Stem Cell Transplantation and Cellular TherapyThe University of Texas MD Anderson Cancer CenterHoustonUSA

Personalised recommendations