Advancement of human leukocyte antigen-partially matched related hematopoietic stem cell transplantation

Abstract

Allogeneic hematopoietic stem cell transplantation (HSCT) is one of the most effective options for hematological malignancies, and human leukocyte antigen-partially matched related donors (PMRDs) are a valuable option for HSCT. Several protocols (with or without ex vivo T-cell depletion (TCD)) have been established worldwide. TCD including CD34⁺ positive selection and CD3/CD19 depletion has successfully overcome the human leukocyte antigen disparity. However, TCD is associated with prolonged immune deficiencies, increased risks of infectious complications, and high transplantation-related mortality. PMRD HSCT without ex vivo TCD is well developed, and numerous patients have benefitted from it. Here, we review the literature on PMRD HSCT.

Keywords

partially matched related donor / hematopoietic stem cell transplantation / allogeneic

References

[1] Aversa F, Tabilio A, Terenzi A, Velardi A, Falzetti F, Giannoni C, Iacucci R, Zei T, Martelli MP, Gambelunghe C, . Successful engraftment of T-cell-depleted haploidentical “three-loci” incompatible transplants in leukemia patients by addition of recombinant human granulocyte colony-stimulating factor-mobilized peripheral blood progenitor cells to bone marrow inoculum. Blood 1994; 84(11): 3948–3955

[2] Aversa F, Tabilio A, Velardi A, Cunningham I, Terenzi A, Falzetti F, Ruggeri L, Barbabietola G, Aristei C, Latini P, Reisner Y, Martelli MF, Felicini R, Falcinelli F, Carotti A, Perruccio K, Ballanti S, Santucci A, Gambelunghe C. 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): 1186–1193

[3] Aversa F, Terenzi A, Tabilio A, Falzetti F, Carotti A, Ballanti S, Felicini R, Falcinelli F, Velardi A, Ruggeri L, Aloisi T, Saab JP, Santucci A, Perruccio K, Martelli MP, Mecucci C, Reisner Y, Martelli MF. Full haplotype-mismatched hematopoietic stem-cell transplantation: a phase II study in patients with acute leukemia at high risk of relapse. J Clin Oncol 2005; 23(15): 3447–3454

[4] Lang P, Bader P, Schumm M, Feuchtinger T, Einsele H, Führer M, Weinstock C, Handgretinger R, Kuci S, Martin D, Niethammer D, Greil J. Transplantation of a combination of CD133+ and CD34+ selected progenitor cells from alternative donors. Br J Haematol 2004; 124(1): 72–79

[5] Chang YJ, Huang XJ. Haploidentical hematopoietic stem cell transplantation with unmanipulated granulocyte colony stimulating factor mobilized marrow and blood grafts. Curr Opin Hematol 2012; 19(6): 454–461

[6] Bethge WA, Haegele M, Faul C, Lang P, Schumm M, Bornhauser M, Handgretinger R, Kanz L. Haploidentical allogeneic hematopoietic cell transplantation in adults with reduced-intensity conditioning and CD3/CD19 depletion: fast engraftment and low toxicity. Exp Hematol 2006; 34(12): 1746–1752

[7] Bethge WA, Faul C, Bornhäuser M, Stuhler G, Beelen DW, Lang P, Stelljes M, Vogel W, Hägele M, Handgretinger R, Kanz L. Haploidentical allogeneic hematopoietic cell transplantation in adults using CD3/CD19 depletion and reduced intensity conditioning: an update. Blood Cells Mol Dis 2008; 40(1): 13–19

[8] Federmann B, Hägele M, Pfeiffer M, Wirths S, Schumm M, Faul C, Vogel W, Handgretinger R, Kanz L, Bethge WA. Immune reconstitution after haploidentical hematopoietic cell transplantation: impact of reduced intensity conditioning and CD3/CD19 depleted grafts. Leukemia 2011; 25(1): 121–129

[9] Lu DP, Dong L, Wu T, Huang XJ, Zhang MJ, Han W, Chen H, Liu DH, Gao ZY, Chen YH, Xu LP, Zhang YC, Ren HY, Li D, Liu KY. Conditioning including antithymocyte globulin followed by unmanipulated HLA-mismatched/haploidentical blood and marrow transplantation can achieve comparable outcomes with HLA-identical sibling transplantation. Blood 2006; 107(8): 3065–3073

[10] Wang Y, Liu DH, Liu KY, Xu LP, Zhang XH, Han W, Chen H, Chen YH, Wang FR, Wang JZ, Sun YQ, Huang XJ. Long-term follow-up of haploidentical hematopoietic stem cell transplantation without in vitro T cell depletion for the treatment of leukemia: nine years of experience at a single center. Cancer 2013;119(5):978–985

[11] Chang YJ, Xu LP, Liu DH, Liu KY, Han W, Chen YH, Yu Wang, Chen H, Wang JZ, Zhang XH, Zhao XY, Huang XJ. Platelet engraftment in patients with hematologic malignancies following unmanipulated haploidentical blood and marrow transplantation: effects of CD34+ cell dose and disease status. Biol Blood Marrow Transplant 2009; 15(5): 632–638

[12] Lazarus HM, Koc ON, Devine SM, Curtin P, Maziarz RT, Holland HK, Shpall EJ, McCarthy P, Atkinson K, Cooper BW, Gerson SL, Laughlin MJ, Loberiza FR Jr, Moseley AB, Bacigalupo A. Cotransplantation of HLA-identical sibling culture-expanded mesenchymal stem cells and hematopoietic stem cells in hematologic malignancy patients. Biol Blood Marrow Transplant 2005; 11(5): 389–398

[13] Liu K, Chen Y, Zeng Y, Xu L, Liu D, Chen H, Zhang X, Han W, Wang Y, Zhao T, Wang J, Wang J, Han Q, Zhao C, Huang X. Coinfusion of mesenchymal stromal cells facilitates platelet recovery without increasing leukemia recurrence in haploidentical hematopoietic stem cell transplantation: a randomized, controlled clinical study. Stem Cells Dev 2011; 20(10): 1679–1685

[14] Huang XJ, Liu DH, Liu KY, Xu LP, Chen H, Han W, Chen YH, Wang JZ, Gao ZY, Zhang YC, Jiang Q, Shi HX, Lu DP. Haploidentical hematopoietic stem cell transplantation without in vitro T-cell depletion for the treatment of hematological malignancies. Bone Marrow Transplant 2006; 38(4): 291–297

[15] Huang XJ, Xu LP, Liu KY, Liu DH, Wang Y, Chen H, Chen YH, Han W, Wang JZ, Chen Y, Zhang XH, Shi HX, Wang FR, Tang FF. Partially matched related donor transplantation can achieve outcomes comparable with unrelated donor transplantation for patients with hematologic malignancies. Clin Cancer Res 2009; 15(14): 4777–4783

[16] Huang XJ, Liu DH, Liu KY, Xu LP, Chen H, Han W, Chen YH, Zhang XH, Lu DP. Treatment of acute leukemia with unmanipulated HLA-mismatched/haploidentical blood and bone marrow transplantation. Biol Blood Marrow Transplant 2009; 15(2): 257–265

[17] Finke J, Bethge WA, Schmoor C, Ottinger HD, Stelljes M, Zander AR, Volin L, Ruutu T, Heim DA, Schwerdtfeger R, Kolbe K, Mayer J, Maertens JA, Linkesch W, Holler E, Koza V, Bornhäuser M, Einsele H, Kolb HJ, Bertz H, Egger M, Grishina O, Socié G; ATG-Fresenius Trial Group. Standard graft-versus-host disease prophylaxis with or without anti-T-cell globulin in haematopoietic cell transplantation from matched unrelated donors: a randomised, open-label, multicentre phase 3 trial. Lancet Oncol 2009; 10(9): 855–864

[18] Basara N, Baurmann H, Kolbe K, Yaman A, Labopin M, Burchardt A, Huber C, Fauser AA, Schwerdtfeger R. Antithymocyte globulin for the prevention of graft-versus-host disease after unrelated hematopoietic stem cell transplantation for acute myeloid leukemia: results from the multicenter German cooperative study group. Bone Marrow Transplant 2005; 35(10): 1011–1018

[19] Huang XJ. HLA-mismatched/haploidentical hematopoietic stem cell transplantation: a field in which Chinese doctors are making great contributions. Chin Med J (Engl) 2010; 123(10): 1235–1240

[20] Luo XH, Chang YJ, Xu LP, Liu DH, Liu KY, Huang XJ. The impact of graft composition on clinical outcomes in unmanipulated HLA-mismatched/haploidentical hematopoietic SCT. Bone Marrow Transplant 2009; 43(1): 29–36

[21] Zhao XY, Chang YJ, Xu LP, Liu DH, Liu KY, Huang XJ. Association of natural killer cells in allografts with transplant outcomes in patients receiving G-CSF-mobilized PBSC grafts and G-CSF-primed BM grafts from HLA-haploidentical donors. Bone Marrow Transplant 2009; 44(11): 721–728

[22] Chang YJ, Zhao XY, Huo MR, Huang XJ. Expression of CD62L on donor CD4(+) T cells in allografts: correlation with graft-versus-host disease after unmanipulated allogeneic blood and marrow transplantation. J Clin Immunol 2009; 29(5): 696–704

[23] Zhao XY, Xu LL, Lu SY, Huang XJ. IL-17-producing T cells contribute to acute graft-versus-host disease in patients undergoing unmanipulated blood and marrow transplantation. Eur J Immunol 2011; 41(2): 514–526

[24] Huo MR, Xu LP, Li D, Liu DH, Liu KY, Chen H, Han W, Chen YH, Wang Y, Wang JZ, Zhang XH, Zhao XY, Huang XJ. The effect of HLA disparity on clinical outcome after HLA-haploidentical blood and marrow transplantation. Clin Transplant 2012; 26(2): 284–291

[25] Zhao XY, Huang XJ, Liu KY, Xu LP, Liu DH. Prognosis after unmanipulated HLA-haploidentical blood and marrow transplantation is correlated to the numbers of KIR ligands in recipients. Eur J Haematol 2007; 78(4): 338–346

[26] Chang YJ, Zhao XY, Huo MR, Xu LP, Liu DH, Liu KY, Huang XJ. Influence of lymphocyte recovery on outcome of haploidentical transplantation for hematologic malignancies. Medicine (Baltimore) 2009; 88(6): 322–330

[27] Chang YJ, Zhao XY, Huo MR, Xu LP, Liu DH, Liu KY, Huang XJ. Clinical impact of absolute lymphocyte count on day 30 after unmanipulated haploidentical blood and marrow transplantation for pediatric patients with hematological malignancies. Am J Hematol 2011; 86(2): 227–230

[28] Huang XJ, Liu DH, Liu KY, Xu LP, Chen H, Han W. Donor lymphocyte infusion for the treatment of leukemia relapse after HLA-mismatched/haploidentical T-cell-replete hematopoietic stem cell transplantation. Haematologica 2007; 92(3): 414–417

[29] Huang XJ, Wang Y, Liu DH, Xu LP, Chen H, Chen YH, Han W, Shi HX, Liu KY. Modified donor lymphocyte infusion (DLI) for the prophylaxis of leukemia relapse after hematopoietic stem cell transplantation in patients with advanced leukemia—feasibility and safety study. J Clin Immunol 2008; 28(4): 390–397

[30] Wang Y, Liu DH, Xu LP, Liu KY, Chen H, Zhang XH, Chen YH, Han W, Wang FR, Wang JZ, Yan CH, Huang XJ. Prevention of relapse using granulocyte CSF-primed PBPCs following HLA-mismatched/haploidentical, T-cell-replete hematopoietic SCT in patients with advanced-stage acute leukemia: a retrospective risk-factor analysis. Bone Marrow Transplant 2012; 47(8): 1099–1104

[31] Schnittger S, Weisser M, Schoch C, Hiddemann W, Haferlach T, Kern W. New score predicting for prognosis in PML-RARA+, AML1-ETO+, or CBFBMYH11+ acute myeloid leukemia based on quantification of fusion transcripts. Blood 2003; 102(8): 2746–2755

[32] Weisser M, Kern W, Rauhut S, Schoch C, Hiddemann W, Haferlach T, Schnittger S. Prognostic impact of RT-PCR-based quantification of WT1 gene expression during MRD monitoring of acute myeloid leukemia. Leukemia 2005; 19(8): 1416–1423

[33] Zhao XS, Jin S, Zhu HH, Xu LP, Liu DH, Chen H, Liu KY, Huang XJ. Wilms’ tumor gene 1 expression: an independent acute leukemia prognostic indicator following allogeneic hematopoietic SCT. Bone Marrow Transplant 2012; 47(4): 499–507

[34] Kern W, Danhauser-Riedl S, Ratei R, Schnittger S, Schoch C, Kolb HJ, Ludwig WD, Hiddemann W, Haferlach T. Detection of minimal residual disease in unselected patients with acute myeloid leukemia using multiparameter flow cytometry for definition of leukemia-associated immunophenotypes and determination of their frequencies in normal bone marrow. Haematologica 2003; 88(6): 646–653

[35] Zhao XS, Liu YR, Zhu HH, Xu LP, Liu DH, Liu KY, Huang XJ. Monitoring MRD with flow cytometry: an effective method to predict relapse for ALL patients after allogeneic hematopoietic stem cell transplantation. Ann Hematol 2012; 91(2): 183–192

[36] Yan CH, Liu DH, Liu KY, Xu LP, Liu YR, Chen H, Han W, Wang Y, Qin YZ, Huang XJ. Risk stratification-directed donor lymphocyte infusion could reduce relapse of standard-risk acute leukemia patients after allogeneic hematopoietic stem cell transplantation. Blood 2012; 119(14): 3256–3262

[37] Huang XJ, Xu LP, Liu KY, Liu DH, Chen H, Han W, Chen YH, Wang JZ, Chen Y, Zhang XH, Shi HX, Lu DP. HLA-mismatched/haploidentical hematopoietic stem cell transplantation without in vitro T cell depletion for chronic myeloid leukemia: improved outcomes in patients in accelerated phase and blast crisis phase. Ann Med 2008; 40(6): 444–455

[38] Chen Y, Liu K, Xu L, Chen H, Liu D, Zhang X, Shi H, Han W, Wang Y, Zhao T, Wang J, Wang J, Huang X. HLA-mismatched hematopoietic SCT without in vitro T-cell depletion for myelodysplastic syndrome. Bone Marrow Transplant 2010; 45(8): 1333–1339

[39] Wang Y, Liu DH, Xu LP, Liu KY, Chen H, Chen YH, Han W, Shi HX, Huang XJ. Superior graft-versus-leukemia effect associated with transplantation of haploidentical compared with HLA-identical sibling donor grafts for high-risk acute leukemia: an historic comparison. Biol Blood Marrow Transplant 2011; 17(6): 821–830

[40] Chang YJ, Zhao XY, Huo MR, Xu LP, Liu DH, Liu KY, Huang XJ. Immune reconstitution following unmanipulated HLA-mismatched/haploidentical transplantation compared with HLA-identical sibling transplantation. J Clin Immunol 2012; 32(2): 268–280

[41] Luo XH, Huang XJ, Li D, Liu KY, Xu LP, Liu DH. Immune reconstitution to cytomegalovirus following partially matched-related donor transplantation: impact of in vivo T-cell depletion and granulocyte colony-stimulating factor-primed peripheral blood/bone marrow mixed grafts. Transpl Infect Dis 2013; 15(1): 22–33

[42] Smith KA. Interleukin-2: inception, impact, and implications. Science 1988; 240(4856): 1169–1176

[43] Chang YJ, Zhao XY, Huang XJ. Effects of the NK cell recovery on outcomes of unmanipulated haploidentical blood and marrow transplantation for patients with hematologic malignancies. Biol Blood Marrow Transplant 2008; 14(3): 323–334

[44] Mo XD, Xu LP, Liu DH, Chen YH, Han W, Zhang XH, Chen H, Wang Y, Wang JZ, Liu KY, Huang XJ. Patients receiving HLA-haploidentical/partially matched related allo-HSCT can achieve desirable health-related QoL that is comparable to that of patients receiving HLA-identical sibling allo-HSCT. Bone Marrow Transplant 2012; 47(9): 1201–1205

[45] Huang XJ, Chang YJ. Unmanipulated HLA-mismatched/haploidentical blood and marrow hematopoietic stem cell transplantation. Biol Blood Marrow Transplant 2011; 17(2): 197–204

[46] Jun HX, Jun CY, Yu ZX. In vivo induction of T-cell hyporesponsiveness and alteration of immunological cells of bone marrow grafts using granulocyte colony-stimulating factor. Haematologica 2004; 89(12): 1517–1524

[47] Chang YJ, Zhao XY, Huo MR, Huang XJ. Expression profiles of adhesion molecules on naïve T cells in bone marrow grafts of healthy donors treated with granulocyte colony-stimulating factor. Transpl Immunol 2009; 21(4): 228–233

[48] Huang XJ, Chang YJ, Zhao XY. Maintaining hyporesponsiveness and polarization potential of T cells after in vitro mixture of G-CSF mobilized peripheral blood grafts and G-CSF primed bone marrow grafts in different proportions. Transpl Immunol 2007; 17(3): 193–197

[49] Huang XJ, Zhao J, Zhao XY, Chang YJ. Treating donor mice with rhIL-11 and rhG-CSF promotes transplant-tolerance and preserves the effects of GVL after allogeneic bone marrow transplantation. Leuk Res 2009; 33(1): 123–128

[50] Xu LP, Liu KY, Liu DH, Chen H, Han W, Chen YH, Wang Y, Huang XJ. The inferiority of G-PB to rhG-CSF-mobilized blood and marrow grafts as a stem cell source in patients with high-risk acute leukemia who underwent unmanipulated HLA-mismatched/haploidentical transplantation: a comparative analysis. Bone Marrow Transplant 2010; 45(6): 985–992

[51] Huang W, Li H, Gao C, Bo J, Wang Q, Zhao Y, Jing Y, Wang S, Zhu H, Dou L, Wang L, Yu L. Unmanipulated HLA-mismatched/haploidentical peripheral blood stem cell transplantation for high-risk hematologic malignancies. Transfusion 2012; 52(6): 1354–1362

[52] Lang P, Handgretinger R. Haploidentical SCT in children: an update and future perspectives. Bone Marrow Transplant 2008; 42(Suppl 2): S54–S59

[53] Klingebiel T, Cornish J, Labopin M, Locatelli F, Darbyshire P, Handgretinger R, Balduzzi A, Owoc-Lempach J, Fagioli F, Or R, Peters C, Aversa F, Polge E, Dini G, Rocha V; Pediatric Diseases and Acute Leukemia Working Parties of the European Group for Blood and Marrow Transplantation (EBMT). Results and factors influencing outcome after fully haploidentical hematopoietic stem cell transplantation in children with very high-risk acute lymphoblastic leukemia: impact of center size: an analysis on behalf of the Acute Leukemia and Pediatric Disease Working Parties of the European Blood and Marrow Transplant group. Blood 2010; 115(17): 3437–3446

[54] Gonzalez-Vicent M, Perez A, Abad L, Sevilla J, Ramirez M, Diaz MA. Graft manipulation and reduced-intensity conditioning for allogeneic hematopoietic stem cell transplantation from mismatched unrelated and mismatched/haploidentical related donors in pediatric leukemia patients. J Pediatr Hematol Oncol 2010; 32(3): e85–e90

[55] Liu D, Huang X, Liu K, Xu L, Chen H, Han W, Chen Y, Zhang X, Jiang Q. Haploidentical hematopoietic stem cell transplantation without in vitro T cell depletion for treatment of hematological malignancies in children. Biol Blood Marrow Transplant 2008; 14(4): 469–477

[56] Rizzieri DA, Koh LP, Long GD, Gasparetto C, Sullivan KM, Horwitz M, Chute J, Smith C, Gong JZ, Lagoo A, Niedzwiecki D, Dowell JM, Waters-Pick B, Liu C, Marshall D, Vredenburgh JJ, Gockerman J, Decastro C, Moore J, Chao NJ. Partially matched, nonmyeloablative allogeneic transplantation: clinical outcomes and immune reconstitution. J Clin Oncol 2007; 25(6): 690–697

[57] Brunstein CG, Fuchs EJ, Carter SL, Karanes C, Costa LJ, Wu J, Devine SM, Wingard JR, Aljitawi OS, Cutler CS, Jagasia MH, Ballen KK, Eapen M, O’Donnell PV; Blood and Marrow Transplant Clinical Trials Network. 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): 282–288

[58] Munchel A, Kesserwan C, Symons HJ, Luznik L, Kasamon YL, Jones RJ, Fuchs EJ. Nonmyeloablative, HLA-haploidentical bone marrow transplantation with high dose, post-transplantation cyclophosphamide. Pediatr Rep 2011; 3( Suppl 2): e15

[59] Lee KH, Lee JH, Lee JH, Kim DY, Seol M, Lee YS, Kang YA, Jeon M, Hwang HJ, Jung AR, Kim SH, Yun SC, Shin HJ. Reduced-intensity conditioning therapy with busulfan, fludarabine, and antithymocyte globulin for HLA-haploidentical hematopoietic cell transplantation in acute leukemia and myelodysplastic syndrome. Blood 2011; 118(9): 2609–2617

Acknowledgements

This work was partly supported by the National High Technology Research and Development Program of China (863 Program) (Grant No. 2011AA020105) and the Key Program of National Natural Science Foundation of China (Grant No. 81230013).

Compliance with ethics guidelines

Xiaodong Mo and Xiaojun Huang declare no conflicts of interest. This manuscript is a review article and does not involve a research protocol requiring approval by the relevant institutional review board or ethics committee.

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