Abstract
In the past, partially HLA-mismatched related donor, or HLA-haploidentical, blood or marrow transplantation (haploBMT), for hematologic malignancies has been complicated by unacceptably high incidences of graft rejection or GvHD resulting from intense bi-directional alloreactivity. Administration of high doses of cyclophosphamide early after haploBMT selectively kills proliferating, alloreactive T cells while sparing non-alloreactive T cells responsible for immune reconstitution and resistance to infection. In the clinic, haploBMT with high-dose, post-transplantation cyclophosphamide is associated with acceptably low incidences of fatal graft rejection, GvHD and non-relapse mortality, and provides an acceptable treatment option for hematologic malignancies patients lacking suitably HLA-matched donors. HaploBMT with PTCy is now being investigated as a treatment of hemoglobinopathy and as a method for inducing tolerance to solid organs transplanted from the same donor. Ongoing and future clinical trials will establish the hierarchy of donor preference for hematologic malignancy patients lacking an HLA-matched sibling.
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References
Anasetti C, Amos D, Beatty PG, Appelbaum FR, Bensinger W, Buckner CD et al. Effect of HLA compatibility on engraftment of bone marrow transplants in patients with leukemia or lymphoma. N Engl J Med 1989; 320: 197–204.
Anasetti C, Beatty PG, Storb R, Martin PJ, Mori M, Sanders JE et al. Effect of HLA incompatibility on graft-versus-host disease, relapse, and survival after marrow transplantation for patients with leukemia or lymphoma. Hum Immunol 1990; 29: 79–91.
Ash RC, Horowitz MM, Gale RP, van Bekkum DW, Casper JT, Gordon-Smith EC et al. Bone marrow transplantation from related donors other than HLA- identical siblings: effect of T cell depletion. Bone Marrow Transplant 1991; 7: 443–452.
Aversa F, Tabilio A, Velardi A, Terenzi A, Falzetti F, Ruggeri L et al. Treatment of high-risk acute leukemia with T-cell-depleted stem cells from related donors with one fully mismatched HLA haplotype [see comments]. N Engl J Med 1998; 339: 1186–1193.
Luznik L, Jalla S, Engstrom LW, Iannone R, Fuchs EJ . Durable engraftment of major histocompatibility complex-incompatible cells after nonmyeloablative conditioning with fludarabine, low-dose total body irradiation, and posttransplantation cyclophosphamide. Blood 2001; 98: 3456–3464.
Matzinger P, Bevan MJ . Hypothesis: why do so many lymphocytes respond to major histocompatibility antigens? Cell Immunol 1977; 29: 1–5.
Adams AB, Williams MA, Jones TR, Shirasugi N, Durham MM, Kaech SM et al. Heterologous immunity provides a potent barrier to transplantation tolerance. J Clin Invest 2003; 111: 1887–1895.
Finberg R, Burakoff SJ, Cantor H, Benacerraf B . Biological significance of alloreactivity: T cells stimulated by Sendai virus-coated syngeneic cells specifically lyse allogeneic target cells. Proc Natl Acad Sci USA 1978; 75: 5145–5149.
Nadazdin O, Boskovic S, Murakami T, Tocco G, Smith RN, Colvin RB et al. Host alloreactive memory T cells influence tolerance to kidney allografts in nonhuman primates. Sci Transl Med 2011; 3: 86ra51.
Schwartz R, Dameshek W . Drug-induced immunological tolerance. Nature 1959; 183: 1682–1683.
Berenbaum MC, Brown IN . Dose-response relationships for agents inhibiting the immune response. Immunology 1964; 7: 65–71.
Mayumi H, Himeno K, Shin T, Nomoto K . Drug-induced tolerance to allografts in mice. VI. Tolerance induction in H-2-haplotype-identical strain combinations in mice. Transplantation 1985; 40: 188–194.
Mayumi H, Himeno K, Tokuda N, Nomoto K . Drug-induced tolerance to allografts in mice. VII. Optimal protocol and mechanism of cyclophosphamide-induced tolerance in an H-2 haplotype-identical strain combination. Transplant Proc 1986; 18: 363–369.
Mayumi H, Himeno K, Tanaka K, Tokuda N, Fan JL, Nomoto K . Drug-induced tolerance to allografts in mice. XII. The relationships between tolerance, chimerism, and graft-versus-host disease. Transplantation 1987; 44: 286–290.
Eto M, Mayumi H, Tomita Y, Yoshikai Y, Nishimura Y, Maeda T et al. Specific destruction of host-reactive mature T cells of donor origin prevents graft-versus-host disease in cyclophosphamide- induced tolerant mice. J Immunol 1991; 146: 1402–1409.
Eto M, Mayumi H, Tomita Y, Yoshikai Y, Nomoto K . Intrathymic clonal deletion of V beta 6+ T cells in cyclophosphamide-induced tolerance to H-2-compatible, Mls- disparate antigens. J Exp Med 1990; 171: 97–113.
Eto M, Mayumi H, Tomita Y, Yoshikai Y, Nishimura Y, Nomoto K et al. Sequential mechanisms of cyclophosphamide-induced skin allograft tolerance including the intrathymic clonal deletion followed by late breakdown of the clonal deletion. J Immunol 1990; 145: 1303–1310.
Eto M, Mayumi H, Tomita Y, Yoshikai Y, Nishimura Y, Nomoto K et al. The requirement of intrathymic mixed chimerism and clonal deletion for a long-lasting skin allograft tolerance in cyclophosphamide-induced tolerance. Eur J Immunol 1990; 20: 2005–2013.
Eto M, Mayumi H, Tomita Y, Yoshikai Y, Nishimura Y, Nomoto K . Sequential mechanisms of cyclophosphamide-induced skin allograft tolerance including the intrathymic clonal deletion followed by late breakdown of the clonal deletion. J Immunol 1990; 145: 1303–1310.
Maeda T, Eto M, Nishimura Y, Nomoto K, Kong YY . Direct evidence for clonal destruction of allo-reactive T cells in the mice treated with cyclophosphamide after allo-priming. Immunology 1993; 78: 113–121.
Maeda T, Eto M, Nishimura Y, Nomoto K, Kong YY . Role of peripheral hemopoietic chimerism in achieving donor- specific tolerance in adult mice. J Immunol 1993; 150: 753–762.
Mayumi H, Good RA . Long-lasting skin allograft tolerance in adult mice induced across fully allogeneic (multimajor H-2 plus multiminor histocompatibility) antigen barriers by a tolerance-inducing method using cyclophosphamide. J Exp Med 1989; 169: 213–238.
Colson YL, Wren SM, Schuchert MJ, Patrene KD, Johnson PC, Boggs SS et al. A nonlethal conditioning approach to achieve durable multilineage mixed chimerism and tolerance across major, minor, and hematopoietic histocompatibility barriers. J Immunol 1995; 155: 4179–4188.
Colson YL, Li H, Boggs SS, Patrene KD, Johnson PC, Ildstad ST et al. Durable mixed allogeneic chimerism and tolerance by a nonlethal radiation-based cytoreductive approach. J Immunol 1996; 157: 2820–2829.
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: 641–650.
Storb R, Gyurkocza B, Storer BE, Sorror ML, Blume K, Niederwieser D et al. Graft-versus-host disease and graft-versus-tumor effects after allogeneic hematopoietic cell transplantation. J Clin Oncol 2013; 31: 1530–1538.
Kasamon YL, Prince G, Bolaños-Meade J, Tsai H-L, Luznik L, Ambinder RF et al. Encouraging outcomes in older patients (pts) following nonmyeloablative (NMA) haploidentical blood or marrow transplantation (haploBMT) with high-dose posttransplantation cyclophosphamide (PT/Cy). Blood 2013; 122: 158.
King AS . Evidence-based focused review of the status of hematopoietic stem cell transplantation as treatment of sickle cell disease and thalassemia. Blood 2014; 123: 3089–3094.
Chakrabarti S, Bareford D . A survey on patient perception of reduced-intensity transplantation in adults with sickle cell disease. Bone Marrow Transplant 2007; 39: 447–451.
Bachar-Lustig E, Rachamim N, Li HW, Lan F, Reisner Y . Megadose of T cell-depleted bone marrow overcomes MHC barriers in sublethally irradiated mice. Nat Med 1995; 1: 1268–1273.
Wekerle T, Kurtz J, Ito H, Ronquillo JV, Dong V, Zhao G et al. Allogeneic bone marrow transplantation with co-stimulatory blockade induces macrochimerism and tolerance without cytoreductive host treatment. Nat Med 2000; 6: 464–469.
Bolaños-Meade J, Fuchs EJ, Luznik L, Lanzkron SM, Gamper CJ, Jones RJ et al. HLA-haploidentical bone marrow transplantation with posttransplant cyclophosphamide expands the donor pool for patients with sickle cell disease. Blood 2012; 120: 4285–4291.
Owen RD . Immunogenetic consequences of vascular anastomoses between bovine twins. Science 1945; 102: 400–401.
Anderson D, Billingham RE, Lampkin GH, Medawar PB . The use of skin grafting to distinguish between monozygotic and dizygotic twins in cattle. Heredity 1951; 5: 379–397.
Billingham RE, Brent L, Medawar PB . Actively acquired tolerance of foreign cells. Nature 1953; 172: 603–606.
Koenecke C, Hertenstein B, Schetelig J, van Biezen A, Dammann E, Gratwohl A et al. Solid organ transplantation after allogeneic hematopoietic stem cell transplantation: a retrospective, multicenter study of the EBMT. Am J Transplant 2010; 10: 1897–1906.
Leventhal J, Abecassis M, Miller J, Gallon L, Ravindra K, Tollerud DJ et al. Chimerism and tolerance without GVHD or engraftment syndrome in HLA-mismatched combined kidney and hematopoietic stem cell transplantation. Sci Transl Med 2012; 4: 124ra28.
Szydlo R, Goldman JM, Klein JP, Gale RP, Ash RC, Bach FH et al. Results of allogeneic bone marrow transplants for leukemia using donors other than HLA-identical siblings. J Clin Oncol 1997; 15: 1767–1777.
Acknowledgements
This work was supported by P01 CA15396 from the National Cancer Institute and by Grant #117279 from the Immune Tolerance Network/Benaroya Research Institute.
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This article was published as part of a supplement, supported by WIS-CSP Foundation, in collaboration with Gilead, Milteny Biotec, Gamida cell, Adienne Pharma and Biotech, Medac hematology, Kiadis Pharma, Almog Diagnostic.
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Fuchs, E. HLA-haploidentical blood or marrow transplantation with high-dose, post-transplantation cyclophosphamide. Bone Marrow Transplant 50 (Suppl 2), S31–S36 (2015). https://doi.org/10.1038/bmt.2015.92
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DOI: https://doi.org/10.1038/bmt.2015.92
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