title: Post-transplantation cyclophosphamide for tolerance induction in HLA-haploidentical bone marrow transplantation.
abstract: Allogeneic hematopoietic stem cell transplantation (alloSCT) is a potentially curative therapy for many hematologic and immunologic diseases. Further, partial or full donor hematopoietic chimerism following alloSCT may be sufficient to guarantee immunologic tolerance to solid organs from the same donor, obviating any requirement for prolonged pharmacologic immunosuppression. Despite alloSCT's potential, the procedure is beset by two major limitations. The first relates to the procedure's toxicity, including conditioning regimen toxicity, graft-versus-host disease (GVHD), and infection. The second limitation is the lack of histocompatible donors. A human leukocyte antigen (HLA)-matched sibling or unrelated donor cannot be identified expeditiously for up to 40% of patients. Historically, alloSCT from partially HLA-mismatched, or HLA-haploidentical, relatives has been complicated by unacceptably high incidences of graft rejection, severe GVHD, and non-relapse mortality. Recently, our groups have developed a method to selectively deplete alloreactive cells in vivo by administering high doses of cyclophosphamide in a narrow window after transplantation. Using high-dose, post-transplantation cyclophosphamide (PT/Cy), crossing the HLA barrier in alloSCT is now feasible and donors can be found for nearly all patients. This review discusses the history of HLA-haploidentical SCT, recent clinical results, and immunologic mechanisms of action of high-dose PT/Cy for prevention of graft rejection and GVHD.
authors.affiliation: Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, USA. luznile@jhmi.edu
authors.forename: Leo
authors.initials: L
authors.lastname: Luznik
authors.forename: Paul V
authors.initials: PV
authors.lastname: O'Donnell
authors.forename: Ephraim J
authors.initials: EJ
authors.lastname: Fuchs
mesh_terms: D000818:Animals; D003520:Cyclophosphamide / Q000627:therapeutic use*; D006086:Graft vs Host Disease / Q000517:prevention & control*; D006680:HLA Antigens / Q000276:immunology; D006239:Haplotypes; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects*; D006801:Humans; D007108:Immune Tolerance / Q000187:drug effects* / Q000276:immunology; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D019172:Transplantation Conditioning / Q000379:methods; D014181:Transplantation Immunology; D014184:Transplantation, Homologous
chemical_list: D006680:HLA Antigens; D007166:Immunosuppressive Agents; D003520:Cyclophosphamide