High-dose, post-transplantation cyclophosphamide to promote graft-host tolerance after allogeneic hematopoietic stem cell transplantation

Abstract

Graft-versus-host disease, or GVHD, is a major complication of allogeneic hematopoietic stem cell transplantation (alloHSCT) for the treatment of hematologic malignancies. Here, we describe a novel method for preventing GVHD after alloHSCT using high-dose, post-transplantation cyclophosphamide (Cy). Post-transplantation Cy promotes tolerance in alloreactive host and donor T cells, leading to suppression of both graft rejection and GVHD after alloHSCT. High-dose, post-transplantation Cy facilitates partially HLA-mismatched HSCT without severe GVHD and is effective as sole prophylaxis of GVHD after HLA-matched alloHSCT. By reducing the morbidity and mortality of alloHSCT, post-transplantation Cy may expand the applications of this therapy to the treatment of autoimmune diseases and non-malignant hematologic disorders such as sickle cell disease.

Fig. 1

Proposed mechanism for the induction of transplantation tolerance by high-dose cyclophosphamide. Top: alloreactive T-cell recognition of alloantigens on dendritic cells leads to T-cell activation, interleukin-2 production, and proliferation. Proliferating, alloreactive T cells are killed by a properly timed dose of Cy, an S phase-specific drug, given on day 3. Bottom: non-alloreactive T cells remain in a resting state and are resistant to being killed by high-dose Cy

Fig. 2

Schema of non-myeloablative, HLA-haploidentical bone marrow transplantation with high-dose, post-transplantation cyclophosphamide. Cy, cyclophosphamide; BMT, bone marrow transplantation; TBI, total body irradiation; G-CSF, granulocyte-colony stimulating factor; MMF, mycophenolate mofetil

Fig. 3

a Event-free survival according to the number of HLA antigen mismatches in either the graft-versus-host or the host-versus-graft direction. Ag MM, antigen mismatch; HR, hazard ratio; CI, confidence interval. b Cumulative incidence of acute, grades II–IV GVHD according to the number of HLA antigen mismatches (composite of HLA-A, -B, -Cw, and -DRB1) in the graft-versus-host direction

Fig. 4

Schema of myeloablative conditioning and HLA-matched bone marrow transplantation with high-dose, post-transplantation cyclophosphamide as sole prophylaxis of GVHD. BMT, bone marrow transplantation; IV, intravenously; Cy, cyclophosphamide