Effect of Intravenous Busulfan Versus Total Body Irradiation on Donor Chimerism and Acute Graft-Versus-Host Disease (GVHD) after Allogeneic Stem Cell Transplantation (AlloSCT) in Mice.

The goals of administering transplantation conditioning to leukemia patients undergoing alloSCT are to kill tumor cells, prevent rejection of the donor graft, create “space” for donor hematopoiesis, and provide an overall milieu that favors a donor T cell-mediated “graft-versus-leukemia” effect. However, transplantation conditioning also increases the incidence and severity of acute GVHD by damaging non-hematopoietic tissues and by inducing lymphopenia, which augments the antigen-driven expansion of alloreactive T cells. The purpose of this study was to compare the relative safety and efficacy of transplantation conditioning with intravenous busulfan (Busulfex; ESP Pharma, Edison, NJ) versus total body irradiation (TBI) by administering titrated doses of either agent to mice and comparing their effects on: 1) donor chimerism after syngeneic and semi-allogeneic (parent into F₁) SCT; 2) graft rejection after MHC-matched allogeneic SCT; and 3) acute GVHD after semi-allogeneic SCT. Both agents induced titratable donor chimerism after syngeneic BMT, but TBI was more immunosuppressive, since allogeneic marrow engrafted after 700 cGy TBI but not after an equivalently myelotoxic dose of Busulfex (60 mg/kg). When given in equivalently myelotoxic doses, TBI always induced more GVHD than did IV busulfan, as measured by weight loss and the augmentation of donor T cell and myeloid chimerism. As a result, stable mixed hematopoietic chimerism was generated more readily in mice conditioned with nonmyeloablative doses of busulfan than in mice conditioned with equitoxic doses of TBI. These results demonstrate that IV busulfan promotes GVHD to a lesser extent than does an equivalently myelotoxic dose of TBI. IV busulfan may be the preferred agent if stable mixed hematopoietic chimerism is the desired outcome. The relative roles of lymphopenia versus tissue damage in the differential outcomes of TBI versus Busulfex conditioning are being investigated.