Durable engraftment of major histocompatibility complex-incompatible cellsafter nonmyeloablative conditioning with fludarabine, low-dose total body irradiation, and posttransplantation cyclophosphamide

Treatment of leukemia by myeloablative conditioning and transplantation of major histocompatibility complex (MHC)-mismatched stem cells is generally a voided because of the high risk of graft rejection or lethal graft-versus-h ost disease (GVHD). This study shows that MHC-incompatible cells can engraf t stably after nonmyeloablative conditioning with immunosuppressive chemoth erapy and low-dose total body irradiation (TBI). Long-term mixed hematopoie tic chimerism, clonal deletion of donor-reactive T cells, and bidirectional cytotoxic T-cell tolerance were achieved by transplanting MHC-mismatched m arrow cells into recipients conditioned with pretransplantation fludarabine or cyclophosphamide (Cy), 50 to 200 cGy TBI on day -1, and Cy 200 mg/kg in traperitoneally on day 3. In this model, long-term donor chimerism was prop ortional to the dose of TBI or donor marrow cells. Pretransplantation fluda rabine and posttransplantation Cy were both required for alloengraftment, b ut the drugs had additional effects. For example, fludarabine sensitized ho st stem cells to the toxicity of TBI, because animals conditioned with both agents had higher chimerism than animals conditioned with TBI alone (P <.0 5). Also, posttransplantation Cy attenuated lethal and nonlethal GVH reacti ons, because F-1 recipients of host-reactive, parental spleen cells survive d longer (P <.05) and had lower donor cell chimerism (P <.01) if they recei ved posttransplantation Cy than if they did not. Finally, delayed infusions of donor lymphocytes into mixed chimeras prolonged survival after leukemia challenge (P <.0001) without causing lethal GVHD. These results indicate t hat stable engraftment of MHC-incompatible cells can be induced after fluda rabine-based, nonmyeloablative conditioning and that It serves as a platfor m for adoptive immunotherapy with donor lymphocyte infusions. (Blood. 2001; 98-.3456-3464) (C) 2001 by The American Society of Hematology.