Reduced Intensity Conditioning With Clofarabine, Antithymocyte Globulin (ATG), Total Lymphoid Irradiation (TLI) Followed by Allogeneic Stem Cell Transplant

One approach to limit the toxicity of allogeneic transplantation has been the use of nonmyeloablative regimens preceding the infusion of allogeneic cells.In this strategy, patients receive immunosuppressive therapy that allows for the engraftment of donor cells without the immediate eradication of patient hematopoiesis.The primary mechanism by which the underlying disease is eradicated is not through chemotherapy mediated cytoreduction, but rather through the donor lymphocyte mediated graft versus tumor effect.As a result, patients experience far less regimen related toxicity.Therefore, the adoption of this strategy may allow for the use of allogeneic transplantation in disease settings and patient populations for which it had not been readily applicable in the past.

Over the past several years, the use nonmyeloablative transplant has rapidly expanded.Several reduced intensity conditioning regimens have been developed including fludarabine and cyclophosphamide; fludarabine and melphalan; fludarabine, ATG and low dose busulfan; and fludarabine and low dose TBI. Investigators have demonstrated the feasibility of this treatment approach with the majority of patients demonstrating donor engraftment,decreased regimen related toxicity, and graft mediated regression of disease.In some studies, patients demonstrate a period of mixed donor/host chimerism in which the infusion of donor lymphocytes is associated with achievement of complete donor chimerism.

Although regimen related toxicity is decreased following reduced intensive conditioning regimens, graft versus host disease and opportunistic infections remain a significant source of morbidity and mortality following nonmyeloablative allogeneic transplantation. The impact of nonmyeloablative transplantation on immunological reconstitution has not been fully defined. Persistence of host antigen presenting cells in the post-transplant period may increase the incidence of GVHD due to the presentation of alloantigens to donor T cells. In contrast, residual host cellular immunity may provide enhanced protection against infectious pathogens and allow for more rapid education of donor lymphocytes.

The use of clofarabine in place of fludarabine in combination with cyclophosphamide may augment the anti-leukemia effect of the regimen, enhance cytoreduction, and increase the efficacy of reduced intensity allogeneic transplantation in this setting.A potential issue associated with the use of clofarabine and cyclophosphamide as pre-transplant conditioning is whether the regimen would be sufficiently immunosuppressive to reliably facilitate engraftment of donor hematopoiesis.Another concern relates to the significant incidence of graft versus host disease which remains a major source of morbidity and mortality following reduced intensity transplantation.The use of TLI and ATG has been studied in the context of allogeneic transplantation and has been shown to effectively support engraftment in animal models and clinical trials.TLI has been shown to promote immune tolerance resulting in a decrease in the incidence of graft versus host disease (GVHD).It has been shown to decrease the incidence of rejection following transplantation of a T cell depleted allograft.The conditioning regimen of TLI and cyclophosphamide results in successful engraftment in patients with aplastic anemia.