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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.

Regulatory T cells represent a population of T lymphocytes that demonstrate an immunosuppressive phenotype and play an important role in the prevention of autoimmunity and transplant rejection.Regulatory cells express the inhibitory cytokines IL-10 and TGFβ and are thought to suppress immune activation through direct cell contact.Similar to activated effector cells they coexpress CD4 and CD25.Regulatory T cells may be identified by the high levels of CD25 expression and the presence of CTLA-4 and FOXP3.Regulatory T cells demonstrate minimal proliferation to allogeneic stimuli and inhibit third party mixed lymphocyte responses. Increased presence of regulatory T cells have been found in the tumor bed, draining lymph nodes, and circulation in patients with malignancy and inhibit host anti-tumor immune responses.

There has been increasing interest in evaluating the role of regulatory T cells as a means of inhibiting graft versus host disease. In animal models, selective introduction of regulatory T cells prevents the development of graft versus host disease without compromising immune reconstitution or anti-tumor immunity. A variety of strategies for the ex vivo expansion and isolation of regulatory T cells have been explored. A limiting factor has been the similar patterns of expression of cell surface markers between regulatory and activated T cell populations. iNKT cells represent another population of immunomodulatory cells thought to be essential for the generation of tolerance.In pre-clinical models, TLI has been shown to modulate immune effector cells resulting in increased levels of circulating regulatory T cells, preventing GVHD in a mismatched transplant setting.It is thought that iNKT cells are selectively preserved after TLI which polarize T cells towards an inhibitory phenotype. In a clinical study, 37 patients with lymphoid malignancies or acute leukemia underwent conditioning with TLI administered as 10 fractions of 80cGy and ATG.Only 2 patients developed acute GVHD despite the observation of a graft versus disease effect.Of note, a significant increase in the number of donor CD4+ T cells expressing IL-4 was observed suggesting that the immune modulation resulting from TLI/ATG polarized cells towards a TH-2 phenotype.As such, TLI/ATG would like facilitate engraftment and decrease the incidence of GVHD in patients undergoing conditioning with clofarabine.Most importantly, by modulating the host immune effectors but not depleting donor T cells, this strategy should not significantly inhibit the graft versus tumor effect.The prevalence of dendritic cell (DC) subsets (DC1 vs. DC2) in the hematopoietic graft have also been shown to effect the risk of GVHD.