A Reduced Intensity Conditioning With Clofarabine Antithymocyte Globulin and Total Lymphoid Irradiation Followed by Allogeneic Hematopoietic Stem Cell Transplantation

Trial Information

A Reduced Intensity Conditioning With Clofarabine Antithymocyte Globulin and Total Lymphoid Irradiation Followed by Allogeneic Hematopoietic Stem Cell Transplantation

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.