Reduced Intensity Conditioning With Clofarabine, Antithymocyte Globulin (ATG), Total Lymphoid Irradiation (TLI) Followed by Allogeneic Stem Cell Transplant
Condition: Acute Myeloid Leukemia; Myelodysplastic Syndrome; Acute Lymphocytic Leukemia; Relapsed/Refractory Chronic Lymphocytic Leukemia; Relapsed/Refractory Non Hodgkin's Lymphoma; Hodgkins Disease; Relapsed Refractory Multiple Myeloma
MeSH terms: Leukemia; Multiple Myeloma; Leukemia, Lymphoid; Leukemia, Lymphocytic, Chronic, B-Cell; Hodgkin Disease; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Myelodysplastic Syndromes
Study type: Interventional
Phase: Phase 1

Summary: 
      This study will examine the safety of clofarabine, TLI and ATG as a reduced conditioning
      regimen prior to allogeneic transplantation. The impact of the conditioning regimen on the
      presence of the circulating regulatory as compared to activated T cell populations will be
      assessed.The recovery of DC populations post-transplant will be examined, along with the
      effect of the regimen on disease free and overall survival.
    

Detailed description: 
      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.
    

Intervention name(s): Antithymocyte Globulin; Clofarabine; Clofarabine; Clofarabine
Intervention type(s): Drug; Drug; Drug; Drug
Intervention description(s): Transplant conditioning will begin day -11 with 5 days of TLI at a dose of 80 cGy per day administered in conjunction with rabbit ATG at a dose of 1.5 mg/kg per day (day -11 to -7). Clofarabine will be given at 20mg/m2/d IV infused over 1 hour x 5 days (day -6 to -2), for a total dose of 100 mg/m(2). TLI will be completed at 80 cGy per day (day -4 to 0) for a total of 10 fractions (800 cGy).; Transplant conditioning will begin day -11 with 5 days of TLI at a dose of 80 cGy per day administered in conjunction with rabbit ATG at a dose of 1.5 mg/kg per day (day -11 to -7). Clofarabine will be given at 30mg/m2/d IV infused over 1 hour x 5 days (day -6 to -2), for a total dose of 150 mg/m(2). TLI will be completed at 80 cGy per day (day -4 to 0) for a total of 10 fractions (800 cGy).; Transplant conditioning will begin day -11 with 5 days of TLI at a dose of 80 cGy per day administered in conjunction with rabbit ATG at a dose of 1.5 mg/kg per day (day -11 to -7). Clofarabine will be given at 40mg/m2/d IV infused over 1 hour x 5 days (day -6 to -2), for a total dose of 200 mg/m(2). TLI will be completed at 80 cGy per day (day -4 to 0) for a total of 10 fractions (800 cGy).
Intervention MeSH terms: Clofarabine; Antilymphocyte Serum
Allocation: Non-Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Reduced Intensity Allogeneic Stem Cell Transplant; Clofarabine; Rabbit Antithymocyte Globulin; Total Lymphoid Radiation