Improving Immunosuppressive Treatment for Patients With Severe Aplastic Anemia
Condition: Severe Aplastic Anemia
MeSH terms: Anemia; Anemia, Aplastic
Study type: Interventional
Phase: Phase 2

Summary: 
      Severe aplastic anemia (SAA) is a life-threatening bone marrow failure disorder characterized
      by pancytopenia and a hypocellular bone marrow. Allogeneic bone marrow transplantation and
      immunosuppressive treatment with anti-thymocyte globulin (ATG) and cyclosporine (CsA) have
      dramatically changed the natural course of this illness, with 5 year survival of 75% in
      patients undergoing either treatment. Since most patients are not suitable candidates for
      hematopoietic stem cell transplantation (HSCT) due to advanced age or lack of a
      histocompatible sibling, efforts at NHLBI have focused on improving immunosuppression
      treatment in order to improve response rates, survival, and to decrease relapse.

      In our experience of 122 patients treated at NHLBI with the combination of ATG and
      cyclosporine, one quarter to one third did not respond; about 50% of responders relapsed; and
      5 year survival was correlated with the robustness in blood cell count improvement at 3
      months (reticulocyte or platelet count greater than or equal to 50,000 /uL). Why some
      patients do not respond initially while others relapse is unclear. Autoreactive T cells may
      be resistant to the effect of ATG/CsA (nonresponders), while in others residual autoreactive
      T cells expand post-treatment leading to hematopoietic stem cell destruction and recurrent
      pancytopenia (relapse). Therefore, novel immunosuppressive regimens to increase response
      rates and hematologic recovery at 3 months and to decrease relapse rates are needed. An
      ongoing NHLBI trial, which is close to completing accrual, has added mycophenolate mofetil
      (MMF) for a total of 18 months to standard ATG + CsA in an attempt to reduce the relapse rate
      after cyclosporine is discontinued. Preliminary results have been disappointing, with no
      marked reduction in relapse among patients who received MMF.

      Sirolimus (rapamycin, Rapamune , RAPA) is a novel immunosuppressive agent, which acts
      synergistically with cyclosporine by blocking T cell activation through CsA-resistant
      pathways. The potentiation of the combination of CsA-RAPA has been established in vitro and
      in the clinical setting, mainly in islet cell and solid organ transplantation. The
      significant increase in response rate seen with the addition of CsA to ATG indicated that an
      inhibitory effect on T lymphocytes is important in blocking autoreactive T cells in aplastic
      anemia. The combination of CsA-RAPA may further block activated autoreactive T cells and
      therefore lead to improved response rates (and survival) and decreased relapse rates.

      This prospective randomized phase II study will investigate two different immunosuppressive
      regimens in patients with severe aplastic anemia who have not received prior
      immunosuppressive therapy. One arm will receive ATG + CsA in addition to sirolimus for 6
      months, and the second arm will receive standard ATG + CsA for 6 months followed by a slow
      taper of CsA with a 25% dose reduction every 3 months for the subsequent 18 months. This
      trial will determine the effectiveness of sirolimus in patients with aplastic anemia as well
      as the role of a cyclosporine taper in preventing relapses. Primary endpoint will be no
      longer meeting criteria for severe aplastic anemia while secondary endpoints are relapse,
      robustness of hematologic recovery at 3 months, survival, clonal evolution to PNH,
      myelodysplasia and acute leukemia.

      10/11/2005. The Sirolimus (Rapamune) arm of the trial was stopped for lack of efficacy. The
      study will continue as a single arm study to establish if slow taper of CsA prevents relapse
      rates after initial standard treatment with ATG followed by CsA for six months.
    

Detailed description: 
      Severe aplastic anemia (SAA) is a life-threatening bone marrow failure disorder characterized
      by pancytopenia and a hypocellular bone marrow. Allogeneic bone marrow transplantation and
      immunosuppressive treatment with anti-thymocyte globulin (ATG) and cyclosporine (CsA) have
      dramatically changed the natural course of this illness, with 5 year survival of 75% in
      patients undergoing either treatment. Since most patients are not suitable candidates for
      hematopoietic stem cell transplantation (HSCT) due to advanced age or lack of a
      histocompatible sibling, efforts at NHLBI have focused on improving immunosuppression
      treatment in order to improve response rates, survival, and to decrease relapse.

      In our experience of 122 patients treated at NHLBI with the combination of ATG and
      cyclosporine, one quarter to one third did not respond; about 50% of responders relapsed; and
      5 year survival was correlated with the robustness in blood cell count improvement at 3
      months (reticulocyte or platelet count greater than or equal to 50,000 /uL). Why some
      patients do not respond initially while others relapse is unclear. Autoreactive T cells may
      be resistant to the effect of ATG/CsA (nonresponders), while in others residual autoreactive
      T cells expand post-treatment leading to hematopoietic stem cell destruction and recurrent
      pancytopenia (relapse). Therefore, novel immunosuppressive regimens to increase response
      rates and hematologic recovery at 3 months and to decrease relapse rates are needed. An
      ongoing NHLBI trial, which is close to completing accrual, has added mycophenolate mofetil
      (MMF) for a total of 18 months to standard ATG + CsA in an attempt to reduce the relapse rate
      after cyclosporine is discontinued. Preliminary results have been disappointing, with no
      marked reduction in relapse among patients who received MMF.

      Sirolimus (rapamycin, Rapamune , RAPA) is a novel immunosuppressive agent, which acts
      synergistically with cyclosporine by blocking T cell activation through CsA-resistant
      pathways. The potentiation of the combination of CsA-RAPA has been established in vitro and
      in the clinical setting, mainly in islet cell and solid organ transplantation. The
      significant increase in response rate seen with the addition of CsA to ATG indicated that an
      inhibitory effect on T lymphocytes is important in blocking autoreactive T cells in aplastic
      anemia. The combination of CsA-RAPA may further block activated autoreactive T cells and
      therefore lead to improved response rates (and survival) and decreased relapse rates.

      This prospective randomized phase II study will investigate two different immunosuppressive
      regimens in patients with severe aplastic anemia who have not received prior
      immunosuppressive therapy. One arm will receive ATG + CsA in addition to sirolimus for 6
      months, and the second arm will receive standard ATG + CsA for 6 months followed by a slow
      taper of CsA with a 25% dose reduction every 3 months for the subsequent 18 months. This
      trial will determine the effectiveness of sirolimus in patients with aplastic anemia as well
      as the role of a cyclosporine taper in preventing relapses. Primary endpoint will be no
      longer meeting criteria for severe aplastic anemia while secondary endpoints are relapse,
      robustness of hematologic recovery at 3 months, survival, clonal evolution to PNH,
      myelodysplasia and acute leukemia.

      10/11/2005. The Sirolimus (Rapamune) arm of the trial was stopped for lack of efficacy. The
      study will continue as a single arm study to establish if slow taper of CsA prevents relapse
      rates after initial standard treatment with ATG followed by CsA for six months.

      3/2/2006. The protocol was closed to new accrual.
    

Intervention name(s): ATG+Rapamune+cyclosporine; ATG+cyclosporine
Intervention type(s): Drug; Drug
Intervention description(s): ATG+Rapamune+cyclosporine; ATG+cyclosporine
Intervention MeSH terms: Cyclosporine; Sirolimus; Cyclosporins
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Bone Marrow Failure; Cyclosporine; Anti Thymocyte Globulin; Severe Aplastic Anemia