Horse ATG/CsA in Aplastic Anemia Patients Unresponsive to or With a Suboptimal Response to Rabbit ATG/CsA Treatment
Condition: Anemia, Aplastic; Anemia, Hypoplastic
MeSH terms: Anemia; Anemia, Aplastic
Study type: Interventional
Phase: Phase 2

Summary: 
      Background:

        -  Severe plastic anemia can lead to problems with bone marrow platelet production and
           result in low blood platelet counts, which require frequent platelet transfusions to
           improve blood clotting.

        -  A standard treatment for SAA involves injections of rabbit-antithymocyte globulin
           (r-ATG). r-ATG is developed by injecting horses with a type of human white blood cells
           called thymocytes. The horse's immune system reacts against these cells and makes
           antibodies that can destroy them. These antibodies are collected and purified to make
           r-ATG. Horses can also be used for this procedure to make horse-antithymocyte globulin
           (h-ATG).

        -  h-ATG is approved by the Food and Drug Administration for the treatment of aplastic
           anemia. h-ATG is a standard first-line method to treat aplastic anemia, but researchers
           do not know how effective it is in patients who were first treated unsuccessfully with
           r-ATG.

      Objectives:

      - To evaluate the effectiveness and safety of horse-ATG (with cyclosporine) in increasing
      blood counts and reducing the need for transfusions in aplastic anemia patients who have
      failed to respond to prior immunosuppressive treatment with rabbit-ATG and cyclosporine.

      Eligibility:

      - Patients 2 years of age and older who have consistently low blood platelet counts related
      to aplastic anemia that has not responded to conventional treatment with rabbit-ATG.

      Design:

        -  After initial screening, medical history, and blood tests, patients will be admitted to
           the inpatient unit at the National Institutes of Health Clinical Center. Researchers
           will perform a skin test with h-ATG to check for allergic or other adverse reaction.

        -  After the skin test, h-ATG will be given into a vein continuously over 4 days.

        -  Cyclosporine will also be given to improve the response rate of ATG treatment. Treatment
           with cyclosporine will start the same day as the h-ATG, either in liquid or capsule
           form, and continued for 6 months. The dose of cyclosporine will be monitored and
           adjusted based on blood levels and signs of side effects in the kidney and liver.

        -  To prevent or treat infections that may result from cyclosporine s effect on the immune
           system, patients will also take inhaled or capsule doses of pentamidine.

        -  After the study is completed, patients will have followup evaluations every 3 months, 6
           months, and annually for 5 years. Evaluations will include blood samples and periodic
           bone marrow biopsies.
    

Detailed description: 
      Severe aplastic anemia (SAA), characterized by pancytopenia and a hypocellular bone marrow,
      is effectively treated by immunosuppressive therapy, usually a combination of antithymocyte
      globulin (ATG) and cyclosporine (CsA). Survival rates following this regimen are equivalent
      to those achieved with allogeneic stem cells transplantation. However, approximately 1/3 of
      patients will not show blood count improvement after ATG/CsA. General experience and small
      pilot studies have suggested that such patients benefit from further immunosuppression.
      Furthermore, analysis of our own clinical data suggests that patients with minimal blood
      count responses to a single course of ATG, even when transfusion independence is achieved,
      have a markedly worse prognosis than patients with robust hematologic improvement.

      The majority of the experience in the US and worldwide has been with horse ATG (h-ATG) plus
      CsA as initial therapy in SAA. Rabbit ATG (r-ATG) plus CsA has been employed successfully in
      about 1/3 of cases in those who are refractory to initial h-ATG/CsA (current NHLBI Protocol
      03-H-0249). In recent years, h-ATG and r-ATG have been used interchangeably in
      treatment-naive patients, and initial therapy with r-ATG/CsA is now frequent in the US and
      the only option in Europe and Japan, where h-ATG is no longer available. An active NHLBI
      randomized study is comparing the efficacy of h- and r-ATG as initial therapy in SAA, and the
      results from a recently completed interim analysis suggest that the hematologic response rate
      ultimately may not be comparable between these two agents (Protocol 06-H-0034). There is no
      published report on the outcome of repeat immunosuppressive therapy in those patients
      refractory to initial r-ATG/CsA, and thus the management of these patients is uncertain. We
      therefore propose this study of h-ATG/CsA in SAA patients who are refractory or have a
      suboptimal response to r-ATG.

      The primary endpoint will be the response rate at 3 months where response is defined as no
      longer meeting criteria for SAA.

      The primary objective is to evaluate the effectiveness (response rate) at 3 months of a
      second course of immunosuppression with h-ATG/CsA in subjects refractory to or with a
      suboptimal response to a course of r-ATG/CsA or cyclophosphamide at least 3 months post
      treatment.

      Secondary objectives include robustness of hematologic recovery, relapse, response rate at 6
      months, clonal evolution and overall survival.

      The primary endpoint will be changes in absolute neutrophil count, platelet count,
      reticulocyte count at 3 months.

      Secondary endpoints will include time to relapse, changes in cytogenetics, time to death.
    

Intervention name(s): h-ATG (ATGAM ); Cyclosporine (Gengraf )
Intervention type(s): Drug; Drug
Intervention MeSH terms: Cyclosporine; Cyclosporins
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: H- ATG; Anti -Thymocyte Globulin; Lymphocyte Immune Globulin; Aplastic Anemia