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
Intervention: h-ATG (ATGAM ); Cyclosporine (Gengraf )
Intervention MeSH terms: Cyclosporine; Cyclosporins
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 23.0
Sex: All
Minimum age: 2 Years
Maximum age: 82 Years
Healthy volunteers: No
Keywords: H- ATG; Anti -Thymocyte Globulin; Lymphocyte Immune Globulin; Aplastic Anemia

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.
    

Eligibility criteria:

        -  All patients 2 years old or over with SAA who have failed initial immunosuppression
             with r-ATG/CsA and are not candidates for a matched sibling marrow transplantation
             will be considered for enrollment. Patients who have a suitable matched sibling donor
             will be referred for consideration of allogeneic bone marrow transplantation. Patients
             not willing to undergo transplantation will be considered for enrollment. Eligibility
             will be determined on another screening Hematology Branch protocol (97-H-0041) or
             another active Hematology branch protocol. The time between determination of
             eligibility and signing consent to participate on this protocol and initiate treatment
             on this protocol will not exceed 90 days.

        INCLUSION CRITERIA:

          1. Diagnosed with SAA characterized by:

               1. Bone marrow cellularity < 30% (excluding lymphocytes)

               2. At least two of the following:

             i. Absolute neutrophil count <500/ microL

             ii. Platelet count <20,000/ microL

             iii. Reticulocyte count <60,000/ microL

          2. Failure to respond to an initial course of r-ATG/CsA or cyclophosphamide at least 3
             months post-treatment or a suboptimal response to initial therapy defined by both
             platelet and reticulocyte count < 50,000 /microL at 3 months post-treatment

          3. Age greater than or equal to 2 years of age

        EXCLUSION CRITERIA:

          1. Diagnosis of Fanconi anemia. Patients with very severe neutropenia (ANC < 200 /microL)
             will not be excluded initially if results of Fanconi anemia testing are not available
             or pending. If evidence of Fanconi anemia is later identified, the subject will go off
             study.

          2. Evidence of a clonal disorder on cytogenetics. Patients with very severe neutropenia
             (ANC < 200/uL) will not be excluded initially if results of cytogenetics are not
             available or pending. If evidence of a clonal disorder is later identified, the
             subject will go off study.

          3. Patients who received prior course(s) of alemtuzumab will not be excluded.

          4. Infection not adequately responding to appropriate therapy

          5. HIV seropositivity

          6. Moribund status or concurrent hepatic, renal, cardiac, neurologic, pulmonary,
             infectious, or metabolic disease of such severity that it would preclude the patient s
             ability to tolerate protocol therapy or that death within 7-10 days is likely.

          7. Subjects with cancer who are on active chemotherapeutic treatment or who take drugs
             with hematological effects will not be eligible

          8. Serum creatinine > 2.5 mg/dL

          9. Current pregnancy, breast-feeding or unwillingness to refrain from pregnancy if of
             child bearing potential

         10. Inability to understand the investigational nature of the study or give informed
             consent