Alemtuzumab to Treat Severe Aplastic Anemia
Condition: Severe Aplastic Anemia, Refractory; Severe Aplastic Anemia, Relapse
MeSH terms: Anemia; Anemia, Aplastic; Anemia, Refractory
Study type: Interventional
Phase: Phase 2

Summary: 
      This study will evaluate the safety and usefulness of a new immunosuppressive drug,
      alemtuzumab (Campath ), in patients with severe aplastic anemia (SAA). SAA is a rare and
      serious blood disorder in which the bone marrow stops making red blood cells, white blood
      cells and platelets. Alemtuzumab is a monoclonal antibody that attaches to and kills white
      blood cells called lymphocytes. In certain types of aplastic anemia, lymphocytes are
      responsible for the destruction of stem cells in the bone marrow, leading to a decrease in
      blood counts. Because alemtuzumab destroys lymphocytes, it may be effective in treating
      aplastic anemia. Alemtuzumab is currently approved to treat chronic lymphocytic leukemia and
      is also helpful in other conditions that require immunosuppression, such as rheumatoid
      arthritis and immune cytopenias.

      Patients 2 years of age and older with severe aplastic anemia whose disease does not respond
      to immunosuppressive therapy or has recurred following immunosuppressive therapy may be
      eligible for this study. Participants undergo the following tests and procedures:

        -  Pretreatment evaluation: Patients have a medical history, physical examination, blood
           tests, electrocardiogram (EKG), echocardiogram, 24-hour Holter monitor (continuous
           24-hour monitoring of electrical activity of the heart), bone marrow biopsy (withdrawal
           through a needle of a small sample of bone marrow for analysis).

        -  Placement of a central line, if needed: An intravenous line (tube) is placed into a
           major vein in the patient's chest. It can stay in the body for the entire treatment
           period and be used to give chemotherapy or other medications, including antibiotics and
           blood transfusions, if needed, and to withdraw blood samples.

        -  Alemtuzumab therapy: Patients are admitted to the NIH Clinical Center for the first few
           injections for close monitoring of side effects. After receiving an initial small test
           dose, patients begin the first of ten daily injections under the skin, each lasting
           about 2 hours. Once patients tolerate the infusions with minimal or no side effects,
           they may be given the remaining infusions on an outpatient basis. Patients who relapse
           after their initial response to alemtuzumab are given cyclosporine to see if this drug
           will boost their immune response.

        -  Patients receive transfusions, growth factors, and antibiotic therapy, as needed.

        -  Infection therapy: Patients are given aerosolized pentamidine to protect against lung
           infections and valacyclovir to protect against herpes infections.

        -  A blood test is done and vital signs are measured every day while patients receive
           alemtuzumab.

        -  Patients have an echocardiogram and 24-hour Holter monitor after the last dose of
           alemtuzumab.

        -  Blood tests are done weekly for the first 3 months after alemtuzumab administration,
           then every other week until 6 months.

      Patients return to the NIH for follow-up visits 1 month, 3 months, 6 months, and yearly for 5
      years after the last dose of alemtuzumab for the following tests and evaluations:

        -  Blood test

        -  Repeat echocardiogram at 3-month visit

        -  Repeat bone marrow biopsy 6 months and 12 months after alemtuzumab, then as clinically
           indicated for 5 years.
    

Detailed description: 
      Hematopoietic stem cell destruction in many human bone marrow failure syndromes is now
      recognized to be secondary to immune mechanisms. Severe aplastic anemia (SAA) is a
      life-threatening blood disease which can be effectively treated with immunosuppressive drug
      regimens. However, a significant minority of patients with SAA fail to respond to a single
      course of horse antithymocyte globulin and cyclosporine, and other patients experience
      relapse, especially on discontinuation of therapy. Pancytopenia secondary to refractory or
      relapsed aplastic anemia has a poor prognosis, with death usually resulting from infectious
      complications. Alemtuzumab (Campath ) is a humanized IgG1 monoclonal antibody directed
      against the CD52 protein; CD52 is expressed on all lymphocytes and monocytes. Alemtuzumab
      (Campath ) produces profound and persistent lymphopenia. The antibody has been used to treat
      a wide range of autoimmune diseases, lymphoid malignancies, and in solid organ and
      hematopoietic stem cell transplantation. In our limited experience with alemtuzumab for the
      treatment of SAA refractory to horse antithymocyte globulin, meaningful hematologic responses
      have been observed and toxicity has been modest.

      We therefore propose a non-randomized pilot phase II study of this humanized monoclonal
      antibody in SAA relapsed or refractory to ATG. Commercially available alemtuzumab (Campath )
      will be administered at 10 mg per day subcutaneously for 10 days total.

      The primary end point of the study is the response rate at 6 months, defined as no longer
      satisfying blood count criteria for SAA.

      Relapse, robustness of the hematopoietic recovery at 3 and 6 months, 3 months responses,
      survival, and clonal evolution to myelodysplasia and acute leukemia will be secondary end
      points.
    

Intervention name(s): Alemtuzumab (Campath ); Cyclosporine
Intervention type(s): Biological; Drug
Intervention description(s): Campath administered at a dose of 10/mg/day for 10 days; Subjects who relapse after initial response to alemtuzumab therapy will have cyclosporine added to the regimen after the 6 month visit. Dosing will be based on ideal body weight and will be adjusted to maintain a target level of 200 - 400 ng /ml.
Intervention MeSH terms: Cyclosporine; Alemtuzumab; Cyclosporins
Allocation: Non-Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Immunosuppression; T-cells; Hematopoiesis; Autoimmunity; Thrombocytopenia; Severe Aplastic Anemia; SAA