Severe aplastic anemia, 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 may benefit from further immunosuppression. Furthermore, analysis of our own clinical data suggest that patients with poor 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 management of such cases is uncertain.

This study will enroll patients who are either refractory to h-ATG (continued severe pancytopenia) or who have only modest improvement in blood counts (weak hematologic responders) to receive a further immunosuppressive therapy, delivered either as rabbit ATG (Thymoglobulin, r-ATG) or a humanized monoclonal antibody to T-cells, alemtuzumab (Campath-1H(Registered Trademark)). Primary endpoint will be response rate at 3 months defined as no longer meeting criteria for severe aplastic anemia. Relapse, robustness of hematopoietic recovery at 3 months, survival and clonal evolution to paroxysmal nocturnal hemoglobinuria (PNH), myelodysplasia and acute leukemia will be the secondary endpoints.

Severe aplastic anemia, 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 may benefit from further immunosuppression. Furthermore, analysis of our own clinical data suggest that patients with poor 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 management of such cases is uncertain.

This study will enroll patients who are either refractory to h-ATG (continued severe pancytopenia) or who have only modest improvement in blood counts (weak hematologic responders) to receive further immunosuppressive therapy, delivered either as rabbit ATG (Thymoglobulin(Registered Trademark), r-ATG) or a humanized monoclonal antibody to T-cells, alemtuzumab (Campath-1H(Registered Trademark)). Primary endpoint will be response rate at 6 months defined as no longer meeting criteria for severe aplastic anemia. Relapse, robustness of hematopoietic recovery at 6 months, survival and clonal evolution to paroxysmal nocturnal hemoglobinuria (PNH), myelodysplasia and acute leukemia will be the secondary endpoints.

• Drug: Alemtuzumab (Campath-1H)
• Drug: Thymoglobulin (r-ATG)
• Drug: Cyclosporine (CsA)

• Young NS, Maciejewski J. The pathophysiology of acquired aplastic anemia. N Engl J Med. 1997 May 8;336(19):1365-72. Review. No abstract available.
• Mathe G, Amiel JL, Schwarzenberg L, Choay J, Trolard P, Schneider M, Hayat M, Schlumberger JR, Jasmin C. Bone marrow graft in man after conditioning by antilymphocytic serum. Br Med J. 1970 Apr 18;2(702):131-6. No abstract available.
• Stein RS, Means RT Jr, Krantz SB, Flexner JM, Greer JP. Treatment of aplastic anemia with an investigational antilymphocyte serum prepared in rabbits. Am J Med Sci. 1994 Dec;308(6):338-43.

• INCLUSION CRITERIA:

Severe aplastic anemia confirmed at NIH by:

Bone marrow cellularity less than 30% (excluding lymphocytes)

At least two of the following:

Absolute neutrophil count less than 500/uL;

Platelet count less than 20,000/ uL;

Reticulocyte count less than 60,000/ uL.

Severe aplastic anemia refractory to prior course(s) of h-ATG/CsA defined after 3 months from treatment with less or equal to 4 years from receiving h-ATG.

OR

Suboptimal response to initial immunosuppression with h-ATG/CsA as defined by platelet and reticulocyte count less than 50,000 /uL at 3 months.

Age greater than or equal to 2 years of age

EXCLUSION CRITERIA:

Diagnosis of Fanconi anemia.

Evidence of a clonal disorder on cytogenetics. Patients with super severe neutropenia (ANC less than 200/microL) 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.

Prior treatment courses with rabbit ATG or high dose cyclophosphamide (200 mg/kg or equivalent).

Infection not adequately responding to appropriate therapy.

Underlying immunodeficiency state including seropositivity for HIV.

Failure to discontinue the herbal supplements Echinacea purpurea or Usnea barbata (Old Man's Beard) within two weeks of enrollment.

Previous hypersensitivity to Campath-1H or its components.

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.

Potential subjects with cancer who are on active chemotherapeutic treatment or who take drugs with hematological effects will not be eligible.

Serum creatinine greater than 2.5 mg/dL.

Current pregnancy or lactation or unwillingness to take contraceptives.

Inability to understand the investigational nature of the study or give informed consent.