This study will compare two new treatments for people with severe aplastic anemia, a potentially fatal disease in which patients do not produce normal numbers of blood cells. Because they have too few red cells, patients may tire easily, have chest pains, and be short of breath even at rest. Too few white cells leave patients vulnerable to serious infections and possibly death. Too few platelets cause abnormal bleeding and easy bruising. Bleeding in the brain (stroke) can be fatal. Standard treatment with horse antithymocyte globulin (h-ATG), cyclosporine (CsA), and corticosteroids is effective, but patients often relapse. The treatments to be evaluated in this study are: 1) rabbit ATG (r-ATG) plus CsA plus corticosteroids; and 2) Campath-1H.

r-ATG is made by injecting rabbits with white blood cells. The rabbit's immune system makes antibodies to destroy the foreign white cells. The antibodies are collected and purified to make r-ATG. CsA is commonly used to prevent rejection of donated tissue after bone marrow or organ transplantation and, in combination with h-ATG, for treating aplastic anemia. Corticosteroids suppress the immune system and are given to prevent or reduce the symptoms of serum sickness, which can develop in response to the rabbit proteins in the r-ATG. Campath-1H is a laboratory-made antibody currently used to treat chronic lymphocytic leukemia. It destroys white blood cells called lymphocytes that, in aplastic anemia, are responsible for destruction of bone marrow stem cells.

Patients 15 years of age and older with severe aplastic anemia may be eligible for this study. Candidates will be screened with a medical history, physical examination, blood tests, and bone marrow biopsy.

Participants are randomly assigned to one of two treatment groups: 1) r-ATG, CsA, and steroids, or 2) Campath-1H. For both treatments, it is suggested that a central venous line (large plastic tube) be placed in a large vein in the neck or chest. This tube can stay in the body and be used the entire treatment period to deliver the study drug and other medications, transfuse blood, and withdraw blood samples. Group 1 patients receive r-ATG by vein for 5 days, CsA by mouth as a liquid or capsule for 6 months, and a full dose of steroids by mouth for at least 2 weeks. After 2 weeks, when the risk of serum sickness-a reaction to the r-ATG-declines, the steroid dose is decreased. Group 2 patients receive Campath-1H by vein for 10 days. Because this drug suppresses the immune system, patients also take medicines to prevent herpes virus infection and Pneumocystis carinii-a type of pneumonia-and to treat cytomegalovirus infection, if it develops.

All patients are hospitalized for the initial testing and treatment (about 2 weeks) when the risk of infection and seizures is highest. In addition to drug treatment, patients undergo the following procedures:

- Blood tests: Throughout the hospital admission, blood samples are drawn daily to check drug side effects and the response to treatment. Samples are drawn less frequently for later tests.

- Bone marrow examination: A bone marrow sample is collected before beginning treatment, at 6 months, and then yearly. For this test, the area above the hip bone is numbed with a local anesthetic and a small sample of bone and marrow is withdrawn through a needle.

- Chest x-ray may be done upon admission.

- Other blood tests and x-rays may be required to evaluate and treat symptoms that may develop.

- Follow-up: Blood tests are done weekly by the patient's private doctor, and patients return to NIH for examinations at 3-month intervals.

Condition	Treatment or Intervention	Phase
Aplastic Anemia	Drug: Alemtuzumab (Campath-1H)	Phase II

Further Study Details: 

Expected Total Enrollment:  120

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 second round of immunosuppression, 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.

Genders Eligible for Study:  Both

Criteria

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 lless or equal to 16 months 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:
Serum creatinine greater than 2.5 mg/dL.
Underlying carcinoma (except local cervical, basal cell, squamous cell).
Current pregnancy or lactation or unwillingness to take contraceptives.
Diagnosis of Fanconi anemia or other congenital bone marrow failure syndromes.
Evidence of a clonal disorder on cytogenetics.
Previous hypersensitivity to Campath-1H or its components.
Prior treatment with rabbit ATG, cyclophosphamide or a comparable agent.
Underlying immunodeficiency state including seropositivity for HIV.
Inability to understand the investigational nature of the study or give informed consent.
Moribound status or concurrent hepatic, renal, cardiac, neurologic, pulmonary, infectious, or metabolic disease of such severity that it would preclude the patients ability to tolerate protocol therapy or that death within 7-10 days is likely.

Maryland
      National Heart, Lung and Blood Institute (NHLBI), 9000 Rockville Pike,  Bethesda,  Maryland,  20892,  United States; Recruiting

Study ID Numbers:  030249; 03-H-0249
Record last reviewed:  July 9, 2004
Last Updated:  January 5, 2005
Record first received:  July 18, 2003
ClinicalTrials.gov Identifier:  NCT00065260
Health Authority: United States: Federal Government
ClinicalTrials.gov processed this record on 2005-04-08