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.

Anemia, Aplastic
Anemia, Hypoplastic

h-ATG (ATGAM(Registered Trademark))
Cyclosporine (Gengraf(Registered Trademark))

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.

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.