Aplastic anemia is characterized by trilineage hematopoietic failure with an apparently empty bone marrow. While the precise mechanism of disease has yet to be elucidated, much evidence indicates an immunologically mediated pathophysiology. Clinical trials have shown that approximately 75-80% of patients who are treated with immunosuppressive drugs, especially the combination of antithymocyte globulin (ATG) and cyclosporine (CSA), demonstrate a return of hematopoieses and improved blood counts. This therapy now is considered standard care for the treatment of aplastic anemia in all patients who lack a histocompatibility antigen-matched sibling donor and also in older patients regardless of donor status. However, with longer length of evaluation of patients after initial treatment, it is becoming increasingly clear that a substantial proportion will suffer relapse of pancytopenia. ATG and CSA do not appear to cure the disease in these patients but only disrupt a chronic autoimmune process. Recent data from our own series of patients treated with ATG and CSA, and studies of European patients who are treated with antilymphocyte globulin (ALG) and CSA, indicate that approximately 1/3 of responding patients will relapse and require treatment within 1-2 years of discontinuation of CSA. About 15% of patients become dependent on continued CSA administration in order to maintain blood counts. Chronic CSA toxicities include increased susceptibility to infections, hypertension, and irreversible renal damage, as well as hypertrichosis, hyperaesthesias, gingival hyperplasia, headaches, tremors, and other troubling complaints; there is also a possible increased risk of late malignant diseases. Therefore, a major priority in clinical research in aplastic anemia is the development of strategies to produce more durable responses, as well as to identify immunosuppressive agents that can be used as effectively and with fewer side affects than cyclosporine. Mycophenolate mofetil (MMF) is a novel immunosuppressive drug with proven efficacy in the treatment of graft rejection in renal transplantation. MMF has a different toxicity profile from cyclosporine, and specifically does not damage the kidneys. In this study, we will randomize patients who are judged to have relapsed to receive either standard treatment with full dose cyclosporine or half dose cyclosporine combined with MMF.

We anticipate that the combination of cyclosporine with MMF will be as effective as conventional high dose cyclosporine for the purpose of treating relapse of aplastic anemia and would provide a less toxic regimen for long-term treatment of this disease.