This study will examine the safety and effectiveness of a new drug combination for treating
patients with severe aplastic anemia. Patients with aplastic anemia produce too few blood
cells, causing fatigue, easy bruising and bleeding, and susceptibility to infections. In
many cases, the very low blood counts result from an autoimmune process-that is, the
patient's own immune system suppresses production of blood cells by the bone marrow.
Although immune-suppressing drugs, such as cyclosporine, can restore normal cell counts,
many patients have disease relapses. These patients require long-term therapy with
cyclosporine, which can cause harmful side effects. This study will examine whether a lower
dose of cyclosporine given together with mycophenolate mofetil (MMF) can maintain blood
counts as effectively as full-dose cyclosporine treatment, and whether MMF alone can reduce
the chances of future relapses.
Patients 4 years of age and older with severe aplastic anemia who have relapsed after immune
suppressing therapy may be eligible for this study. Participants will be randomly assigned
to receive either standard cyclosporine therapy or experimental therapy with cyclosporine
Patients receiving standard cyclosporine therapy will receive a full dose of the drug for at
least 3 months. Those taking both cyclosporine and MMF will take MMF plus half-dose
cyclosporine for 3 months and continue MMF for an additional 6 months. Both drugs are taken
twice a day by mouth. All patients will have about 120 milliliters (4 ounces) of blood
drawn at the beginning of the study to evaluate immune system activity and bone marrow
function, and to look for genetic material of certain viruses. Bone marrow aspirations and
biopsies will be done at the beginning of the study, and at 6 and 12 months. For these
tests, the area of the hip is anesthetized and a special needle is used to draw bone marrow
from the hipbone.
The patient's local doctor will be asked to do blood tests for chemistries, liver function
and cyclosporine levels weekly for the first month and then every other week. Patients will
return to NIH for evaluations 3, 6 and 12 months after treatment and then once a year.
About 100 ml (7 tablespoons) of blood will be drawn at each visit.
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
Subjects with a history of severe aplastic anemia successfully treated by
immunosuppression will be included.
Subjects with relapse, as defined above by either return of blood counts to satisfy
criteria for severity or consistently declining blood counts will be included.
Subjects age 4 and above will be included.
Subjects with the presence of a medical or surgical condition making survival for at least
3 months unlikely will be excluded.
Subjects with inability to confer informed consent or assent, in the case of a child,
either written or verbal, will be excluded.