This study will test the safety and effectiveness of a combination of three drugs in
treating severe aplastic anemia and preventing its recurrence. Two drugs used in this trial
ATG and cyclosporine are standard combination therapy for aplastic anemia. This study will
try to improve this therapy in three ways: 1) by altering the drug regimen to allow the
drugs to work better; 2) by reducing the risk of kidney damage; and 3) by adding a third
drug mycophenolate mofetil to try to prevent disease relapse.
Patients with severe aplastic anemia who do not have a suitable bone marrow donor or who
decline bone marrow transplantation may participate in this study. Patients will have a skin
test for ATG allergy, chest X-ray, blood test, and bone marrow aspiration before treatment
begins. ATG will then be started, infused through a vein continuously for 4 days. Ten days
after ATG is stopped, cyclosporine treatment will begin, taken twice a day by mouth in
either liquid or capsule form and will continue for 6 months. Also, in the first 2 weeks of
treatment, patients will be given a full dose of corticosteroid (prednisone) to prevent
serum sickness that could develop as a side effect of ATG therapy. The dosage will be
decreased after that. Mycophenolate will be started at the same time as ATG, in two daily
doses by mouth, and will continue for 18 months.
Patients will be hospitalized at the beginning of the study. During this time, blood will be
drawn at 3-week intervals and a bone marrow examination will be repeated 3 months after
treatment has begun. Additional tests, including X-rays may be required. After hospital
discharge, patients will be followed on an outpatient basis at 3-month intervals. The
patients own physician will perform blood tests weekly and kidney and liver function tests
every 2 weeks during cyclosporine therapy. Transfusions may be required initially.
Severe acquired aplastic anemia (SAA) has a poor prognosis if untreated. Bone marrow
transplantation is available to only a minority of patients due to lack of a matched sibling
donor, advanced age of the patient, or cost. Clinical studies at NIH and elsewhere have
demonstrated excellent response rates and improved survival with immunosuppressive
treatments. Laboratory data implicate underlying cytotoxic T-lymphocyte-mediated suppression
of hematopoiesis as the likely proximal cause of disease in most patients. In earlier
clinical protocols we treated SAA with cyclosporine A (CSA) (86-H-0007), antithymocyte
globulin (ATG) (87-H-0124), and combined ATG and CSA (90-H-0146). While intensive
immunosuppression is most effective, relapse is common and some patients also develop second
hematologic complications like myelodysplasia. In this protocol, we modify our regimen by
delaying the introduction of cyclosporine to promote ATG tolerizing effects and adding
mycophenolate mofetil (MMF), a new agent that, like ATG may be relatively specific for
activated lymphocytes, in an effort to reduce the high relapse rate.
- INCLUSION CRITERIA:
Only patients with SAA will be admitted, defined as:
Bone marrow cellularity less than 30%.
At least two of the following blood count findings: absolute granulocyte count less than
500/mm(3); platelet count less than 20,000/mm(3); reticulocyte count less than
Age greater than or equal to 1 years.
Weight greater than 12 kg.
Serum creatinine greater than 2 mg/dl or estimated creatinine clearance less than 40
Underlying carcinoma, recent history of radiation or chemotherapy.
Current pregnancy or unwillingness to be treated with oral contraceptives.
Inability to comprehend the investigational nature of the study.
Moribund status or concurrent hepatic, renal, cardiac, neurologic, or metabolic disease of
such severity that death within 7 to 10 days is likely.
Evidence of other etiology than AA for bone marrow failure, including positive clastogenic
stress cytogenetic assay for Fanconi anemia and marrow chromosome abnormalities typical of
Neal S Young, M.D.
National Heart, Lung, and Blood Institute (NHLBI)