Severe Aplastic Anemia (SAA) is a rare and very serious blood disorder in which the bone
marrow stops producing the cells which make up blood; red blood cells, white blood cells,
Researchers believe this is caused by an autoimmune reaction, a condition in which the
natural defense system of the body begins attacking itself. In SAA the immune system begins
attacking the bone marrow. Red blood cells are responsible for carrying oxygen to all of the
organ systems in the body, and low numbers (anemia) can cause difficulty breathing and
fatigue. Platelets are responsible for normal blood clotting and low numbers can result in
easy bruising and bleeding which can be deadly. White blood cells are responsible for
fighting infections, and low numbers of these can lead to frequent infections, the most
common cause of death in patients with aplastic anemia.
SAA can be treated by bone marrow transplant (BMT) or by drugs designed to slow down the
immune system (immunosuppressants). BMT can be successful, but it requires a donor with
matched bone marrow, making this therapy available only to a few patients. BMT with
unmatched bone marrow can fail and cause dangerous side effects.
Presently, the two drugs used to treat SAA by slowing down the immune system
(immunosuppression) are antithymocyte globulin (ATG) and cyclosporin A (CSA). When used in
combination these two drugs can improve most patients condition. However, one third of the
patients who respond to this therapy experience a relapse of SAA. In addition, some patients
treated with ATG/CSA can later develop other disorders of the blood.
Recently, researchers have found that another immunosuppressive drug called
cyclophosphamide, has been successful at treating patients with SAA. In addition, patients
treated with cyclophosphamide do not experience relapses or develop other disorders of the
In this study researchers would like to compare the combinations of antithymocyte globulin
(ATG) and cyclosporin A (CSA) to cyclophosphamide and cyclosporin A (CSA) for the treatment
Severe aplastic anemia (SAA) is a disorder with a poor prognosis if untreated. Current
accepted therapeutic strategies include bone marrow transplantation (BMT) and
immunosuppression, both offering cure or amelioration in the majority of patients. Although
BMT is successful using human leukocyte antigen (HLA) matched sibling bone marrow, the 25%
probability of finding an HLA identical sibling within a family renders this approach
available to only a minority of patients. BMT utilizing HLA-matched, unrelated donors
carries a high risk of treatment failure along with considerable toxicity. While combined
immunosuppression with both antithymocyte globulin (ATG) and cyclosporine A (CSA) produces
hematologic improvement in most patients, relapse is common, occurring in about a third of
responders. Late evolution of aplastic anemia to other serious hematologic disorders is a
significant problem following successful treatment with ATG/CSA with paroxysmal nocturnal
hemoglobinuria (PNH) occurs in approximately 13%, myelodysplasia in about 10%, and acute
leukemia in about 7%. Recently, results of immunosuppression in SAA with another potent
immunosuppressive agent, cyclophosphamide, were reported in 10 patients. In this small
group, the overall response rate was similar to that seen with ATG/CSA, but relapse and late
clonal disease were not seen during a median follow-up of greater than 10 years. In the
larger randomized trial proposed here, we will compare sustained hematologic response rates
to either conventional immunosuppression with ATG/CSA or high dose cyclophosphamide and CSA.
Secondary endpoints include response duration, event free survival, and overall survival.
- INCLUSION CRITERIA:
Severe aplastic anemia confirmed at NIH by:
1. Bone marrow cellularity less than thirty percent (excluding lymphocytes).
2. At least two of the following:
Absolute neutrophil count less that 500/mm(3);
Platelet count less than 20,000/mm(3);
Reticulocyte count less than 60,000/mm(3).
Serum creatinine greater than to 2.5 mg/dl.
Cardiac ejection fraction less than 45% by MUGA.
Underlying carcinoma (except local cervical, basal cell, squamous cell or melanoma).
Current pregnancy or unwilling to take oral contraceptives.
Diagnosis of Fanconi anemia or other congenital bone marrow failure syndromes.
Evidence of a clonal disorder on cytogenetics.
Inability to understand the investigational nature of the study.
Patients who are moribund or have hepatic, renal, cardiac, metabolic or other concurrent
diseases of such severity that death within 7-10 days is likely.
Previous treatment with ATG, or cyclophosphamide.
Neal S Young, M.D.
National Heart, Lung, and Blood Institute (NHLBI)