High-dose cyclophosphamide in severe aplastic anaemia: a randomised trial.
BACKGROUND
High-dose cyclophosphamide has been proposed as an alternative immunosuppressive agent for treatment of severe aplastic anaemia, with a response rate similar to that with regimens containing antithymocyte globulin (ATG) but neither relapse nor clonal haematological complications. We undertook a phase III, prospective, randomised trial to compare response rates to immunosuppression with either high-dose cyclophosphamide plus cyclosporin or conventional immunosuppression with ATG plus cyclosporin in previously untreated patients.


METHODS
Between June, 1997, and March, 2000, 31 patients were enrolled. 15 were assigned cyclophosphamide (1 h intravenous infusion of 50 mg/kg daily for 4 days) and 16 were assigned ATG (40 mg/kg daily for 4 days); both groups received cyclosporin, initially at 12 mg/kg daily with adjustment to maintain concentrations at 200-400 microg/L, for 6 months. The primary endpoint was haematological response (no longer meeting criteria for severe aplastic anaemia). The trial was terminated prematurely after three early deaths in the cyclophosphamide group. Analyses were by intention to treat.


RESULTS
Median follow-up was 21.9 months (range 1-33). There was excess morbidity in the cyclophosphamide group (invasive fungal infections, four cyclophosphamide vs no ATG patients; p=0.043) as well as excess early mortality (three deaths within the first 3 months cyclophosphamide vs no ATG patients; p=0.101). There was no significant difference at 6 months after treatment in the overall response rates among evaluable patients (six of 13 [46%] cyclophosphamide vs nine of 12 [75%] ATG).


CONCLUSIONS
A longer period of observation will be necessary to assess the secondary endpoints of relapse and late clonal complications as well as disease-free and overall survival. However, cyclophosphamide seems a dangerous choice for treatment of this disorder, given the good results achievable with standard therapy.
Tisdale
J F
JF
Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA. johntis@intra.niddk.nih.gov
Dunn
D E
DE
Geller
N
N
Plante
M
M
Nunez
O
O
Dunbar
C E
CE
Barrett
A J
AJ
Walsh
T J
TJ
Rosenfeld
S J
SJ
Young
N S
NS
D000328:Adult; D000368:Aged; D000741:Anemia, Aplastic / Q000188:drug therapy* / Q000401:mortality; D000961:Antilymphocyte Serum / Q000008:administration & dosage / Q000627:therapeutic use*; D003520:Cyclophosphamide / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use; D016572:Cyclosporine / Q000008:administration & dosage / Q000627:therapeutic use*; D004334:Drug Administration Schedule; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use; D007262:Infusions, Intravenous; D008875:Middle Aged; D009181:Mycoses / Q000209:etiology; D012307:Risk Factors
D000961:Antilymphocyte Serum; D007166:Immunosuppressive Agents; D016572:Cyclosporine; D003520:Cyclophosphamide