Tisdale J F, Dunn D E, Geller N, Plante M, Nunez O, Dunbar C E, Barrett A J, Walsh T J, Rosenfeld S J, Young N S
Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA.
Lancet. 2000 Nov 4;356(9241):1554-9. doi: 10.1016/S0140-6736(00)03126-3.
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.
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.
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).
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.
大剂量环磷酰胺已被提议作为治疗重型再生障碍性贫血的一种替代免疫抑制剂，其缓解率与含抗胸腺细胞球蛋白（ATG）的方案相似，但既无复发也无克隆性血液学并发症。我们进行了一项III期前瞻性随机试验，比较既往未治疗的患者接受大剂量环磷酰胺加环孢素免疫抑制与接受ATG加环孢素传统免疫抑制的缓解率。
1997年6月至2000年3月，招募了31例患者。15例被分配接受环磷酰胺治疗（50mg/kg静脉输注1小时，每日1次，共4天），16例被分配接受ATG治疗（40mg/kg每日1次，共4天）；两组均接受环孢素治疗，初始剂量为每日12mg/kg，并进行调整以维持血药浓度在200 - 400μg/L，持续6个月。主要终点为血液学缓解（不再符合重型再生障碍性贫血标准）。环磷酰胺组出现3例早期死亡后，试验提前终止。分析采用意向性治疗。
中位随访时间为21.9个月（范围1 - 33个月）。环磷酰胺组有更高的发病率（侵袭性真菌感染，环磷酰胺组4例，ATG组无；p = 0.043）以及更高的早期死亡率（环磷酰胺组在前3个月内有3例死亡，ATG组无；p = 0.101）。在可评估患者中，治疗6个月时总体缓解率无显著差异（环磷酰胺组13例中有6例[46%]，ATG组12例中有9例[75%]）。
需要更长时间的观察来评估复发和晚期克隆性并发症以及无病生存期和总生存期等次要终点。然而，鉴于标准疗法可取得良好效果，环磷酰胺似乎不是治疗该疾病的安全选择。
