Bray G L, Gomperts E D, Courter S, Gruppo R, Gordon E M, Manco-Johnson M, Shapiro A, Scheibel E, White G, Lee M
Department of Hematology/Oncology, Children's National Medical Center, Washington, DC.
Blood. 1994 May 1;83(9):2428-35.
In July 1990, the Recombinate Study Group initiated a prospective, open-labeled investigation of recombinant factor VIII (r-FVIII) to assess its safety and efficacy and to characterize the natural history of inhibitor development in previously untreated patients (PUPs) with hemophilia A. All study subjects have severe FVIII deficiency (baseline FVIII level < or = 2% of normal) and no history of blood product exposure before study entry. Following the first r-FVIII infusion, plasma was screened for inhibitors once every 3 months, and plasma recovery of r-FVIII at 30 minutes and 24 hours postinfusion was assayed at least once every 6 months. As of May 1993, 73 of 79 patients originally enrolled in the trial continue to participate. The median number of r-FVIII exposure-days for the 71 subjects who have received at least one r-FVIII infusion is 11. A total of 1,785 infusions have been administered to treat 810 bleeding events. Ninety-two percent of bleeding events responded as anticipated to one or two infusions. Two, nonrecurring, acute adverse reactions occurred coincident with r-FVIII infusion, one of which was unrelated and the other, possibly related to the infusion. Seventeen (23.9%) subjects have developed inhibitors: five with peak titers more than 10 Bethesda units (BU) and 12 with peak titers < or = 10 BU (range, 0.5 to 10). Survival analysis showed that the probability of remaining inhibitor-free in this group of patients with severe hemophilia A is 88.4% after 8, 73.6% after 10, and 61.6% after 25 r-FVIII exposure-days. Inhibitors disappeared in five (29.4%) subjects on retesting 2 to 16 months after the last positive inhibitor assay. r-FVIII is safe and effective in the treatment of hemophilia A-related bleeding. To date, the inhibitor risk associated with its use is comparable to that in patients treated with plasma-derived concentrates. The majority of inhibitors identified are low in titer and do not preclude continued on-demand therapy with r-FVIII.
1990年7月，重组凝血因子VIII（r-FVIII）研究小组启动了一项前瞻性、开放标签的研究，以评估重组凝血因子VIII的安全性和疗效，并描述既往未接受治疗的甲型血友病患者（PUPs）中抑制物产生的自然病程。所有研究对象都有严重的FVIII缺乏症（基线FVIII水平≤正常水平的2%），且在研究入组前无血液制品接触史。首次输注r-FVIII后，每3个月筛查一次血浆中的抑制物，输注后30分钟和24小时的r-FVIII血浆回收率至少每6个月检测一次。截至1993年5月，最初入组该试验的79名患者中有73名继续参与研究。71名至少接受过一次r-FVIII输注的受试者接受r-FVIII暴露的天数中位数为11天。共进行了1785次输注，以治疗810次出血事件。92%的出血事件对一或两次输注有预期反应。两次非复发性急性不良反应与r-FVIII输注同时发生，其中一次无关，另一次可能与输注有关。17名（23.9%）受试者产生了抑制物：5名峰值效价超过10 Bethesda单位（BU），12名峰值效价≤10 BU（范围为0.5至10）。生存分析表明，在这组严重甲型血友病患者中，在8次r-FVIII暴露日后仍无抑制物的概率为88.4%，10次后为73.6%，25次后为61.6%。在最后一次抑制物检测呈阳性后2至16个月重新检测时，5名（29.4%）受试者的抑制物消失。r-FVIII在治疗甲型血友病相关出血方面安全有效。迄今为止，与其使用相关的抑制物风险与接受血浆源性浓缩物治疗的患者相当。所发现的大多数抑制物效价较低，并不妨碍继续按需使用r-FVIII治疗。
