Quon Doris V, Wang Jiaan-Der, Wang Michael, Pepperell Dominic, Park Young-Shil, Kenet Gili, Mahlangu Johnny, Khoo Teh-Liane, Robinson Tara M, Chavele Konstantia-Maria, Pipe Steven W
Orthopaedic Hemophilia Treatment Center, 403 West Adams Blvd., Los Angeles, CA 90007, USA.
Center for Rare Disease and Hemophilia, Taichung Veterans General Hospital, Taichung, Taiwan.
Ther Adv Hematol. 2024 Dec 19;15:20406207241304645. doi: 10.1177/20406207241304645. eCollection 2024.
Hemophilia A is caused by coagulation factor VIII (FVIII) deficiency and increases bleeding risk during invasive procedures.
To investigate FVIII concentrate use and bleeding outcomes for invasive procedures after valoctocogene roxaparvovec gene transfer.
This manuscript presents post hoc analysis of the phase III GENEr8-1 trial.
A post hoc analysis was performed for GENEr8-1, a global, single-arm, open-label, phase III trial that enrolled 134 adults with severe hemophilia A. FVIII activity and bleeding were evaluated after 2 years of follow-up. Invasive procedures were reviewed and categorized as major or minor. FVIII activity was measured with a chromogenic assay. Bleeding was self-reported by participants. Principal investigators completed questionnaires about perioperative management.
In total, 111 invasive procedures were performed in 65 participants during GENEr8-1 as of the data cut. Procedures performed with FVIII treatment included 33 minor and 11 major procedures. The remaining 67 invasive procedures were minor and performed without FVIII treatment. When considering these 67 minor procedures, 43/46 investigators completing the questionnaires reported that the gene-therapy-derived FVIII activity was sufficient for the type of procedure. Minor procedures performed without FVIII treatment were associated with participants' higher mean endogenous FVIII activity (50.5 IU/dL) compared with major procedures (14.2 IU/dL) or minor procedures (16.4 IU/dL) performed with concomitant FVIII. Fourteen participants experienced 18 procedure-related bleeds (13 co-occurring with FVIII use). Participants who received FVIII treatment for procedure-related bleeds had numerically lower mean endogenous FVIII activity than those who did not receive FVIII treatment.
Invasive procedures were safely performed in participants following treatment with valoctocogene roxaparvovec. The questionnaire responses from investigators generally suggest they used endogenous FVIII activity derived from valoctocogene roxaparvovec to inform clinical decisions in a manner comparable to exogenously administered FVIII, and more commonly prescribed supplementary FVIII concentrate in the peri-procedural period for participants with lower FVIII activity levels.
甲型血友病由凝血因子 VIII（FVIII）缺乏引起，会增加侵入性操作期间的出血风险。
研究在接受 valoctocogene roxaparvovec 基因转移后，侵入性操作中 FVIII 浓缩物的使用情况及出血结局。
本手稿展示了 III 期 GENEr8-1 试验的事后分析。
对 GENEr8-1 进行事后分析，这是一项全球性、单臂、开放标签的 III 期试验，纳入了 134 名重度甲型血友病成人患者。随访 2 年后评估 FVIII 活性和出血情况。对侵入性操作进行审查并分为大手术或小手术。用发色底物法测量 FVIII 活性。出血情况由参与者自行报告。主要研究者完成了关于围手术期管理的问卷。
截至数据截止时，在 GENEr8-1 试验期间，65 名参与者共进行了 111 次侵入性操作。接受 FVIII 治疗的操作包括 33 次小手术和 11 次大手术。其余 67 次侵入性操作是小手术，未接受 FVIII 治疗。在考虑这 67 次小手术时，46 名完成问卷的研究者中有 43 名报告称基因疗法衍生的 FVIII 活性足以应对该类型手术。与接受 FVIII 治疗的大手术（14.2 IU/dL）或小手术（16.4 IU/dL）相比，未接受 FVIII 治疗的小手术参与者的平均内源性 FVIII 活性更高（50.5 IU/dL）。14 名参与者发生了 18 次与手术相关的出血（13 次与使用 FVIII 同时发生）。因手术相关出血接受 FVIII 治疗的参与者的平均内源性 FVIII 活性在数值上低于未接受 FVIII 治疗的参与者。
接受 valoctocogene roxaparvovec 治疗的参与者安全地进行了侵入性操作。研究者的问卷回复总体表明，他们使用 valoctocogene roxaparvovec 衍生的内源性 FVIII 活性来指导临床决策，其方式与外源性给予 FVIII 相当，并且更常在围手术期为 FVIII 活性水平较低的参与者开具补充 FVIII 浓缩物。
