前瞻性无血浆和无白蛋白重组因子VIII的ADVATE免疫耐受诱导注册研究（PAIR）的最终结果。

Final Results of the Prospective ADVATE Immune Tolerance Induction Registry (PAIR) Study with Plasma- and Albumin-Free Recombinant Factor VIII.

作者信息

Shapiro Amy D, Fernandez Alejandro, Teitel Jerome, Botha Jaco, Khair Kate

机构信息

Indiana Hemophilia & Thrombosis Center, Indianapolis, IN, USA.

Takeda Pharmaceutical International AG, Zürich, Switzerland.

出版信息

J Blood Med. 2021 Nov 20;12:991-1001. doi: 10.2147/JBM.S329883. eCollection 2021.

DOI:10.2147/JBM.S329883

PMID:34849043

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8612659/

Abstract

INTRODUCTION

Neutralizing antibodies to coagulation factor VIII (FVIII) remain a major complication associated with FVIII replacement therapy.

AIM

To assess safety and efficacy of immune tolerance induction (ITI) therapy with ADVATE (antihemophilic factor [recombinant] [rAHF]) in patients who participated in the Prospective ADVATE Immune Tolerance Induction Registry (PAIR) study.

METHODS

The PAIR study was an international, multicenter, open-label, prospective, observational study in patients with hemophilia A and inhibitors, prescribed rAHF ITI therapy in clinical practice. The primary endpoint was adverse event (AE) reporting; the secondary endpoints included incidence of central venous access device-related complications and success rates of ITI therapy. Maintenance of immune tolerance was monitored for 12 months post-ITI therapy.

RESULTS

Of 44 patients, 36 completed ITI therapy, including 31 completing the 12-month follow-up. Most patients received rAHF 90-130 IU/kg/day (59.1%) and a mean of 6.0 doses/week; the median duration of rAHF ITI therapy during the PAIR study was 600 days. Overall, 284 AEs were reported; 56 AEs were serious, of which none were considered rAHF-related. Of 228 nonserious AEs, 14 (in six patients) were deemed rAHF-related: increase of FVIII inhibitors titer due to anamnestic response, nausea, catheter site pain, pyrexia, urticaria, upper respiratory tract infection, arthralgia, and hemarthrosis. None were severe or led to ITI discontinuation. Eighteen patients experienced ≥1 central venous access device-related complication, and 21 of 36 completers achieved a negative inhibitor titer. The Kaplan-Meier estimate of success for achievement of first negative titer at 18 months of ITI therapy was 68.3% (95% confidence interval 51.8-83.6%) among completers. Of patients with partial or complete success post-ITI, 87% (20/23) maintained immune tolerance at 12-month follow-up.

CONCLUSION

Data suggest that rAHF ITI therapy in the PAIR study was effective, with no unexpected safety signals reported.

摘要

引言

凝血因子VIII（FVIII）中和抗体仍然是FVIII替代疗法的主要并发症。

目的

评估在参与前瞻性ADVATE免疫耐受诱导注册研究（PAIR）的患者中，使用ADVATE（重组抗血友病因子[rAHF]）进行免疫耐受诱导（ITI）治疗的安全性和有效性。

方法

PAIR研究是一项针对患有A型血友病且产生抑制剂的患者的国际多中心、开放标签、前瞻性观察性研究，在临床实践中规定了rAHF ITI治疗。主要终点是不良事件（AE）报告；次要终点包括中心静脉通路装置相关并发症的发生率和ITI治疗的成功率。在ITI治疗后12个月监测免疫耐受的维持情况。

结果

44例患者中，36例完成了ITI治疗，其中31例完成了12个月的随访。大多数患者接受rAHF 90 - 130 IU/kg/天（59.1%），平均每周6.0剂；PAIR研究期间rAHF ITI治疗的中位持续时间为600天。总体而言，报告了284例AE；56例AE为严重不良事件，其中无一例被认为与rAHF相关。在228例非严重AE中，14例（6例患者）被认为与rAHF相关：因回忆反应导致FVIII抑制剂滴度升高、恶心、导管部位疼痛、发热、荨麻疹、上呼吸道感染、关节痛和关节积血。均无严重情况或导致ITI治疗中断。18例患者经历了≥1次中心静脉通路装置相关并发症，36例完成治疗者中有21例抑制剂滴度转阴。在完成治疗者中，ITI治疗18个月时首次转阴的Kaplan-Meier成功率估计为68.3%（95%置信区间51.8 - 83.6%）。在ITI治疗后部分或完全成功的患者中，87%（20/23）在12个月随访时维持了免疫耐受。