A 随机对照试验VIII 因子和中和抗体在血友病 A.

A Randomized Trial of Factor VIII and Neutralizing Antibodies in Hemophilia A.

机构信息

From the Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Ca' Granda Ospedale Maggiore Policlinico (F.P., P.M.M., E.S., M.E.M.), and Department of Pathophysiology and Transplantation, Università degli Studi di Milano (F.P., P.M.M., I.G.), Milan, Clinica Medica II, Azienda Ospedaliera di Padova, Centro Emofilia, Padua (E.Z.), and Ematologia, Unità Operativa Diagnostica Speciale e Terapia delle Malattie dell'Emostasi e della Trombosi, Università Sapienza, Policlinico Umberto I, Rome (M.G.M.) - all in Italy; the Pediatric Hematology Department, Cairo University Pediatric Hospital (A.E.-B.), and Department of Pediatrics, Faculty of Medicine, Ain Shams University (M.E.), Cairo; Jehangir Clinical Development Center, Department of Hematology, Jehangir Hospital Premises (V.R.), and Sahyadri Speciality Hospital (S.A.), Pune, Jagadguru Jayadeva Murugarajendra Medical College, Davangere (S.H.), Center for Blood Disorders, Chennai (R.V.), Lokmanya Tilak Municipal Medical College and General Hospital, Mumbai (M.V.M.); St. John's Medical College Hospital, Bangalore (C.R.), All India Institute of Medical Sciences, Department of Hematology (T.S.), and Pediatric Hematology Oncology and Bone Marrow Transplantation, Institute for Child Health, Sir Ganga Ram Hospital (A.S.), New Delhi, Melaka-Manipal Medical College, Manipal University, Manipal (D.M.N.), and Kerala Institute of Medical Science, Trivandrum (M.T.) - all in India; the Congenital Pediatric Hematologic Disorders Research Center, Shahid Beheshti University of Medical Sciences, Tehran (P.E.), and Hematology Research Center, Shiraz University of Medical Sciences, Shiraz (M.K.) - both in Iran; Children's Hospital Los Angeles, Los Angeles (G.Y.), and City of Hope National Medical Center, Duarte (N.P.E.) - both in California; Hospital de Especialidades Unidad Médica de Alta Especialidad, Instituto Mexicano del Seguro Social, Monterrey (A.C.S.G.), an

出版信息

N Engl J Med. 2016 May 26;374(21):2054-64. doi: 10.1056/NEJMoa1516437.

DOI:10.1056/NEJMoa1516437

PMID:27223147

Abstract

BACKGROUND

The development of neutralizing anti-factor VIII alloantibodies (inhibitors) in patients with severe hemophilia A may depend on the concentrate used for replacement therapy.

METHODS

We conducted a randomized trial to assess the incidence of factor VIII inhibitors among patients treated with plasma-derived factor VIII containing von Willebrand factor or recombinant factor VIII. Patients who met the eligibility criteria (male sex, age <6 years, severe hemophilia A, and no previous treatment with any factor VIII concentrate or only minimal treatment with blood components) were included from 42 sites.

RESULTS

Of 303 patients screened, 264 underwent randomization and 251 were analyzed. Inhibitors developed in 76 patients, 50 of whom had high-titer inhibitors (≥5 Bethesda units). Inhibitors developed in 29 of the 125 patients treated with plasma-derived factor VIII (20 patients had high-titer inhibitors) and in 47 of the 126 patients treated with recombinant factor VIII (30 patients had high-titer inhibitors). The cumulative incidence of all inhibitors was 26.8% (95% confidence interval [CI], 18.4 to 35.2) with plasma-derived factor VIII and 44.5% (95% CI, 34.7 to 54.3) with recombinant factor VIII; the cumulative incidence of high-titer inhibitors was 18.6% (95% CI, 11.2 to 26.0) and 28.4% (95% CI, 19.6 to 37.2), respectively. In Cox regression models for the primary end point of all inhibitors, recombinant factor VIII was associated with an 87% higher incidence than plasma-derived factor VIII (hazard ratio, 1.87; 95% CI, 1.17 to 2.96). This association did not change in multivariable analysis. For high-titer inhibitors, the hazard ratio was 1.69 (95% CI, 0.96 to 2.98). When the analysis was restricted to recombinant factor VIII products other than second-generation full-length recombinant factor VIII, effect estimates remained similar for all inhibitors (hazard ratio, 1.98; 95% CI, 0.99 to 3.97) and high-titer inhibitors (hazard ratio, 2.59; 95% CI, 1.11 to 6.00).

CONCLUSIONS

Patients treated with plasma-derived factor VIII containing von Willebrand factor had a lower incidence of inhibitors than those treated with recombinant factor VIII. (Funded by the Angelo Bianchi Bonomi Foundation and others; ClinicalTrials.gov number, NCT01064284; EudraCT number, 2009-011186-88.).

摘要

背景

在重度 A 型血友病患者中，抗因子 VIII 同种异体抗体（抑制剂）的产生可能取决于用于替代治疗的浓缩物。

方法

我们进行了一项随机试验，以评估含有血管性血友病因子的血浆源性因子 VIII 或重组因子 VIII 治疗的患者中因子 VIII 抑制剂的发生率。符合入选标准（男性，年龄<6 岁，重度 A 型血友病，且以前未接受任何因子 VIII 浓缩物治疗或仅接受过最低限度的血液成分治疗）的 42 个地点的 303 名患者进行了筛选。

结果

在 303 名筛选出的患者中，有 264 名进行了随机分组，251 名进行了分析。76 名患者产生了抑制剂，其中 50 名患者具有高滴度抑制剂（≥5 个贝塞斯达单位）。125 名接受血浆源性因子 VIII 治疗的患者中有 29 名（20 名患者具有高滴度抑制剂）和 126 名接受重组因子 VIII 治疗的患者中有 47 名（30 名患者具有高滴度抑制剂）产生了抑制剂。所有抑制剂的累积发生率为血浆源性因子 VIII 组 26.8%（95%置信区间 [CI]，18.4 至 35.2），重组因子 VIII 组 44.5%（95%CI，34.7 至 54.3）；高滴度抑制剂的累积发生率分别为血浆源性因子 VIII 组 18.6%（95%CI，11.2 至 26.0）和重组因子 VIII 组 28.4%（95%CI，19.6 至 37.2）。在所有抑制剂的主要终点的 Cox 回归模型中，重组因子 VIII 与血浆源性因子 VIII 相比，发生率高出 87%（风险比，1.87；95%CI，1.17 至 2.96）。多变量分析中并未改变这种关联。对于高滴度抑制剂，风险比为 1.69（95%CI，0.96 至 2.98）。当分析仅限于第二代全长重组因子 VIII 以外的重组因子 VIII 产品时，所有抑制剂（风险比，1.98；95%CI，0.99 至 3.97）和高滴度抑制剂（风险比，2.59；95%CI，1.11 至 6.00）的效应估计值仍相似。

结论

与接受重组因子 VIII 治疗的患者相比，接受含有血管性血友病因子的血浆源性因子 VIII 治疗的患者抑制剂发生率较低。（由 Angelo Bianchi Bonomi 基金会等资助；ClinicalTrials.gov 编号，NCT01064284；EudraCT 编号，2009-011186-88.）。