Gelbenegger Georg, Schoergenhofer Christian, Derhaschnig Ulla, Buchtele Nina, Sillaber Christian, Fillitz Michael, Schenk Thomas M, D'Sa Shirley, Cartwright Ronwyn, Gilbert James C, Jilma Bernd, Jaeger Ulrich
Department of Clinical Pharmacology.
Department of Emergency Medicine.
Blood Adv. 2020 Mar 24;4(6):997-1005. doi: 10.1182/bloodadvances.2019001321.
Cold agglutinin disease (CAD) causes predominantly extravascular hemolysis and anemia via complement activation. Sutimlimab is a novel humanized monoclonal antibody directed against classical pathway complement factor C1s. We aimed to evaluate the safety and efficacy of long-term maintenance treatment with sutimlimab in patients with CAD. Seven CAD patients treated with sutimlimab as part of a phase 1B study were transitioned to a named patient program. After a loading dose, patients received biweekly (once every 2 weeks) infusions of sutimlimab at various doses. When a patient's laboratory data showed signs of breakthrough hemolysis, the dose of sutimlimab was increased. Three patients started with a dose of 45 mg/kg, another 3 with 60 mg/kg, and 1 with a fixed dose of 5.5 g every other week. All CAD patients responded to re-treatment, and sutimlimab increased hemoglobin from a median initial level of 7.7 g/dL to a median peak of 12.5 g/dL (P = .016). Patients maintained near normal hemoglobin levels except for a few breakthrough events that were related to underdosing and which resolved after the appropriate dose increase. Four of the patients included were eventually treated with a biweekly 5.5 g fixed-dose regimen of sutimlimab. None of them had any breakthrough hemolysis. All patients remained transfusion free while receiving sutimlimab. There were no treatment-related serious adverse events. Overlapping treatment with erythropoietin, rituximab, or ibrutinib in individual patients was safe and did not cause untoward drug interactions. Long-term maintenance treatment with sutimlimab was safe, effectively inhibited hemolysis, and significantly increased hemoglobin levels in re-exposed, previously transfusion-dependent CAD patients.
冷凝集素病（CAD）主要通过补体激活导致血管外溶血和贫血。苏替利单抗是一种新型的人源化单克隆抗体，可靶向经典途径补体因子C1s。我们旨在评估苏替利单抗对CAD患者进行长期维持治疗的安全性和有效性。作为1B期研究的一部分，7例接受苏替利单抗治疗的CAD患者转入了指定患者计划。在给予负荷剂量后，患者每两周（每2周一次）接受不同剂量的苏替利单抗输注。当患者的实验室数据显示有突破性溶血迹象时，增加苏替利单抗的剂量。3例患者起始剂量为45mg/kg，另外3例为60mg/kg，1例每隔一周固定剂量为5.5g。所有CAD患者再次治疗均有反应，苏替利单抗使血红蛋白从中位初始水平7.7g/dL升至中位峰值12.5g/dL（P = 0.016）。除了少数与剂量不足相关的突破性事件外，患者维持了接近正常的血红蛋白水平，适当增加剂量后这些事件得到解决。纳入的患者中有4例最终接受了每两周5.5g固定剂量的苏替利单抗治疗方案。他们均未发生任何突破性溶血。所有患者在接受苏替利单抗治疗期间均未输血。没有与治疗相关的严重不良事件。个别患者同时使用促红细胞生成素、利妥昔单抗或伊布替尼进行重叠治疗是安全的，且未引起不良药物相互作用。苏替利单抗的长期维持治疗是安全的，有效抑制了溶血，并显著提高了再次暴露的、先前依赖输血的CAD患者的血红蛋白水平。
