Expert consensus on the management of pharmacodynamic breakthrough-hemolysis in treated paroxysmal nocturnal hemoglobinuria

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, acquired, non-malignant hematologic disease characterized by complement-mediated hemolysis (with or without hemoglobinuria), fatigue, increased susceptibility to thrombosis, and bone marrow dysfunction. The development of complement inhibitors has transformed outcomes for patients with PNH, but patients may still experience pharmacodynamic breakthrough hemolysis (BTH), which can be caused by exposure to a complement amplifying condition (CAC), such as vaccination, infection, or surgery. A 13-member expert panel used a validated methodology (a RAND/UCLA modified Delphi panel) to develop consensus on how to classify pharmacodynamic BTH in patients with complement-inhibitor treated PNH. Physicians reviewed literature, rated the appropriateness of over 400 scenarios, and discussed the ratings at an in-person meeting. After the meeting, the panel agreed on 77% of scenarios. Here, we present the group’s agreed-upon recommendations on how to manage BTH caused by a CAC, as well as provide a severity classification system for BTH and strategies to mitigate risk of BTH in special circumstances (e.g. vaccination, planned or unplanned surgery, and pregnancy). In general, as severity of BTH increased, experts agreed more interventions to manage the BTH were appropriate. These recommendations are based on clinical experience and opinion. Without clear data from randomized trials to guide the management of BTH, expert opinion can be useful to support patient care.

阵发性睡眠性血红蛋白尿症（Paroxysmal nocturnal hemoglobinuria, PNH）是一种罕见的获得性非恶性血液系统疾病，以补体介导的溶血（伴或不伴血红蛋白尿）、疲劳、血栓形成易感性增加以及骨髓功能异常为特征。补体抑制剂的研发彻底改善了PNH患者的预后，但患者仍可能出现药效学突破性溶血（pharmacodynamic breakthrough hemolysis, BTH），此类事件可由补体扩增状态（complement amplifying condition, CAC）诱发，例如疫苗接种、感染或外科手术等。由13名专家组成的专家组采用经过验证的方法（兰德/加州大学洛杉矶分校改良德尔菲法），就如何对接受补体抑制剂治疗的PNH患者的药效学突破性溶血进行分类达成共识。专家们审阅了相关文献，对400余个临床场景的适宜性进行评分，并在现场会议中对评分结果展开讨论。会议结束后，专家组对77%的临床场景达成共识。本文将介绍该专家组达成的关于如何管理由补体扩增状态诱发的药效学突破性溶血的共识建议，同时提供了药效学突破性溶血的严重程度分级系统，以及在特殊场景（如疫苗接种、计划性或非计划性外科手术以及妊娠）中降低该事件发生风险的策略。总体而言，随着药效学突破性溶血的严重程度越高，专家们越一致认为采用更多干预措施来管理该事件是合理的。本共识基于临床经验与专家意见，由于尚无随机对照试验的明确数据来指导药效学突破性溶血的管理，因此专家意见可为患者的临床诊疗提供支持。