依托泊苷彻底改变了原发性和继发性噬血细胞性淋巴组织细胞增生症(HLH)的治疗,它是,连同皮质类固醇,最广泛使用的HLH疗法。在1980年代初期,原发性HLH的长期生存率<5%,但采用基于依托泊苷/地塞米松的方案HLH-94和HLH-2004,结合干细胞移植,原发性HLH的5年生存率急剧增加到约60%,根据HLH-2004研究的分析,可能还有进一步改进的空间。生物学,依托泊苷给药导致活化T细胞的有效选择性缺失以及炎性细胞因子产生的有效抑制。此外,依托泊苷还被报道促进程序性细胞死亡(凋亡)而不是促炎性裂解细胞死亡(焦亡),可以想象改善随后的全身性炎症,即,非常适合细胞因子风暴综合征(CSS)的治疗。依托泊苷和皮质类固醇的组合在严重或难治性继发性HLH(sHLH)伴有即将发生的器官衰竭的情况下也可能是有益的。例如由EB病毒(EBV)引起的感染相关HLH或恶性肿瘤引发的HLH。在与风湿性疾病相关的CSS中(巨噬细胞活化综合征,MAS或MAS-HLH),依托泊苷目前用作二线或三线治疗。最近的研究表明,依托泊苷也许应该是对重度难治性或复发性MAS患者的积极治疗干预的一部分。特别是如果有中枢神经系统受累。重要的是,必须进一步提高对sHLH的认识,因为sHLH的治疗经常延迟,从而错过了及时的机会之窗,有效,以及可能挽救生命的HLH指导治疗。
Etoposide has revolutionized the treatment of primary as well as secondary hemophagocytic lymphohistiocytosis (HLH), and it is, together with corticosteroids, the most widely used therapy for HLH. In the early 1980s, long-term survival in primary HLH was <5% but with the etoposide-/dexamethasone-based protocols HLH-94 and HLH-2004, in combination with stem cell transplantation, 5-year survival increased dramatically to around 60% in primary HLH, and based on analyses from the HLH-2004 study, there is likely room for further improvement. Biologically, etoposide administration results in potent selective deletion of activated T cells as well as efficient suppression of inflammatory cytokine production. Moreover, etoposide has also been reported to promote programmed cell death (apoptosis) rather than proinflammatory lytic cell death (pyroptosis), conceivably ameliorating subsequent systemic inflammation, i.e., a treatment very suitable for cytokine storm syndromes (CSS). The combination of etoposide and corticosteroids may also be beneficial in cases of severe or refractory secondary HLH (sHLH) with imminent organ failure, such as infection-associated HLH caused by Epstein-Barr virus (EBV) or malignancy-triggered HLH. In CSS associated with rheumatic diseases (macrophage activation syndrome, MAS or MAS-HLH), etoposide is currently used as second- or third-line therapy. Recent studies suggest that etoposide perhaps should be part of an aggressive therapeutic intervention for patients with severe refractory or relapsing MAS, in particular if there is CNS involvement. Importantly, awareness of sHLH must be further increased since treatment of sHLH is often delayed, thereby missing the window of opportunity for a timely, effective, and potentially life-saving HLH-directed treatment.