Division of Clinical Pharmacology and Toxicology, Institute of Pharmacological Sciences of Southern Switzerland, Ente Ospedaliero Cantonale, Via Tesserete 46, 6903, Lugano, Switzerland.
Department of Clinical Pharmacology and Toxicology, University Hospital Zurich, Zurich, Switzerland.
J Immunother Cancer. 2019 May 2;7(1):117. doi: 10.1186/s40425-019-0598-9.
Immune checkpoint inhibitor (ICI) use in clinical practice has unravelled a spectrum of immune-related adverse events (irAEs) due to immune system hyper-activation. ICI-related haemophagocytic lymphohistiocytosis (HLH) has been recently outlined in single case reports, raising a concern about the need of increasing our knowledge on this rare yet life threatening ICI haematological toxicity.
To determine ICI-related HLH clinical, haematological, and coagulation features, its timing and outcome, concurrent irAEs and concomitant infections, we performed a retrospective observational cross-sectional study and queried VigiBase, the WHO global database of suspected adverse drug reactions (ADRs), on September 30th, 2018. We retrieved the individual case safety reports reporting HLH in association with ipilimumab, nivolumab, pembrolizumab, atezolizumab, avelumab or durvalumab, gathered in the database starting from the ICIs' approval dates by the US Food and Drug Administration. The main outcome measures were co-suspected drugs, concurrent irAEs, HLH clinical, haematological and coagulation features, concomitant infections, HLH median time to onset and outcome.
Among 49'883 ICI-related ADRs collated in VigiBase as of September 30th, 2018, HLH was reported in 38 cases of which 34 (90%) mentioned ICIs as the solely suspected drugs. ICI-related HLH showed clinical, haematological and coagulation features similar to those of HLH with different etiology. Concurrent irAEs occurred in 5 (13%) patients and 6 (16%) reported concomitant viral infections. 31 (82%) cases defined ICI-related HLH outcome, which resolved in 19 (61%) cases. HLH developed a median of 6.7 weeks after initiation of ICI treatment (IQR 2.9-15.4, n = 18, 47%).
By evaluating the largest cohort of ICI-related HLH cases, we observed that ICI-related HLH arises with a delayed timing with respect to initiation of ICI treatment, and usually presents without other irAEs and concomitant infections. Keeping in mind these findings, clinicians should consider ICIs' involvement in the onset of HLH whenever they diagnose a disease of this group of syndromes in cancer patients treated with ICIs.
免疫检查点抑制剂（ICI）在临床实践中的应用揭示了一系列由于免疫系统过度激活而导致的免疫相关不良事件（irAEs）。最近在个案报告中描述了与 ICI 相关的噬血细胞性淋巴组织细胞增生症（HLH），这引起了人们对增加对这种罕见但危及生命的 ICI 血液学毒性认识的关注。
为了确定与 ICI 相关的 HLH 的临床、血液学和凝血特征、其时间和结局、同时发生的 irAEs 和伴随感染、同时发生的 irAEs 和伴随感染，我们进行了一项回顾性观察性横断面研究，并于 2018 年 9 月 30 日查询了世界卫生组织（WHO）全球药物不良反应可疑报告数据库（VigiBase）。我们检索了在数据库中从美国食品和药物管理局（FDA）批准 ICI 之日起开始报告与伊匹单抗、纳武单抗、派姆单抗、阿特珠单抗、avelumab 或度伐单抗相关的 HLH 的个例安全报告，汇集了与 ICI 相关的 HLH 报告。主要观察指标为可疑药物共疑、同时发生的 irAEs、HLH 的临床、血液学和凝血特征、伴随感染、HLH 的中位发病时间和结局。
截至 2018 年 9 月 30 日，在 VigiBase 中收集的 49883 例与 ICI 相关的 ADR 中，报告了 38 例 HLH，其中 34 例（90%）提到 ICI 是唯一可疑药物。与 ICI 相关的 HLH 表现出与不同病因的 HLH 相似的临床、血液学和凝血特征。同时发生的 irAEs 发生在 5 例（13%）患者中，6 例（16%）报告了伴随的病毒感染。31 例（82%）定义了与 ICI 相关的 HLH 结局，其中 19 例（61%）得到解决。HLH 在开始 ICI 治疗后中位 6.7 周（IQR 2.9-15.4，n=18，47%）时发生。
通过评估最大的 ICI 相关 HLH 病例队列，我们观察到与 ICI 相关的 HLH 发生时间较 ICI 治疗开始时间延迟，通常在没有其他 irAEs 和伴随感染的情况下发生。考虑到这些发现，临床医生应在诊断癌症患者接受 ICI 治疗时发生此类综合征疾病时，考虑 ICI 参与 HLH 的发病。
