Center for Hematology, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts, USA.
Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.
J Med Genet. 2019 Jan;56(1):39-42. doi: 10.1136/jmedgenet-2018-105485. Epub 2018 Oct 4.
Immune checkpoint inhibitor therapy is a modern breakthrough in medical oncology, but it can precipitate inflammatory and autoimmune adverse effects. Among the most serious of these toxicities is haemophagocytic lymphohistiocytosis (HLH), a life-threatening disorder of unbridled immune activation that results in injury to multiple organ systems.
Description of a case of pembrolizumab-associated HLH in a patient with a proposed underlying genetic risk factor for its occurrence.
We describe a patient with aggressive metastatic breast cancer who developed HLH while undergoing experimental treatment with pembrolizumab, resulting in critical illness and multiorgan system failure. Pembrolizumab discontinuation and high-dose corticosteroids were effective in managing HLH. Subsequent next-generation sequencing of 15 genes associated with HLH revealed a germline polymorphism in perforin-1 (), , that may have predisposed the patient to develop HLH. The patient has had no evidence of malignancy for 2 years following recovery despite receiving no further cancer-directed treatment.
HLH is a rare but serious complication of immune checkpoint blockade. Patients with underlying hypomorphic alleles in may be predisposed to develop this toxicity. Further studies are necessary to confirm a possible link between perforin gene mutations and immune checkpoint blockade-associated HLH.
免疫检查点抑制剂治疗是肿瘤医学的一项现代突破，但它可能引发炎症和自身免疫的不良反应。其中最严重的毒性之一是噬血细胞性淋巴组织细胞增生症（HLH），这是一种不受控制的免疫激活导致多器官系统损伤的危及生命的疾病。
描述一例 pembrolizumab 相关 HLH 病例，该患者存在发生 HLH 的潜在遗传危险因素。
我们描述了一例患有侵袭性转移性乳腺癌的患者，在接受 pembrolizumab 的实验性治疗期间发生了 HLH，导致严重疾病和多器官系统衰竭。停用 pembrolizumab 和大剂量皮质类固醇治疗 HLH 有效。随后对与 HLH 相关的 15 个基因进行下一代测序，发现穿孔素-1（）中的种系多态性，这可能使患者易发生 HLH。尽管未接受进一步的癌症治疗，但患者在恢复后 2 年内未发现恶性肿瘤。
HLH 是免疫检查点阻断的罕见但严重的并发症。在 中存在潜在功能丧失等位基因的患者可能易发生这种毒性。需要进一步的研究来证实穿孔素基因突变与免疫检查点抑制剂相关的 HLH 之间可能存在联系。
