Acute neurological adverse events during immune checkpoint inhibition therapy in patients with melanoma brain metastases
Acute neurological adverse events during immune checkpoint inhibition therapy in patients with melanoma brain metastases
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DOI：
10.1097/cmr.0000000000000597
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发表时间：
2019-10-01
影响因子：
2.2
通讯作者：
Terheyden, Patrick
中科院分区：
文献类型：
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作者：
Graetz, Victoria;Langan, Ewan A.;Terheyden, Patrick
免疫检查点阻断疗法的常见不良反应已得到充分认可。然而，检查点抑制剂治疗的神经系统不良反应不太普遍，其临床管理仍然具有挑战性。因此，我们报告了在免疫检查点抑制剂治疗期间管理急性、危及生命的神经毒性的经验。5例IV期黑色素瘤男性患者接受了抗程序性细胞死亡蛋白1治疗（单药治疗或与抗细胞毒性T淋巴细胞抗原-4抗体联合治疗），并出现了严重的神经系统症状和体征，包括头痛、轻偏瘫和构音障碍。其中3例患者的脑转移的初步诊断实际上发生在开始检查点抑制剂治疗后，而2例患者既存中枢神经转移，并在免疫治疗期间发生脑水肿和出血。在BRAF抑制剂和MEK抑制剂耐药后，2例接受免疫治疗的患者发生了快速致死性结局。其中四名患者因神经系统并发症死亡，其中一名患者取得了完全的脑部反应。免疫治疗和肿瘤进展都可能导致神经系统症状和体征的发展，因此难以确定因果关系。然而，神经系统症状的发展与首次治疗之间的时间关系意味着应密切监测患者神经系统后遗症的发展，这甚至可能预示着隐匿性脑转移的存在。决定是否继续免疫治疗必须平衡症状与疾病进展的风险。然而，在我们的病例系列中，令人鼓舞的是注意到最初的急性神经症状往往是短暂的。尽管如此，治疗前应考虑脑成像，以排除隐匿性脑转移，并对脑内水肿和出血的风险进行分层。
The common adverse effects of immune checkpoint blockade therapy are well recognised. However, neurological adverse effects of checkpoint inhibitor therapy are less widely appreciated, and their clinical management remains challenging. Therefore, we report our experience of managing acute, life-threatening neurological toxicity during immune checkpoint inhibitor therapy. Five male patients with stage IV melanoma underwent anti-programmed cell death protein 1 therapy (monotherapy or combination therapy with anti-cytotoxic T-lymphocyte antigen-4 antibodies) and developed severe neurological symptoms and signs including headache, hemiparesis and dysarthria. The initial diagnosis of brain metastases actually occurred after initiation of checkpoint inhibitor therapy in three of the patients, whereas two patients had pre-existing central nervous metastases and developed cerebral oedema and haemorrhage during immunotherapy. A rapidly fatal outcome occurred in two patients treated with immunotherapy following the development of BRAF-inhibitor and MEK-inhibitor resistance. Four of the patients died owing to neurological complications, and one achieved a complete cerebral response. Immunotherapy and tumour progression can both result in the development of neurological symptoms and signs, making it difficult to determine causality. However, the temporal relationship between the development of neurological symptoms and the first administration of therapy means that patients should be closely monitored for the development of neurological sequelae, which may even herald the presence of occult brain metastases. The decision on whether to continue immunotherapy must balance the risks of symptom - versus disease progression. However, in our case series, it is encouraging to note that the initial acute neurological symptoms were often transient. Nevertheless, pretherapeutic brain imaging to exclude occult brain metastases and stratify the risk of intracerebral oedema and haemorrhage should be considered.