• 自2014年FDA批准上市至2016年5月19日,梅奥癌症药品数据库中收录的所有使用抗PD-1单抗后12个月内发生神经系统并发症的患者,总计347例,10例(2.9%)发生亚急性神经系统并发症;
  • 并发症的范围、发病时间及严重程度各不相同,包括肌病、各种神经病变、小脑共济失调、头痛;
  • 接受抗PD-1治疗的患者,出现亚急性起病的神经系统症状,应立刻考虑不良事件的相关性,并停用抗PD-1药物,根据严重程度采用糖皮质激素或其他免疫治疗。
JAMA Neurology [IF:13.608]

Neurological Complications Associated With Anti-Programmed Death 1 (PD-1) Antibodies



2017-09-05, Article

Abstract & Authors:展开

Importance: Neurological complications are an increasingly recognized consequence of the use of anti-programmed death 1 (PD-1) antibodies in the treatment of solid-organ tumors, with an estimated frequency of 4.2%. To date, the clinical spectrum and optimum treatment approach are not established.
Objective: To investigate the frequency, clinical spectrum, and optimum treatment approach to neurological complications associated with anti-PD-1 therapy.
Design, Setting, and Participants: This single-center, retrospective cohort study was conducted from either September or December 2014 (the approval dates of the study drugs by the US Food and Drug Administration) to May 19, 2016. All patients receiving anti-PD-1 monoclonal antibodies were identified using the Mayo Cancer Pharmacy Database. Patients with development of neurological symptoms within 12 months of anti-PD-1 therapy were included. Patients with neurological complications directly attributable to metastatic disease or other concurrent cancer-related treatments were excluded.
Main Outcomes and Measures: Clinical and pathological characteristics, time to development of neurological symptoms, and modified Rankin Scale (mRS) score.
Results: Among 347 patients treated with anti-PD1 monoclonal antibodies (pembrolizumab or nivolumab), 10 (2.9%) developed subacute onset of neurological complications. Seven patients were receiving pembrolizumab, and 3 patients were receiving nivolumab. The patients included 8 men and 2 women. Their median age was 71 years (age range, 31-78 years). Neurological complications occurred after a median of 5.5 (range, 1-20) cycles of anti-PD-1 inhibitors. Complications included myopathy (n = 2), varied neuropathies (n = 4), cerebellar ataxia (n = 1), autoimmune retinopathy (n = 1), bilateral internuclear ophthalmoplegia (n = 1), and headache (n = 1). Peripheral neuropathies included axonal and demyelinating polyradiculoneuropathies (n = 2), length-dependent neuropathies (n = 1), and asymmetric vasculitic neuropathy (n = 1). The time to maximum symptom severity varied from 1 day to more than 3 months. The median mRS score was 2.5 (range, 1-5), indicating mild to moderate disability. Five patients experienced other systemic immune-mediated complications, including hypothyroidism (n = 3), colitis (n = 2), and hepatitis (n = 1). Treatment with anti-PD-1 antibodies was discontinued in all patients. Treatment included corticosteroids (n = 7), intravenous immunoglobulin (n = 3), and plasma exchange (n = 1). Nine patients improved, with a median mRS score of 2 (range, 0-6). One patient with severe necrotizing myopathy died.
Conclusions and Relevance: Neurological adverse events associated with anti-PD-1 therapy have a diverse phenotype, with more frequent neuromuscular complications. Although rare, they will likely be encountered with increasing frequency as anti-PD-1 therapy expands to other cancers. The time of onset is unpredictable, and evolution may be rapid and life-threatening. Prompt recognition and discontinuation of anti-PD-1 therapy is recommended. In some cases, immune rescue treatment may be required.

First Authors:
Justin C Kao

Correspondence Authors:
Michelle L Mauermann

All Authors:
Justin C Kao,Bing Liao,Svetomir N Markovic,Christopher J Klein,Elie Naddaf,Nathan P Staff,Teerin Liewluck,Julie E Hammack,Paola Sandroni,Heidi Finnes,Michelle L Mauermann