Gustave Roussy, Université Paris-Saclay, Département des Innovations Thérapeutiques et Essais Précoces, F-94800, Villejuif, France.
Gustave Roussy, Université Paris-Saclay, Unité de Pharmacovigilance, F-94800, Villejuif, France.
Eur J Cancer. 2021 Nov;158:217-224. doi: 10.1016/j.ejca.2021.08.048. Epub 2021 Oct 7.
Immune-related adverse events (irAEs) remain generally unpredictable, and severe irAEs remain challenging to detect early and manage. Very severe (grade IV-V) irAEs have not been extensively characterised in prospective studies, and their predictive factors remain unknown.
The objective of the study was to describe and identify predictive factors of very severe (grade IV-V) irAEs.
The French Registre des Effets Indésirables Sévères des Anticorps Monoclonaux Immunomodulateurs en Cancérologie (REISAMIC) registry has prospectively collected all clinically significant irAEs occurring in patients treated with immune checkpoint inhibitors at Gustave Roussy Institute since 2014.
This was a single-centre prospective cohort study at the Gustave Roussy Institute cancer centre (Villejuif, France).
The participants were all adult patients with a solid or haematological cancer treated with an anti-programmed cell death 1 (PD-1) or an anti-programmed cell death-ligand 1 (PD-L1) and who presented a clinically significant irAE.
The main outcomes included the clinical and laboratory characteristics of patients with very severe irAEs, including tumour type, affected organs, time to irAE occurrence, blood cell count and serum biochemistry parameters.
Of the 1187 patients prospectively followed in REISAMIC between December 2014 and January 2020, 380 (32.0%) had at least one irAE, and 34 (2.86%) presented with very severe irAEs (grades IV-V). Among the 380 patients with an irAE, the distribution of very severe irAEs (grades IV-V) was 8.95% and death (grade V) was 3.95%. Among the 34 patients with very severe irAEs, 33 were treated with monotherapy of PD-1 or PD-L1 inhibitors, and one patient was treated with a combination of PD-1 and cytotoxic T-lymphocyte-associated protein 4 inhibitors. The median time to occurrence was shorter for very severe irAEs (median [interquartile range]: 41 days [0-634] for grades IV-V; versus 91 days [0-1123] for grades I-III; p = 0.01680). On initiation of immunotherapy, the predictive factors for very severe irAEs were performance status ≥2, elevated neutrophil/lymphocyte ratio and treatment for lung cancer.
Very severe (grade IV-V) immunological toxicities occurred earlier than mild severe toxicities. On initiation of immunotherapy, patients with poor performance status, elevated neutrophil/lymphocyte ratio and lung cancer are identified at risk of developing these very severe toxicities. These results could help to develop risk scores to identify patients at risk of developing severe toxicities.
免疫相关不良事件（irAEs）通常难以预测，严重的 irAEs 也难以早期发现和处理。严重程度为 4 级-5 级（very severe [grade IV-V]）的 irAEs 在前瞻性研究中并未得到广泛描述，其预测因素也未知。
本研究旨在描述并确定严重程度为 4 级-5 级（very severe [grade IV-V]）irAEs 的预测因素。
法国 Gustave Roussy 研究所的免疫调节单克隆抗体严重不良事件登记处（REISAMIC）前瞻性收集了自 2014 年以来接受免疫检查点抑制剂治疗的癌症患者发生的所有具有临床意义的 irAEs。
这是 Gustave Roussy 癌症中心（法国 Villejuif）的一项单中心前瞻性队列研究。
参与者为接受抗程序性细胞死亡蛋白 1（PD-1）或抗程序性细胞死亡配体 1（PD-L1）治疗的实体瘤或血液系统恶性肿瘤成年患者，且发生具有临床意义的 irAE。
主要结局包括严重 irAE 患者的临床和实验室特征，包括肿瘤类型、受累器官、irAE 发生时间、血细胞计数和血清生化参数。
在 2014 年 12 月至 2020 年 1 月期间，REISAMIC 前瞻性随访的 1187 例患者中，380 例（32.0%）至少发生过一次 irAE，34 例（2.86%）发生严重 irAE（4 级-5 级）。在 380 例发生 irAE 的患者中，严重 irAE（4 级-5 级）的分布为 8.95%，死亡（5 级）为 3.95%。在 34 例发生严重 irAE 的患者中，33 例接受 PD-1 或 PD-L1 抑制剂单药治疗，1 例接受 PD-1 和细胞毒性 T 淋巴细胞相关蛋白 4 抑制剂联合治疗。严重 irAE（4 级-5 级）的发生时间中位数（四分位距）更短（41 天[0-634]与 91 天[0-1123]；p=0.01680）。免疫治疗开始时，严重 irAE 的预测因素为体力状态评分≥2、中性粒细胞/淋巴细胞比值升高和肺癌治疗。
严重程度为 4 级-5 级（very severe [grade IV-V]）的免疫毒性发生早于轻-重度毒性。在免疫治疗开始时，身体状况不佳、中性粒细胞/淋巴细胞比值升高和患有肺癌的患者有发生这些严重毒性的风险。这些结果有助于开发风险评分来识别发生严重毒性的患者。
