Han Xinpu, Xu Jing, Cui Meichen, Yun Zhangjun, Zhao Hongbin, Tian Shaodan, Mi Suicai, Hou Li
Department of Oncology and Hematology, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China.
Beijing University of Chinese Medicine, Beijing, China.
Clin Exp Med. 2025 May 13;25(1):157. doi: 10.1007/s10238-025-01688-x.
This study aims to comprehensively evaluate the hematologic toxicity profiles, toxicity spectrum, and safety rankings of immune checkpoint inhibitors (ICIs) used for digestive system tumors. The PubMed, Cochrane Library, Web of Science, and Embase databases were systematically searched from inception to August 2024 to identify randomized controlled trials (RCTs). The primary outcome was anemia, while secondary outcomes included neutropenia, neutrophil count decreased, thrombocytopenia, platelet count decreased, leukopenia, white blood cell (WBC) count decreased, lymphocyte count decreased, and febrile neutropenia (FN). Subgroup analyses were performed based on tumor type, country category, study phase, ICI regimen, control group, chemotherapy regimen, ICI plus different chemotherapy regimens. Two reviewers independently selected the studies, extracted data according to pre-specified criteria, and assessed the risk of bias using the Cochrane Collaboration risk of bias tool. RevMan 5.4 software was utilized to visualize the risk of bias assessments. Stata 16.0 was used to conduct network meta-analysis, sensitivity analysis and meta-regression. 25 phase II and III RCTs (n = 15216) were included. The general safety of ICIs ranked from high to low for grade 1-5 anemia were as follows: avelumab, nivolumab, pembrolizumab, sintilimab, camrelizumab, and tislelizumab. For grade 3-5 anemia, the general safety profile of the ICIs were as follows, from highest to lowest: avelumab, nivolumab, pembrolizumab, sintilimab, and camrelizumab. Compared to chemotherapy, treatment-related hematologic toxicities with ICIs occurred primarily in grade 1-5 anemia, neutropenia, thrombocytopenia, leukopenia, and WBC count decreased. Taking ICI monotherapy, nivolumab plus ipilimumab were generally safer than taking chemotherapy, one ICI drug with chemotherapy, or two ICI drugs with chemotherapy. In terms of grade 1-5 hematologic toxicities, tislelizumab had the highest risk of neutropenia and leukopenia; the primary treatment-adverse events (AEs) for sintilimab was neutrophil count decreased and WBC count decreased; the primary treatment-related AE associated with nivolumab was platelet count decreased; camrelizumab posed the highest risk for lymphocyte count decreased. In terms of grade 3-5 hematologic toxicities, pembrolizumab was predominantly linked to neutropenia; sintilimab showed the greatest risk for neutrophil count decreased, platelet count decreased, and lymphocyte count decreased; avelumab was most associated with WBC count decreased. FN primarily manifested as grade 3-5, with camrelizumab having the highest risk. Among agents used in gastric or gastroesophageal junction cancer, avelumab demonstrated the most favorable safety profile for anemia. Each treatment regimen has its unique safety profile. Early identification and management of ICI-related hematologic toxicities are essential in clinical practice.Systematic Review Registration: PROSPERO CRD42024571508.
本研究旨在全面评估用于消化系统肿瘤的免疫检查点抑制剂（ICI）的血液学毒性特征、毒性谱及安全性排名。从数据库建立至2024年8月，系统检索了PubMed、Cochrane图书馆、Web of Science和Embase数据库，以识别随机对照试验（RCT）。主要结局为贫血，次要结局包括中性粒细胞减少、中性粒细胞计数降低、血小板减少、血小板计数降低、白细胞减少、白细胞（WBC）计数降低、淋巴细胞计数降低和发热性中性粒细胞减少（FN）。基于肿瘤类型、国家类别、研究阶段、ICI方案、对照组、化疗方案、ICI加不同化疗方案进行亚组分析。两名研究者独立选择研究，根据预先指定的标准提取数据，并使用Cochrane协作偏倚风险工具评估偏倚风险。使用RevMan 5.4软件直观展示偏倚风险评估结果。使用Stata 16.0进行网络荟萃分析、敏感性分析和Meta回归。纳入了25项II期和III期RCT（n = 15216）。ICI 1 - 5级贫血的总体安全性从高到低依次为：阿维鲁单抗、纳武利尤单抗、帕博利珠单抗、信迪利单抗、卡瑞利珠单抗和替雷利珠单抗。对于3 - 5级贫血，ICI的总体安全性概况从高到低依次为：阿维鲁单抗、纳武利尤单抗、帕博利珠单抗、信迪利单抗和卡瑞利珠单抗。与化疗相比，ICI相关的血液学毒性主要发生在1 - 5级贫血、中性粒细胞减少、血小板减少、白细胞减少和WBC计数降低。采用ICI单药治疗时，纳武利尤单抗联合伊匹木单抗通常比化疗、一种ICI药物联合化疗或两种ICI药物联合化疗更安全。在1 - 5级血液学毒性方面，替雷利珠单抗发生中性粒细胞减少和白细胞减少的风险最高；信迪利单抗的主要治疗不良事件（AE）是中性粒细胞计数降低和WBC计数降低；与纳武利尤单抗相关的主要治疗相关AE是血小板计数降低；卡瑞利珠单抗导致淋巴细胞计数降低的风险最高。在3 - 5级血液学毒性方面，帕博利珠单抗主要与中性粒细胞减少有关；信迪利单抗在中性粒细胞计数降低、血小板计数降低和淋巴细胞计数降低方面风险最高；阿维鲁单抗与WBC计数降低关联最大。FN主要表现为3 - 5级，卡瑞利珠单抗风险最高。在用于胃癌或胃食管交界癌的药物中，阿维鲁单抗在贫血方面显示出最有利的安全性概况。每种治疗方案都有其独特的安全性特征。在临床实践中，早期识别和管理ICI相关的血液学毒性至关重要。系统评价注册：PROSPERO CRD42024571508。
