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Abstract：
Immune checkpoint inhibitor (ICI) gastrointestinal toxicity (gastritis, enteritis, colitis) is a major cause of morbidity and treatment-related death. Guidelines agree steroid-refractory cases warrant infliximab, however best management of infliximab-refractory ICI gastrointestinal toxicity (IRIGItox) is unknown.
We conducted an international multicenter retrospective case series. IRIGItox was defined as failure of symptom resolution ≤grade 1 (Common Terminology Criteria for Adverse Events V.5.0) following ≥2 infliximab doses or failure of symptom resolution ≤grade 2 after one dose. Data were extracted regarding demographics, steroid use, response to treatment, and survival outcomes. Toxicity was graded at symptom onset and time of infliximab failure. Efficacy of infliximab refractory therapy was assessed by symptom resolution, time to resolution and steroid wean duration. Survival outcomes were examined based on immunosuppressive therapy received.
78 patients were identified: median age 60 years; 56% men; majority melanoma (N=70, 90%); 60 (77%) received anti-cytotoxic T-lymphocyte-associated protein 4 alone or in combination with anti-programmed cell death protein-1 and most had colitis (N=74, 95%). 106 post-infliximab treatments were given: 31 calcineurin inhibitors (CNIs); 27 antimetabolites (mycophenolate, azathioprine); 16 non-systemic immunomodulatory agents (eg, mesalazine or budesonide); 15 vedolizumab; 5 other biologics (anti-interleukin-12/23, 16, Janus kinase inhibitors) and 7 interventional procedures (including colectomy); 5 did not receive post-infliximab therapy. Symptom resolution was achieved in most (N=23/31, 74%) patients treated with CNIs; 12/27 (44%) with antimetabolites; 7/16 (44%) with non-systemic immunomodulation, 8/15 (53%) with vedolizumab and 5/7 (71%) with interventional procedures. No non-vedolizumab biologics resulted in toxicity resolution. CNIs had the shortest time to symptom resolution (12 days) and steroid wean (43 days); however, were associated with poorer event-free survival (6.3 months) and overall survival (26.8 months) than other agents. Conversely, vedolizumab had the longest time to toxicity resolution and steroid wean, 66 and 124 days, but most favorable survival data: EFS 24.5 months; median OS not reached. Six death occurred (three due to IRIGItox or management of toxicity; three with persisting IRIGItox and progressive disease).
IRIGItox causes major morbidity and mortality. Management is heterogeneous. CNIs appear most likely to result in toxicity resolution in the shortest time period, however, are associated with poorer oncological outcomes in contrast to vedolizumab.
We conducted an international multicenter retrospective case series. IRIGItox was defined as failure of symptom resolution ≤grade 1 (Common Terminology Criteria for Adverse Events V.5.0) following ≥2 infliximab doses or failure of symptom resolution ≤grade 2 after one dose. Data were extracted regarding demographics, steroid use, response to treatment, and survival outcomes. Toxicity was graded at symptom onset and time of infliximab failure. Efficacy of infliximab refractory therapy was assessed by symptom resolution, time to resolution and steroid wean duration. Survival outcomes were examined based on immunosuppressive therapy received.
78 patients were identified: median age 60 years; 56% men; majority melanoma (N=70, 90%); 60 (77%) received anti-cytotoxic T-lymphocyte-associated protein 4 alone or in combination with anti-programmed cell death protein-1 and most had colitis (N=74, 95%). 106 post-infliximab treatments were given: 31 calcineurin inhibitors (CNIs); 27 antimetabolites (mycophenolate, azathioprine); 16 non-systemic immunomodulatory agents (eg, mesalazine or budesonide); 15 vedolizumab; 5 other biologics (anti-interleukin-12/23, 16, Janus kinase inhibitors) and 7 interventional procedures (including colectomy); 5 did not receive post-infliximab therapy. Symptom resolution was achieved in most (N=23/31, 74%) patients treated with CNIs; 12/27 (44%) with antimetabolites; 7/16 (44%) with non-systemic immunomodulation, 8/15 (53%) with vedolizumab and 5/7 (71%) with interventional procedures. No non-vedolizumab biologics resulted in toxicity resolution. CNIs had the shortest time to symptom resolution (12 days) and steroid wean (43 days); however, were associated with poorer event-free survival (6.3 months) and overall survival (26.8 months) than other agents. Conversely, vedolizumab had the longest time to toxicity resolution and steroid wean, 66 and 124 days, but most favorable survival data: EFS 24.5 months; median OS not reached. Six death occurred (three due to IRIGItox or management of toxicity; three with persisting IRIGItox and progressive disease).
IRIGItox causes major morbidity and mortality. Management is heterogeneous. CNIs appear most likely to result in toxicity resolution in the shortest time period, however, are associated with poorer oncological outcomes in contrast to vedolizumab.
摘要：
背景：免疫检查点抑制剂（ICI）胃肠道毒性（胃炎，肠炎,结肠炎）是发病和治疗相关死亡的主要原因。指南同意类固醇难治性病例需要英夫利昔单抗，然而,英夫利昔单抗难治性ICI胃肠道毒性(IRIGItox)的最佳治疗方法尚不清楚.
方法：我们进行了一项国际多中心回顾性病例系列研究。IRIGItox定义为≥2次英夫利昔单抗剂量后症状缓解≤1级（不良事件通用术语标准V.5.0）失败或一次剂量后症状缓解≤2级。提取了关于人口统计学的数据，使用类固醇,对治疗的反应，和生存结果。在症状发作和英夫利昔单抗失败的时间对毒性进行分级。通过症状缓解评估英夫利昔单抗难治性治疗的疗效，时间解决和类固醇断奶持续时间。根据接受的免疫抑制治疗检查生存结果。
结果：确定了78例患者：中位年龄60岁；56％的男性；大多数黑色素瘤（N=70，90％）；60（77％）单独接受抗细胞毒性T淋巴细胞相关蛋白4或与抗程序性细胞死亡蛋白1联合使用，大多数患有结肠炎（N=74，95％）。给予106次英夫利昔单抗治疗：31次钙调磷酸酶抑制剂（CNIs）；27次抗代谢物（霉酚酸酯，硫唑嘌呤）；16种非全身性免疫调节剂（例如，美沙拉嗪或布地奈德）；15维多珠单抗；5种其他生物制剂（抗白介素12/23，16，Janus激酶抑制剂）和7种介入治疗（包括结肠切除术）；5没有接受英夫利昔单抗后治疗。大多数（N=23/31，74％）接受CNIs治疗的患者实现了症状缓解；12/27（44％）使用抗代谢物；7/16（44％）使用非全身免疫调节，8/15（53%）使用维多珠单抗，5/7（71%）使用介入手术。没有非维多珠单抗生物制剂导致毒性消退。CNI的症状缓解时间最短（12天）和类固醇断奶时间最短（43天）；然而，与其他药物相比,无事件生存期(6.3个月)和总生存期(26.8个月)较差.相反，维多珠单抗的毒性消退和类固醇断奶时间最长，66和124天，但最有利的生存数据：EFS24.5个月；中位OS未达到。发生了六例死亡（三例是由于IRIGItox或毒性管理；三例是持续的IRIGItox和进行性疾病）。
结论：IRIGItox导致主要的发病率和死亡率。管理是异构的。CNIs似乎最有可能在最短的时间内导致毒性消退，然而,与维多珠单抗相比，与较差的肿瘤结局相关。
方法：我们进行了一项国际多中心回顾性病例系列研究。IRIGItox定义为≥2次英夫利昔单抗剂量后症状缓解≤1级（不良事件通用术语标准V.5.0）失败或一次剂量后症状缓解≤2级。提取了关于人口统计学的数据，使用类固醇,对治疗的反应，和生存结果。在症状发作和英夫利昔单抗失败的时间对毒性进行分级。通过症状缓解评估英夫利昔单抗难治性治疗的疗效，时间解决和类固醇断奶持续时间。根据接受的免疫抑制治疗检查生存结果。
结果：确定了78例患者：中位年龄60岁；56％的男性；大多数黑色素瘤（N=70，90％）；60（77％）单独接受抗细胞毒性T淋巴细胞相关蛋白4或与抗程序性细胞死亡蛋白1联合使用，大多数患有结肠炎（N=74，95％）。给予106次英夫利昔单抗治疗：31次钙调磷酸酶抑制剂（CNIs）；27次抗代谢物（霉酚酸酯，硫唑嘌呤）；16种非全身性免疫调节剂（例如，美沙拉嗪或布地奈德）；15维多珠单抗；5种其他生物制剂（抗白介素12/23，16，Janus激酶抑制剂）和7种介入治疗（包括结肠切除术）；5没有接受英夫利昔单抗后治疗。大多数（N=23/31，74％）接受CNIs治疗的患者实现了症状缓解；12/27（44％）使用抗代谢物；7/16（44％）使用非全身免疫调节，8/15（53%）使用维多珠单抗，5/7（71%）使用介入手术。没有非维多珠单抗生物制剂导致毒性消退。CNI的症状缓解时间最短（12天）和类固醇断奶时间最短（43天）；然而，与其他药物相比,无事件生存期(6.3个月)和总生存期(26.8个月)较差.相反，维多珠单抗的毒性消退和类固醇断奶时间最长，66和124天，但最有利的生存数据：EFS24.5个月；中位OS未达到。发生了六例死亡（三例是由于IRIGItox或毒性管理；三例是持续的IRIGItox和进行性疾病）。
结论：IRIGItox导致主要的发病率和死亡率。管理是异构的。CNIs似乎最有可能在最短的时间内导致毒性消退，然而,与维多珠单抗相比，与较差的肿瘤结局相关。
