Robert W. Franz Cancer Center, Providence Portland Medical Center, 2N35 North Pavilion, 4805 N.E. Glisan St, Portland, OR, 97213, USA.
Providence Neurological Specialties-West, Providence St. Vincent Medical Center, 9135 Southwest Barnes Road, Suite 461, Portland, OR, 97225, USA.
J Immunother Cancer. 2019 Jul 3;7(1):165. doi: 10.1186/s40425-019-0645-6.
The risk of delayed autoimmunity occurring months or years after discontinuation of immunotherapy is frequently asserted in the literature. However, specific cases were rarely described until 2018, when a wave of reports surfaced. With expanding I-O indications in the adjuvant/neoadjuvant curative setting, growing numbers of patients will receive limited courses of immunotherapy before entering routine surveillance. In this context, under-recognition of DIRE could pose a growing clinical hazard.
The aim of this study was to characterize DIRE through identification of existing reports of delayed post-treatment irAE in cancer patients treated with immunotherapy. We performed a PubMed literature review from 2008 through 2018 to determine the median data safety reporting window from existing I-O clinical trials, which we then applied to define the DIRE cutoff, and collated all qualifying reports over the same time span. DIRE was defined as new immune-related adverse events (irAE) manifesting ≥90 days after discontinuation of immunotherapy.
Median duration of I-O clinical trials data safety reporting was 90 days (82% ≤ 90 days). DIRE cutoff was thus set as ≥90 days post-immunotherapy. We identified 23 qualifying cases; 21 by literature review and 2 from our institution. Median off-treatment interval to DIRE was 6 months (range: 3 to 28). Median cumulative immunotherapy exposure was 4 doses (range: 3 to 42). Involvement included endocrine, neurologic, GI, pulmonary, cardiac, rheumatologic and dermatologic irAE.
As immunotherapy indications expand into the curative setting, often with brief exposure and potentially sequenced with multimodality treatments, it will be necessary to recognize an emerging diagnostic complex, which we have termed delayed immune-related events (DIRE). Clinical vigilance has the potential to reduce morbidity from diagnostic delay, as irAE are generally manageable with prompt initiation of treatment - or from misdiagnosis - as misattribution can lead to unnecessary or harmful interventions as we describe. DIRE should therefore figure prominently in the differential diagnosis of patients presenting with illnesses of unclear etiology, irrespective of intervening treatments or interval post-immunotherapy, both of which can confound diagnosis. Increased recognition will rest on delineation of DIRE as a clinical diagnostic entity.
免疫治疗停止数月或数年后发生迟发性自身免疫的风险在文献中经常被提及。然而，直到 2018 年，随着一波报告的出现，才很少有具体病例被描述。随着免疫治疗在辅助/新辅助治疗中的适应证不断扩大，越来越多的患者在接受常规监测之前将接受有限疗程的免疫治疗。在这种情况下，对 DIRE 的认识不足可能会带来越来越大的临床危害。
本研究旨在通过确定接受免疫治疗的癌症患者治疗后迟发性免疫相关不良事件的现有报告，来描述 DIRE。我们对 2008 年至 2018 年的 PubMed 文献进行了回顾，以确定现有免疫肿瘤学临床试验的数据安全报告中位时间窗口，然后应用该时间窗口来定义 DIRE 截止值，并在同一时间范围内整理所有符合条件的报告。DIRE 被定义为免疫治疗停止后≥90 天出现的新的免疫相关不良事件（irAE）。
免疫肿瘤学临床试验数据安全报告的中位时间为 90 天（82%≤90 天）。因此，DIRE 截止值设定为免疫治疗后≥90 天。我们共确定了 23 例符合条件的病例；其中 21 例通过文献回顾确定，2 例来自我们机构。从治疗结束到 DIRE 的中位间隔时间为 6 个月（范围：3 至 28 个月）。中位累积免疫治疗暴露剂量为 4 剂（范围：3 至 42 剂）。累及的器官包括内分泌、神经、胃肠道、肺、心脏、风湿和皮肤的 irAE。
随着免疫治疗适应证扩展到治疗领域，通常免疫治疗疗程较短，并且可能与多模式治疗序贯进行，因此有必要认识到一种新的诊断性疾病，我们将其称为迟发性免疫相关事件（DIRE）。临床警惕性有可能降低因诊断延迟而导致的发病率，因为 irAE 通常可以通过及时开始治疗来控制——或者通过误诊来控制，正如我们所描述的那样，误诊可能导致不必要或有害的干预。因此，无论治疗间隔时间和免疫治疗后时间如何，在病因不明的患者出现疾病时，都应将 DIRE 作为鉴别诊断的重点，这一点很重要。提高对 DIRE 的认识取决于将其作为一个临床诊断实体进行描述。
