Delayed immune-related events (DIRE) after discontinuation of immunotherapy: diagnostic hazard of autoimmunity at a distance

Abstract

Background 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. Methods 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. Results 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. Conclusions 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. Electronic supplementary material The online version of this article (10.1186/s40425-019-0645-6) contains supplementary material, which is available to authorized users.

Immune checkpoint inhibitor-induced inflammatory arthritis persists after immunotherapy cessation

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Conditional immune toxicity rate in patients with metastatic renal and urothelial cancer treated with immune checkpoint inhibitors

“…10 11 Nonetheless, delayed or latent irAEs have been reported months or even years after initiating therapy with onset extending beyond treatment discontinuation. 12 In clinical trials, the analysis of ICI safety in terms of irAEs is generally reported as incidence proportions. Incidence proportion is typically calculated by crude rates, that is, the ratio of the number of patients who developed the specific adverse event at any point in time to the total number of patients in the cohort.…”

Durvalumab-Induced Diffuse Alveolar Hemorrhage: An Autopsy Case Report

“…Therefore, edoxaban did not cause DAH in our case. There were 2 cases in which lung injury as an irAE had occurred 6 and 8 months after stopping ICIs [12]. These 2 cases do not contradict our finding that DAH continued for more than 10 weeks after discontinuation of durvalumab.…”