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Background: Although the temporality of immune-related adverse events (irAE) is well-recognized during immunotherapy to be highly variable and often delayed, post-immunotherapy irAE are rarely described and potentially under-recognized. In 2013, two cases were reported in abstract form in Deutschen Dermatologischen Gesellschaft. In July 2018 a case of autoimmune hepatitis eight months post-immunotherapy was reported in The Oncologist and a dermatologic series appeared online in JAMA Dermatology. With expanding indications for IO and an increasing number of clinical trials in the curative-neoadjuvant setting, larger numbers of patients are being treated in earlier stages of disease and often for short courses. Given this trend, under-recognition of delayed immune-related events (DIRE) after completion of immunotherapy could pose a growing clinical hazard.
Methods: We performed a literature review in PubMed and Google Scholar (search terms included in Table 1); DIRE syndrome was defined as immune-related events post-immunotherapy, newly incident beyond two elimination half- lives (t 1/2) of drug.
Results: We identified 10 cases, 6 by literature review (5 melanoma, 1 cutaneous SCC) and an additional 4 cases at our institution (4 HNSCC). Median cumulative immunotherapy exposure was 4 doses (range: 2 to 22 doses). Median interval from last immunotherapy dose to DIRE onset was 5 months (range: 2 to 28 months). All literature cases were in the recurrent/metastatic context; we report four cases in the curative-neoadjuvant context (italicized) with one recurrence.
Conclusions: An influx of neoadjuvant clinical trial design over the last 2-3 years, incorporating brief IO exposure (typically checkpoint blockade) followed by surgical resection and/or adjuvant therapy, is attracting interest in multiple tumor types in the curative setting.[5–9] In this context, it will be necessary to recognize an emerging phenomenon, which we have termed DIRE syndrome (delayed immune-related events). Clinical vigilance has the potential to reduce morbidity from delayed diagnosis, as these conditions are generally manageable with prompt initiation of treatment; or from misdiagnosis, to avert unnecessary/harmful interventions (in the autoimmune meningitis case we report, an Omaya reservoir was placed at an out-of-state hospital based on erroneous diagnosis of leptomeningeal carcinomatosis). Several factors confound diagnosis in the neoadjuvant-IO context: 1) intervening treatments with potentially overlapping toxicities; 2) brief and remote IO exposure; 3) reduced vigilance during NED surveillance, in contrast to active disease follow-up; 4) protracted process of diagnosis-by-exclusion. DIRE syndrome should therefore figure prominently in the differential diagnosis of patients presenting with diseases of unclear etiology, irrespective of elapsed post-immunotherapy interval.
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Cancer, immunotherapy, immuno-oncology, immune related adverse event, irAE, delayed immune related event, DIRE syndrome
Couey, Marcus; Bell, R. Bryan; Patel, Ashish; Crittenden, Marka R; Curti, Brendan; and Leidner, Rom, "Delayed immune-related events after discontinuation of immunotherapy – DIRE syndrome?" (2018). Society for Immunotherapy of Cancer 2018 Annual Meeting Posters. 11.