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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,[1] post-immunotherapy irAE are rarely described and potentially under-recognized. In 2013, two cases were reported in abstract form in Deutschen Dermatologischen Gesellschaft.[2] In July 2018 a case of autoimmune hepatitis eight months post-immunotherapy was reported in The Oncologist[3] and a dermatologic series appeared online in JAMA Dermatology.[4] 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.


  1. Champiat S, et al. Management of immune checkpoint blockade dysimmune toxicities: a collaborative position paper. Ann. Oncol. Off. J. Eur. Soc. Med. Oncol. 2016;27:559–574.
  2. Abstracts of the 8th World Congress of Melanoma, the 9th Congress of the European Association of Dermatology (EADO), the 7th Interdisciplinary Melanoma/Skin Cancer Meeting, and the 3rd European Post-Chicago Melanoma Meeting. July 17-20, 2013. Hamburg, Germany. J. Dtsch. Dermatol. Ges. J. Ger. Soc. Dermatol. 2013;JDDG 11 Suppl 7:1–119.
  3. Parakh S, Cebon J, Klein O. Delayed autoimmune toxicity occurring several months after cessation of anti-PD-1 therapy. The Oncologist. 2018;23:849–851.
  4. Wang L, et al. Timing of onset of adverse cutaneous reactions associated with programmed cell death protein 1 inhibitor therapy. JAMA Dermatol. 2018; doi:10.1001/jamadermatol.2018.1912
  5. Forde P, et al. Neoadjuvant PD-1 blockade in resectable lung cancer. N. Engl. J. Med. 2018;378:1976–1986.
  6. Uppaluri R, et al. Neoadjuvant pembrolizumab in surgically resectable, locally advanced HPV negative head and neck squamous cell carcinoma (HNSCC). J. Clin. Oncol. 2017;35:6012–6012.
  7. Ferris R, et al. LBA46An open-label, multicohort, phase 1/2 study in patients with virus-associated cancers (CheckMate 358): Safety and efficacy of neoadjuvant nivolumab in squamous cell carcinoma of the head and neck (SCCHN). Ann. Oncol. 2017;28.
  8. Necchi, A. et al. Interim results from PURE-01: A phase 2, open-label study of neoadjuvant pembrolizumab (pembro) before radical cystectomy for muscle-invasive urothelial bladder carcinoma (MIUC). J. Clin. Oncol. 2018;36:TPS533-TPS533.
  9. Powles, T. et al. A phase II study investigating the safety and efficacy of neoadjuvant atezolizumab in muscle invasive bladder cancer (ABACUS). J. Clin. Oncol. 2018;36: 4506–4506.

Publication Date


Clinical Institute





Earle A. Chiles Research Institute


Cancer, immunotherapy, immuno-oncology, immune related adverse event, irAE, delayed immune related event, DIRE syndrome




Poster presented at Society for Immunotherapy of Cancer Annual Meeting, Washington, D.C., November 7 – 11, 2018.

Delayed immune-related events after discontinuation of immunotherapy – DIRE syndrome?

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