Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2019 Jul 3;7(1):165.
doi: 10.1186/s40425-019-0645-6.

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

Marcus A Couey  1 , R Bryan Bell  1 , Ashish A Patel  1 , Meghan C Romba  2 , Marka R Crittenden  3 , Brendan D Curti  1 , Walter J Urba  1 , Rom S Leidner  4
Affiliations
Review

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

Marcus A Couey et al. J Immunother Cancer. .

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.

Keywords: Checkpoint inhibitor; Costimulatory agonist; Delayed toxicity; Immune-related adverse events; Immunotherapy.

PubMed Disclaimer

Conflict of interest statement

RBB receives research funding from the Oral and Maxillofacial Surgery Foundation, BMS, Abbvie, Safeway Foundation, Providence Portland Medical Center Foundation, receives institutional support from BMS, MedImmune, Prometheus, Merck, and is a member of the speakers bureaus for Merck and BMS, MRC receives institutional research support from Nanobiotix, Jounce, Celldex, Mavupharma and BMS, BDC receives institutional research support from MedImmune/AstraZeneca, BMS, Viralytics, and Gallectin Therapeutics, and serves as consultant to BMS, Eisai, Alligator, and Iovance, WJU has received renumeration from MedImmune and Leidos Biomedical Research, serves on the board of directors for Leidos, and serves on the advisory board for Bionical EMAS, RSL receives institutional research support from Bristol Myers Squibb and Medimmune/AstraZeneca, and serves as a consultant to Merck and Regeneron.

Figures

Fig. 1
Fig. 1
Serious adverse event (SAE) reporting. a Literature review to identify immuno-oncology clinical trials. b Clinical trials SAE reporting duration after discontinuation of immunotherapy
Fig. 2
Fig. 2
DIRE cases. a Literature review to identify DIRE cases – immune-related adverse events presenting ≥90 days after discontinuation of immunotherapy
See this image and copyright information in PMC

Comment in

References

    1. Ludlow SP, Kay N. Delayed dermatologic hypersensitivity reaction secondary to ipilimumab. J Immunother Hagerstown Md 1997. 2015;38:165–166. - PubMed
    1. Mandalà M, Merelli B, Indriolo A, Tondini C. Late-occurring toxicity induced by an immune checkpoint blockade in adjuvant treatment of a stage III melanoma patient. Eur J Cancer Oxf Engl 1990. 2018;95:130–132. - PubMed
    1. Diamantopoulos PT, Gaggadi M, Kassi E, Benopoulou O, Anastasopoulou A, Gogas H. Late-onset nivolumab-mediated pneumonitis in a patient with melanoma and multiple immune-related adverse events. Melanoma Res. 2017;27:391–395. doi: 10.1097/CMR.0000000000000355. - DOI - PubMed
    1. Garcia CA, El-Ali A, Rath TJ, Contis LC, Gorantla V, Drappatz J, et al. Neurologic immune-related adverse events associated with adjuvant ipilimumab: report of two cases. J Immunother Cancer. 2018;6:83. doi: 10.1186/s40425-018-0393-z. - DOI - PMC - PubMed
    1. Sarofim M, Winn R. Rare case of delayed onset colitis due to immunotherapy for malignant melanoma. ANZ J Surg. 2018;0. 10.1111/ans.14768. - PubMed

Publication types