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
. 2021 Jan 7;21(1):38.
doi: 10.1186/s12885-020-07741-0.

Immune checkpoint inhibitors-related myocarditis in patients with cancer: an analysis of international spontaneous reporting systems

Rulan Ma  1 , Quanziang Wang  2 , Deyu Meng  2 , Kang Li  3 , Yong Zhang  4
Affiliations

Immune checkpoint inhibitors-related myocarditis in patients with cancer: an analysis of international spontaneous reporting systems

Rulan Ma et al. BMC Cancer. .

Abstract

Background: Immune checkpoint inhibitors-induced myocarditis presents unique clinical challenges. Here, we assessed post-marketing safety of cytotoxic T-lymphocyte-associated protein-4 (CTLA-4), programmed cell death-1 (PD-1), and programmed death-ligand 1 (PD-L1) inhibitors by mining the real-world data reported in two international pharmacovigilance databases.

Methods: We analyzed immune checkpoint inhibitors (ICIs)-associated fatal adverse drug events (ADEs) reports from the US Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) collected from July 1, 2014 to December 31, 2019 and data from EudraVigilance (EV) database accessed on February 29, 2020. Three different data mining approaches were used to detect the signal of fatal myocarditis caused by ICIs.

Results: Based on 7613 ICIs-related ADEs reported to the EV database and 5786 ICIs-associated ADEs submitted to the FAERS database, the most frequently reported ADE was ipilimumab-related colitis. For myocarditis, nivolumab-associated myocarditis was the most common. Among the five fatal toxic effects associated with ICIs, the lethality rate of myocarditis was the highest. Therefore, we further analyzed ICI-associated myocarditis and found that elderly patients and male patients were more likely to develop ICIs-related myocarditis. The results of signal detection showed that the risk signal of avelumab-related myocarditis detected by reporting odds ratio (ROR) method and proportional reporting ratios (PRR) method was the highest, whereas the signal strength of ipilimumab-related myocarditis detected by Bayesian confidence propagation neural networks (BCPNN) method was the strongest.

Conclusion: The findings of this study indicated the potential safety issues of developing myocarditis when using ICIs, which were consistent with the results of previous clinical trials and could provide a reference for clinical workers when using ICIs.

Keywords: Adverse drug reactions; Immune checkpoint inhibitors; Myocarditis; Signal detection.

PubMed Disclaimer

Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
The number of ICIs-associated ADR reports submitted to EV database. A The number of ICIs-related ADR reports submitted to EV database. B, C The proportion of different ICIs-related ADR reports from EV database. Abbreviations: ADR, adverse drug reaction; EV, EudraVigilance
Fig. 2
Fig. 2
The number of ICIs-associated ADR reports submitted to FAERS database. A The number of ICIs-related ADR reports submitted to FAERS database. B, C The proportion of different ICIs-related ADR reports from FAERS database. Abbreviations: ADR, adverse drug reaction; FAERS, Food and Drug Administration (FDA) Adverse Event Reporting System
Fig. 3
Fig. 3
Lethality rates of five fatal ICIs-associated adverse drug reactions
Fig. 4
Fig. 4
Signal values of ICIs-associated myocarditis. A Singal values of ICIs-related myocarditis was detected by using ROR method. B Singal values of ICIs-related myocarditis was detected by using PRR method. C Singal values of ICIs-related myocarditis was detected by using IC method. Abbreviations: ROR, reporting odds ratio; PRR, proportional reporting ratios; IC, information component; CI, confidence interval
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Veronese G, Ammirati E. Differences in clinical presentation and outcome between immune checkpoint inhibitor-associated myocarditis and classical acute myocarditis: same disease, distinct challenges to face. Int J Cardiol. 2019;296:124–126. doi: 10.1016/j.ijcard.2019.08.038. - DOI - PubMed
    1. Postow MA, Sidlow R, Hellmann MD. Immune-related adverse events associated with immune checkpoint blockade. N Engl J Med. 2018;378(2):158–168. doi: 10.1056/NEJMra1703481. - DOI - PubMed
    1. Puzanov I, Diab A, Abdallah K, Bingham CO, 3rd, Brogdon C, Dadu R, Hamad L, Kim S, Lacouture ME, LeBoeuf NR, et al. Managing toxicities associated with immune checkpoint inhibitors: consensus recommendations from the Society for Immunotherapy of Cancer (SITC) toxicity management working group. J Immunother Cancer. 2017;5(1):95. doi: 10.1186/s40425-017-0300-z. - DOI - PMC - PubMed
    1. Raschi E, Gatti M, Gelsomino F, Ardizzoni A, Poluzzi E, De Ponti F. Lessons to be learnt from real-world studies on immune-related adverse events with checkpoint inhibitors: a clinical perspective from Pharmacovigilance. Target Oncol. 2020;15(4):449–466. doi: 10.1007/s11523-020-00738-6. - DOI - PMC - PubMed
    1. Wang DY, Salem JE, Cohen JV, Chandra S, Menzer C, Ye F, Zhao S, Das S, Beckermann KE, Ha L, et al. Fatal toxic effects associated with immune checkpoint inhibitors: a systematic review and meta-analysis. JAMA Oncol. 2018;4(12):1721–1728. doi: 10.1001/jamaoncol.2018.3923. - DOI - PMC - PubMed

Substances