Re: Cardiotoxicity of immune checkpoint inhibitors: A systematic review and meta-analysis of randomised clinical trials

Immune checkpoint inhibitors (ICIs) are revolutionary anticancer drugs approved in an expanding variety of cancer types [ [1] Geraud A. Gougis P. Vozy et al. Clinical pharmacology and interplay immune Agents: a yin-yang balance. Annu Rev Pharmacol Toxicol. 2021 Jan 6; 61 (Epub 2020 Sep 1. PMID: 32871087): 85-112https://doi.org/10.1146/annurev-pharmtox-022820-093805 Crossref PubMed Scopus (13) Google Scholar ]. ICIs restore the activity system primarily T cells to destroy neoplastic Currently, monoclonal antibodies blocking cytotoxic T-lymphocyte–associated protein 4 (CTLA-4) programmed cell death 1 (PD1), which brakes expressed on also include anti–PD-L1 (PD1 ligand located cells) normally interacting with PD1 tone down may induce immune-related adverse events (irAEs) autoimmune reaction, targeting potentially any organ eventually being fatal ~0.5–1% ICI-treated patients [2] Wang D.Y. Salem J.E. Cohen J.V. Fatal toxic effects associated inhibitors: systematic review meta-analysis. JAMA Oncol. 2018; 4: 1721-1728 (769) irAEs, when symptomatic, generally treated by withholding starting immunosuppressants including glucocorticoids first place irAEs affecting cardiovascular mainly myocarditis, pericarditis, arrhythmias vasculitis [3] J.-E. Manouchehri Moey M. Cardiovascular toxicities observational, retrospective, pharmacovigilance study. Lancet 19: 1579-1589 Abstract Full Text PDF (329) Myocarditis is fortunately rare event but top life-threatening irAE, fatality rates reaching up 50% cohorts reported Johnson [4] D.B. Balko J.M. Compton M.L. Fulminant myocarditis combination blockade. N Engl J Med. 2016; 375: 1749-1755 (1007) ] described two ICI-induced cases, analyses autopsied tissues, activated macrophages leading heart peripheral muscles necrosis, providing main pathophysiological processes this novel condition. The incidence has been estimated be around 0.06% clinical trials evaluating ICI monotherapies ~1% real-life involving medical teams oncologists cardiologists , But increased use multiplication indications, number deadly glucocorticoid-resistant exploded, representing important concern for clinicians regulatory institutions 5 Allenbach Y. Abatacept severe inhibitor-associated myocarditis. 2019; 380: 2377-2379 (154) 6 Moslehi J.J. Sosman J.A. Lebrun-Vignes B. Increased reporting Lancet. 391: 933 (369) 7 Amiri-Kordestani L. J. Cheng inhibitor trials: U.S. Food Drug Administration pooled analysis. Clin 36: 3009 Combinations ICIs, anti–CTLA-4 anti-PD1 agent, have repeatedly shown risk factor using multiple study designs [8] Wei S.C. Meijers W.C. Axelrod A genetic mouse model recapitulates supports mechanism-based therapeutic intervention. Canc Discov. 2020; 11: 614-625 (26) First, analysis Bristol Myers Squibb corporate safety databases as April 2016 showed significantly higher who received therapy (an anti–CTLA-4; 8/2974 [0.27%]) than those alone (10/17,620 [0.06%]; P < 0.001) Second, query VigiBase, World Health Organisation database, was over-reported versus monotherapy (reporting odds ratio = 4.31 [2.86–6.38]) Third, US 59 (N 21,664), vasculitis, ischaemia, arrhythmia pericardial disease non-ICI [7] When were used 1533), across most categories compared 17,072), particularly (0.13% 0.02%; relative 7.42) Finally, preclinical models, deleterious interaction between CTLA-4 further confirmed. identified dose-dependent functional cell–negative costimulatory genes Ctla4 Pdcd1, manifests Ctla4+/− Pdcd1−/− mice, contrasting absence phenotype Ctla4+/+ or Pdcd1+/− mice. In context, results meta-analysis randomised Agostinetto [9] E. Eiger D. Lambertini Cardiotoxicity trials. Eur Canc. 2021; 148: 76-91 (6) showing no association monotherapies, even therapies control stand out remarkably. Herein, we investigated reason such discordant findings. trialsEuropean Journal CancerVol. 148PreviewImmune cause (AEs), cardiotoxicity not fully investigated. It unknown whether combinations increase single ICI. We aimed assess range tumour types. Full-Text Response letter entitled: Re: 155PreviewImmune-related yet treatment immune-checkpoint (ICI) [1,2]. our meta-analysis, focusing broad cardiac [3]. As expected, since events, many included present did report arms. Overall, 16 (0.12%) observed among receiving ICI, while only one (0.01%)