A retrospective analysis of cardiovascular adverse events associated with immune checkpoint inhibitors

Cardio-Oncology - Tập 7 - Trang 1-10 - 2021
Jessica Castrillon Lal1,2, Sherry-Ann Brown3, Patrick Collier2,4, Feixiong Cheng1,2,5
1Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, USA
2Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine, Case Western Reserve University, Cleveland, USA
3Cardio-Oncology Program, Division of Cardiovascular Medicine, Medical College of Wisconsin, Milwaukee, USA
4Robert and Suzanne Tomsich Department of Cardiovascular Medicine, Cleveland Clinic, Sydell and Arnold Miller Family Heart and Vascular Institute, Cleveland, USA
5Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, USA

Tóm tắt

Modern therapies in oncology have increased cancer survivorship, as well as the incidence of cardiovascular adverse events. While immune checkpoint inhibitors have shown significant clinical impact in several cancer types, the incidence of immune-related cardiovascular (CV) adverse events poses an additional health concern and has been reported. We performed a retrospective analysis of the FDA Adverse Event Reporting System data of suspect product reports for immunotherapy and classical chemotherapy from January 2010–March 2020. We identified 90,740 total adverse event reports related to immune checkpoint inhibitors and classical chemotherapy. We found that myocarditis was significantly associated with patients receiving anti-program cell death protein 1 (PD-1) or anti-program death ligand 1 (PD-L1), odds ratio (OR) = 23.86 (95% confidence interval [CI] 11.76–48.42, (adjusted p-value) q <  0.001), and combination immunotherapy, OR = 7.29 (95% CI 1.03–51.89, q = 0.047). Heart failure was significantly associated in chemotherapy compared to PD-(L)1, OR = 0.50 (95% CI 0.37–0.69, q <  0.001), CTLA4, OR = 0.08 (95% CI 0.03–0.20, q <  0.001), and combination immunotherapy, OR = 0.25 (95% CI 0.13–0.48, q <  0.001). Additionally, we observe a sex-specificity towards males in cardiac adverse reports for arrhythmias, OR = 0.81 (95% CI 0.75–0.87, q <  0.001), coronary artery disease, 0.63 (95% CI 0.53–0.76, q <  0.001), myocardial infarction, OR = 0.60 (95% CI 0.53–0.67, q <  0.001), myocarditis, OR = 0.59 (95% CI 0.47–0.75, q <  0.001) and pericarditis, OR = 0.5 (95% CI 0.35–0.73, q <  0.001). Our study provides the current risk estimates of cardiac adverse events in patients treated with immunotherapy compared to conventional chemotherapy. Understanding the clinical risk factors that predispose immunotherapy-treated cancer patients to often fatal CV adverse events will be crucial in Cardio-Oncology management.

Tài liệu tham khảo

Schachter J, Ribas A, Long GV, Arance A, Grob JJ, Mortier L, et al. Pembrolizumab versus ipilimumab for advanced melanoma: final overall survival results of a multicentre, randomised, open-label phase 3 study (KEYNOTE-006). Lancet. 2017;390(10105):1853–62. https://doi.org/10.1016/S0140-6736(17)31601-X. Motzer RJ, Tannir NM, McDermott DF, Arén Frontera O, Melichar B, Choueiri TK, et al. Nivolumab plus Ipilimumab versus Sunitinib in advanced renal-cell carcinoma. N Engl J Med. 2018;378(14):1277–90. https://doi.org/10.1056/NEJMoa1712126. Rizvi NA, Mazières J, Planchard D, Stinchcombe TE, Dy GK, Antonia SJ, et al. Activity and safety of nivolumab, an anti-PD-1 immune checkpoint inhibitor, for patients with advanced, refractory squamous non-small-cell lung cancer (CheckMate 063): a phase 2, single-arm trial. Lancet Oncol. 2015;16(3):257–65. https://doi.org/10.1016/S1470-2045(15)70054-9. Castrillon JA, Eng C, Cheng F. Pharmacogenomics for immunotherapy and immune-related cardiotoxicity. Hum Mol Genet. 2020;29(R2):R186–96. https://doi.org/10.1093/hmg/ddaa137. Upadhaya S, Neftelino ST, Hodge JP, Oliva C, Campbell JR, Yu JX. Combinations take centre stage in PD1/PDL1 inhibitor clinical trials. Nat Rev Drug Discov. 2021;20(3):168-9. Dougan M, Pietropaolo M. Time to dissect the autoimmune etiology of cancer antibody immunotherapy. J Clin Invest. 2020;130(1):51–61. https://doi.org/10.1172/JCI131194. Cautela J, Zeriouh S, Gaubert M, Bonello L, Laine M, Peyrol M, et al. Intensified immunosuppressive therapy in patients with immune checkpoint inhibitor-induced myocarditis. J ImmunoTher Cancer. 2020;8(2):e001887. https://doi.org/10.1136/jitc-2020-001887. D’Souza M, Nielsen D, Svane IM, Iversen K, Rasmussen PV, Madelaire C, et al. The risk of cardiac events in patients receiving immune checkpoint inhibitors: a nationwide Danish study. Eur Heart J. 2021;42(16):1621-31. Bharadwaj A, Potts J, Mohamed MO, Parwani P, Swamy P, Lopez-Mattei JC, et al. Acute myocardial infarction treatments and outcomes in 6.5 million patients with a current or historical diagnosis of cancer in the USA. Eur Heart J. 2019;41(23):2183–93. Wang DY, Salem JE, Cohen JV, Chandra S, Menzer C, Ye F, et al. Fatal toxic effects associated with immune checkpoint inhibitors: a systematic review and meta-analysis. JAMA Oncol. 2018;4(12):1721–8. https://doi.org/10.1001/jamaoncol.2018.3923. Salem JE, Manouchehri A, Moey M, Lebrun-Vignes B, Bastarache L, Pariente A, et al. Cardiovascular toxicities associated with immune checkpoint inhibitors: an observational, retrospective, pharmacovigilance study. Lancet Oncol. 2018;19(12):1579–89. https://doi.org/10.1016/S1470-2045(18)30608-9. FDA Adverse Events Reporting System Public Dashboard [https://www.fda.gov/drugs/questions-and-answers-fdas-adverse-event-reporting-system-faers/fda-adverse-event-reporting-system-faers-public-dashboard) ]. Wickham H. stringr: Simple, Consistent Wrappers for Common String Operations; 2019. Ho D, Imai K, King G, Stuart EA: MatchIt: Nonparametric Preprocessing for Parametric Causal Inference. 2011 2011, 42(8):28. Mark Stevenson with contributions from Telmo Nunes CH, Jonathon Marshall, Javier Sanchez, Ron Thornton, Jeno Reiczigel, Jim Robison-Cox, Paola Sebastiani, Peter Solymos, Kazuki Yoshida, Geoff Jones, Sarah Pirikahu, Simon Firestone, Ryan Kyle, Johann Popp, Mathew Jay and Charles Reynard epiR: Tools for the Analysis of Epidemiological Data. 2020. Chongsuvivatwong V. epiDisplay: Epidemiological Data Display Package. In: vol. R package version 3.5.0.1; 2018. Viechtbauer W: Conducting Meta-Analyses in R with the metafor Package. 2010 2010, 36(3):48. Al-Kindi SG, Oliveira GH. Reporting of immune checkpoint inhibitor-associated myocarditis. Lancet. 2018;392(10145):382-3. Hu JR, Florido R, Lipson EJ, Naidoo J, Ardehali R, Tocchetti CG, et al. Cardiovascular toxicities associated with immune checkpoint inhibitors. Cardiovasc Res. 2019;115(5):854–68. https://doi.org/10.1093/cvr/cvz026. Johnson DB, Balko JM, Compton ML, Chalkias S, Gorham J, Xu Y, et al. Fulminant myocarditis with combination immune checkpoint blockade. N Engl J Med. 2016;375(18):1749–55. https://doi.org/10.1056/NEJMoa1609214. Martinez-Calle N, Rodriguez-Otero P, Villar S, Mejías L, Melero I, Prosper F, et al. Anti-PD1 associated fulminant myocarditis after a single pembrolizumab dose: the role of occult pre-existing autoimmunity. Haematologica. 2018;103(7):e318–21. https://doi.org/10.3324/haematol.2017.185777. Ederhy S, Voisin AL, Champiat S. Myocarditis with immune checkpoint blockade. N Engl J Med. 2017;376(3):290–1. https://doi.org/10.1056/NEJMc1615251. Bonaca MP, Olenchock BA, Salem JE, Wiviott SD, Ederhy S, Cohen A, et al. Myocarditis in the setting of Cancer therapeutics: proposed case definitions for emerging clinical syndromes in cardio-oncology. Circulation. 2019;140(2):80–91. https://doi.org/10.1161/CIRCULATIONAHA.118.034497. Puzanov I, Diab A, Abdallah K, Bingham CO, Brogdon C, Dadu R, 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. https://doi.org/10.1186/s40425-017-0300-z. Smith LA, Cornelius VR, Plummer CJ, Levitt G, Verrill M, Canney P, et al. Cardiotoxicity of anthracycline agents for the treatment of cancer: systematic review and meta-analysis of randomised controlled trials. BMC Cancer. 2010;10(1):337. https://doi.org/10.1186/1471-2407-10-337. Allen A. The cardiotoxicity of chemotherapeutic drugs. Semin Oncol. 1992;19(5):529–42. Jensen BV, Skovsgaard T, Nielsen SL. Functional monitoring of anthracycline cardiotoxicity:a prospective, blinded, long-term observational study of outcome in 120 patients. Ann Oncol. 2002;13(5):699–709. https://doi.org/10.1093/annonc/mdf132. Conforti F, Pala L, Bagnardi V, De Pas T, Martinetti M, Viale G, et al. Cancer immunotherapy efficacy and patients' sex: a systematic review and meta-analysis. Lancet Oncol. 2018;19(6):737–46. https://doi.org/10.1016/S1470-2045(18)30261-4. Reck M, Rodríguez-Abreu D, Robinson AG, Hui R, Csőszi T, Fülöp A, et al. Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung Cancer. N Engl J Med. 2016;375(19):1823–33. https://doi.org/10.1056/NEJMoa1606774. Castro A, Pyke RM, Zhang X, Thompson WK, Day C-P, Alexandrov LB, et al. Strength of immune selection in tumors varies with sex and age. Nat Commun. 2020;11(1):4128. https://doi.org/10.1038/s41467-020-17981-0. Oliva M, Muñoz-Aguirre M, Kim-Hellmuth S, Wucher V, Gewirtz ADH, Cotter DJ, et al. The impact of sex on gene expression across human tissues. Science. 2020;369(6509). Barbarino JM, Whirl-Carrillo M, Altman RB, Klein TE. PharmGKB: A worldwide resource for pharmacogenomic information. Wiley Interdiscip Rev Syst Biol Med. 2018;10(4):e1417. Kerns SL, Fachal L, Dorling L, Barnett GC, Baran A, Peterson DR, et al. Radiogenomics consortium genome-wide association study meta-analysis of late toxicity after prostate Cancer radiotherapy. J Natl Cancer Inst. 2020;112(2):179–90. https://doi.org/10.1093/jnci/djz075. Relling MV, Klein TE. CPIC: clinical Pharmacogenetics implementation consortium of the pharmacogenomics research network. Clin Pharmacol Ther. 2011;89(3):464–7. https://doi.org/10.1038/clpt.2010.279. Hussain M, Hou Y, Watson C, Moudgil R, Shah C, Abraham J, et al. Temporal trends of cardiac outcomes and impact on survival in patients with Cancer. Am J Cardiol. 2020;137:118–24. https://doi.org/10.1016/j.amjcard.2020.09.030. Hussain M, Misbah R, Donnellan E, Alkharabsheh S, Hou Y, Cheng F, et al. Impact of timing of atrial fibrillation, CHA (2) DS (2)-VASc score and cancer therapeutics on mortality in oncology patients. Open Heart. 2020;7(2). Lapirow D, La Gerche A, Toro C, Masango E, Costello B, Porello E, et al. The Australia and New Zealand Cardio-Oncology Registry: evaluation of chemotherapy-related cardiotoxicity in a national cohort of pediatric cancer patients. Intern Med J. 2021;51(2):229-34. Mulrooney DA, Armstrong GT, Huang S, Ness KK, Ehrhardt MJ, Joshi VM, et al. Cardiac outcomes in adult survivors of childhood cancer exposed to cardiotoxic therapy. Ann Intern Med. 2016;164(2):93. Zhou Y, Hou Y, Hussain M, Brown SA, Budd T, Tang WHW, et al. Machine learning–based risk assessment for Cancer therapy–related cardiac dysfunction in 4300 longitudinal oncology patients. J Am Heart Assoc. 2020;9(23):e019628. https://doi.org/10.1161/JAHA.120.019628. Xu B, Kocyigit D, Grimm R, Griffin BP, Cheng F. Applications of artificial intelligence in multimodality cardiovascular imaging: a state-of-the-art review. Prog Cardiovasc Dis. 2020;63(3):367–76. https://doi.org/10.1016/j.pcad.2020.03.003. Sevakula RK, Au-Yeung WTM, Singh JP, Heist EK, Isselbacher EM, Armoundas AA. State&#x2010;of&#x2010;the&#x2010;Art Machine Learning Techniques Aiming to Improve Patient Outcomes Pertaining to the Cardiovascular System. J Am Heart Assoc. 2020;9(4). https://doi.org/10.1161/JAHA.119.013924. Attia ZI, Noseworthy PA, Lopez-Jimenez F, Asirvatham SJ, Deshmukh AJ, Gersh BJ, et al. An artificial intelligence-enabled ECG algorithm for the identification of patients with atrial fibrillation during sinus rhythm: a retrospective analysis of outcome prediction. Lancet. 2019;394(10201):861–7. https://doi.org/10.1016/S0140-6736(19)31721-0.