Cardiac MRI study of adverse events in patients treated with immune checkpoint inhibitors: a prospective cohort study of cardiac adverse events

Abstract

Immune checkpoint inhibitors (ICIs) revolutionized cancer therapy, yet require management of immune-related adverse events (irAEs). Fulminant myocarditis is a rare irAE, but lower-severity cardiac events are being reported more frequently, leading to an unmet need for irAE prevention, early diagnosis, and treatment, especially for long-life-expectancy patients. We recruited 57 patients, stratified according to therapy regime (monotherapy (30%) or combination (33%) cohort) or history of cardiac disease or presence of at least two cardiovascular risk factors other than prior or active smoking (cardiovascular cohort (37%)). We performed a complete cardiological assessment with clinical visit, 12-lead ECG, multiparametric cardiac MRI as well as peripheral blood mononuclear cell immunophenotyping, prior to ICI initiation and around 2 months later. ICI treatment was associated with a significant left ventricular ejection function (LVEF) reduction pre-ICI versus post-ICI treatment (60.1±8% to 58.1±8%, p=0.002, paired t-test) and more than 3% LVEF loss in a substantial proportion of patients (18; 32%). These patients also showed significantly higher T2 values (p=0.037, unpaired t-test), putative sign of cardiac edema. The loss of cardiac function did not differ among patients with different tumor types, therapy regimes or history of cardiac disease. Immunophenotyping analyses showed a reduction of programmed cell death protein 1 staining on both CD4⁺ and CD8⁺ T cells, and an upregulation of HLA-DR on CD8⁺ T cells. Using a very sensitive and comprehensive approach in patients unselected for cardiac history, we found a subclinical but significant LVEF decrease. These findings may inform ongoing discussions on optimal management of cardiac irAEs in patients undergoing ICI treatment and warrant further evaluation.

Keywords: Cardiotoxicity; Immune Checkpoint Inhibitors; Immune related adverse event - irAE.

Figure 1. ICI treatment activates T cells across the entire patient cohort. Box-violin plot showing the mean fluorescence intensity (MFI) of different surface and intracellular markers on T cell subsets of patients with cancer pre-ICI and post-ICI treatment. Bold frames highlight significant changes in the MFI of PD1 and HLA-DR-expressing cells among CD4⁺ and/or CD8⁺ T cells. Wilcoxon signed-rank test (p=0.02; p=0.005; p=0.02). ICI, immune checkpoint inhibitor; PD1, programmed cell death protein 1.

Figure 2. cMRI shows loss of systolic function across the entire patient cohort A. Scatter dot plot showing change in left ventricle ejection fraction (%) pre-ICI versus post-ICI treatment. Paired t-test (p=0.0024). (B) Scatter dot plot showing change in T2 cMRI values post-ICI versus pre-ICI treatment; patients split on the basis of their loss of ejection fraction of more than versus less than or equal to 3%. Unpaired t-test (p=0.0367). cMRI, cardiac MRI; EF, ejection fraction; ICI, immune checkpoint inhibitor.