More heart damage than expected with cancer checkpoint inhibitors

According to a large Danish cohort study, immune checkpoint inhibitor (ICI) therapy for cancer was more cardiotoxic than previously reported.

Within one year after the first ICI administration, the absolute risk of cardiac events (ie, arrhythmia, pericarditis or myocarditis, heart failure, or cardiovascular death) was:

• 9.7% of lung cancer patients treated with programmed cell death-1 (PD1) inhibitor
• 6.6% of patients with malignant melanoma treated with PD1 inhibitors
• 7.5% of patients with malignant melanoma who received cytotoxic T lymphocyte-related protein-4 (CTLA-4) inhibitor therapy

“The findings help raise awareness of heart events in patients undergoing ICI,” said a study author led by Maria D’Souza, MD, and PhD of Herlev-Gentofte, Copenhagen University Hospital, Denmark. There is. European Heart Journal..

The 1.8% incidence of pericarditis or myocarditis in patients treated in this study was observed in a previous pharmacovigilance study in which myocarditis was found only in 0.06% to 0.27% of people. It was much higher than. Ancillary editorial By Tomas Neilan, MD, MPH, and two colleagues at Massachusetts General Hospital in Boston.

“These findings emphasize that we are just beginning to understand the full nature and increased relevance of potential ICI-related cardiac complications. Cardiac oncology care.. Given the wide variety of presentations and associated morbidity and mortality, therapeutic approaches represent challenges, “the editors write.

Key questions include how to manage patients with ICI suffering from heart failure without imaging evidence of arrhythmias or isolated troponin elevations, or active cardiac inflammation, Neilan et al.

“Recent data suggesting an association between ICI use and accelerated atherosclerosis and atherosclerosis-related cardiovascular events, with vascular events such as ischemic stroke and MI in the ICI setting. What do you do with the patient? ”The group asked.

D’Souza’s team conducted a retrospective study based on Denmark’s national registration. The survey period ranged from 2011, when ICI was first introduced, to 2017, last year, with data available to investigators.

Included were 25,573 consecutive people with accidental lung cancer (median age 71 years, 50.5% male) and another 13,568 with malignant melanoma (median age 60 years, 45.7% male). Met. The prevalence of hypertension was 37.2% and 21.5%, respectively, while the prevalence of diabetes was 13.2% and 6.6%, respectively.

Of the lung cancer patients, 743 were treated with PD1 inhibitors. For malignant melanoma, 145 received PD1 inhibitor therapy and 212 received CTLA-4 inhibitor therapy.

Comparing cancer patients who received PD1 inhibitor therapy with controls who did not, D’Souza’s team found that the former had a relatively high number of cardiac events over various periods of time.

• Lung cancer patients within 6 months of first PD1 inhibitor administration: adjusted HR 2.14, 95% CI 1.50-3.05
• Lung cancer patients 6-12 months: Adjusted HR 2.26, 95% CI 1.27-4.02
• Patients with malignant melanoma within 6 months: Adjusted HR 4.30, 95% CI 1.38-13.42

Cardiac risk in patients with malignant melanoma who received PD1 inhibitors did not last for 6-12 months (adjusted HR 2.46, 95% CI 0.34-17.56).

CTLA-4 inhibitors showed a short-term and medium-term increase in heart risk.

• Patients with malignant melanoma within 6 months: Adjusted HR 4.93, 95% CI 2.45-9.94
• Patients with malignant melanoma 6-12 months: adjusted HR 3.48, 95% CI 1.91-6.35

“Most people are suspected Side effects of the heart [of ICIs] It occurs early within a week to a few months after treatment. Our results suggest that an increase in cardiac events is also seen 6 months after the first dose of the first dose, “said D’Souza and colleagues.

They warned that the study was limited by its observational nature and lack of data on smoking status, cancer stage, and other clinical risk factors.

“The mechanism behind immune-related side effects is not fully understood: increased T cell activity against antigens present in muscle cells, increased levels of autoantibodies and inflammatory cytokines, and complement-mediated inflammation. There are several hypotheses of different mechanisms, such as augmentation. ” To the investigator.

“”[M]Inflammation of the myocardium with the involvement of the adaptive immune system and lymphocyte infiltration induces a cascade of reversible or irreversible damage to the affected tissue. Infiltrative lymphocytes have been found in the myocardium of patients with ICI-related myocarditis in postmortem samples and endocardial myocardial biopsy. But the basic questions remain unanswered, “Neilan et al. Commented.

Cardiotoxicity is a problem in early-generation cancer treatments, including: Traditional chemotherapy And radiation Not only new Target agent..