In the Journals

Immune checkpoint inhibitors associated with range of cardiovascular toxicities

Javid J. Moslehi, MD
Javid J. Moslehi

The use of immune checkpoint inhibitors to treat various types of cancer appeared linked to severe, inflammatory cardiovascular immune-related adverse events soon after the start of treatment, according to an observational, retrospective, pharmacovigilance study published in The Lancet Oncology.

“Immune checkpoint inhibitors have been revolutionary in treating many cancer types,” researcher Javid J. Moslehi, MD, director of cardio-oncology and assistant professor of medicine at Vanderbilt University Medical Center, told HemOnc Today. “There are at least seven immune checkpoint inhibitor drugs approved for more than 15 cancer types. Virtually every company has an immune checkpoint inhibitor coming to the market.

“However, as we’ve started combining the drugs, we’re seeing some toxicities arise from the therapies themselves,” Moslehi added.

Researchers identified all cardiovascular immune-related adverse events documented in VigiBase, WHO’s database of individual safety reports, that occurred between Nov. 14, 1967, and Jan. 2, 2018.

Researchers compared 31,321 adverse events among patients who received immune checkpoint inhibitors —including anti-PD-1 antibodies, anti-PD-L1 antibodies and anti-CTLA-4 antibodies — with 16,343,451 reported events from the entire database. Each report included general administrative data, patient characteristics, drugs and reactions, MedDRA classification terms, date of onset, end date and final outcome.

Researchers used reporting odds ratio (ROR) and information component (IC) to calculate correlations between immune checkpoint inhibitors and cardiovascular adverse events. The IC compares observed and expected values to identify associations between drugs and adverse events, for which an IC025 represents the lower end of the IC 95% CI, and an IC025 value of more than zero is deemed significant.

Results revealed Researchers identified four broad areas of cardiovascular conditions for which cardiovascular adverse event reporting appeared significantly elevated after immune checkpoint inhibitor treatment vs. reporting in the full database. These included myocarditis (5,515 reports for full database vs. 122 for immune checkpoint inhibitors; ROR = 11.21; 95% CI, 9.36-13.43; IC025 = 3.2); pericardial diseases (12,800 vs. 95; ROR = 3.8; 95% CI, 3.08-4.62); IC025 = 1.63); supraventricular arrhythmias (68,597 vs. 222; ROR = 1.72; 95% CI, 1.51-1.97; IC025 = 0.56); and vasculitis (33,289 vs. 82; ROR = 1.56; 95% CI, 1.25-1.94; IC025 = 0.03).

Patients with lung cancer frequently had pericardial diseases (56% of n = 87), whereas patients with melanoma frequently had myocarditis (41% of n = 103) and vasculitis (60% of n = 70; 2 test for overall subgroup comparison, P < .0001).

Five (28%) patients with temporal arteritis had impaired vision.

In more than 80% of cases, cardiovascular immune-related adverse events were severe, with mortality occurring in 61 (50%) of 122 myocarditis cases, 20 (21%) of 95 pericardial disease cases and five (6%) of 82 cases of vasculitis (2 test to compare pericardial diseases, myocarditis and vasculitis, P < .0001).

The researchers noted that the replication of disproportionality analysis in other, smaller databases — such as European Medicine Agency or FDA adverse event reporting databases — is biased by an essential overlap of individual case safety reports.

Moslehi said further research is needed to identify patients most likely to face risk for an immune-related adverse event.
“With the expanded use of immune checkpoint inhibitors and the growing recognition of myotoxicity,” he told HemOnc Today. “we must get better at identifying patients at risk. Maybe these toxicities occur more often in women, or maybe they affect patients with heart problems or with autoimmune disorders such as lupus? We don’t have many answers yet, but one thing our group is doing is collaborate with other researchers nationally and internationally to identify patients at risk and to develop preventive and treatment strategies.” – by Jennifer Byrne

For more information:

Javid J. Moslehi, MD, can be reached at Vanderbilt University Medical Center, 1215 21st Ave. S. 5th Floor, Nashville, TN 3723; email: javid.moslehi@vumc.org.

Disclosures : Moslehi reports advisory board roles with Bristol-Myers Squibb, MyoKardia, Novartis, Pfizer and Takeda and research funding from Bristol-Myers Squibb and Pfizer. Please see the study for all other authors’ relevant financial disclosures.

Javid J. Moslehi, MD
Javid J. Moslehi

The use of immune checkpoint inhibitors to treat various types of cancer appeared linked to severe, inflammatory cardiovascular immune-related adverse events soon after the start of treatment, according to an observational, retrospective, pharmacovigilance study published in The Lancet Oncology.

“Immune checkpoint inhibitors have been revolutionary in treating many cancer types,” researcher Javid J. Moslehi, MD, director of cardio-oncology and assistant professor of medicine at Vanderbilt University Medical Center, told HemOnc Today. “There are at least seven immune checkpoint inhibitor drugs approved for more than 15 cancer types. Virtually every company has an immune checkpoint inhibitor coming to the market.

“However, as we’ve started combining the drugs, we’re seeing some toxicities arise from the therapies themselves,” Moslehi added.

Researchers identified all cardiovascular immune-related adverse events documented in VigiBase, WHO’s database of individual safety reports, that occurred between Nov. 14, 1967, and Jan. 2, 2018.

Researchers compared 31,321 adverse events among patients who received immune checkpoint inhibitors —including anti-PD-1 antibodies, anti-PD-L1 antibodies and anti-CTLA-4 antibodies — with 16,343,451 reported events from the entire database. Each report included general administrative data, patient characteristics, drugs and reactions, MedDRA classification terms, date of onset, end date and final outcome.

Researchers used reporting odds ratio (ROR) and information component (IC) to calculate correlations between immune checkpoint inhibitors and cardiovascular adverse events. The IC compares observed and expected values to identify associations between drugs and adverse events, for which an IC025 represents the lower end of the IC 95% CI, and an IC025 value of more than zero is deemed significant.

Results revealed Researchers identified four broad areas of cardiovascular conditions for which cardiovascular adverse event reporting appeared significantly elevated after immune checkpoint inhibitor treatment vs. reporting in the full database. These included myocarditis (5,515 reports for full database vs. 122 for immune checkpoint inhibitors; ROR = 11.21; 95% CI, 9.36-13.43; IC025 = 3.2); pericardial diseases (12,800 vs. 95; ROR = 3.8; 95% CI, 3.08-4.62); IC025 = 1.63); supraventricular arrhythmias (68,597 vs. 222; ROR = 1.72; 95% CI, 1.51-1.97; IC025 = 0.56); and vasculitis (33,289 vs. 82; ROR = 1.56; 95% CI, 1.25-1.94; IC025 = 0.03).

Patients with lung cancer frequently had pericardial diseases (56% of n = 87), whereas patients with melanoma frequently had myocarditis (41% of n = 103) and vasculitis (60% of n = 70; 2 test for overall subgroup comparison, P < .0001).

Five (28%) patients with temporal arteritis had impaired vision.

In more than 80% of cases, cardiovascular immune-related adverse events were severe, with mortality occurring in 61 (50%) of 122 myocarditis cases, 20 (21%) of 95 pericardial disease cases and five (6%) of 82 cases of vasculitis (2 test to compare pericardial diseases, myocarditis and vasculitis, P < .0001).

The researchers noted that the replication of disproportionality analysis in other, smaller databases — such as European Medicine Agency or FDA adverse event reporting databases — is biased by an essential overlap of individual case safety reports.

Moslehi said further research is needed to identify patients most likely to face risk for an immune-related adverse event.
“With the expanded use of immune checkpoint inhibitors and the growing recognition of myotoxicity,” he told HemOnc Today. “we must get better at identifying patients at risk. Maybe these toxicities occur more often in women, or maybe they affect patients with heart problems or with autoimmune disorders such as lupus? We don’t have many answers yet, but one thing our group is doing is collaborate with other researchers nationally and internationally to identify patients at risk and to develop preventive and treatment strategies.” – by Jennifer Byrne

For more information:

Javid J. Moslehi, MD, can be reached at Vanderbilt University Medical Center, 1215 21st Ave. S. 5th Floor, Nashville, TN 3723; email: javid.moslehi@vumc.org.

Disclosures : Moslehi reports advisory board roles with Bristol-Myers Squibb, MyoKardia, Novartis, Pfizer and Takeda and research funding from Bristol-Myers Squibb and Pfizer. Please see the study for all other authors’ relevant financial disclosures.

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