Spectrum of cardiovascular toxicities with immunotherapy for cancer is wide

Presenter: Han Zhu, MD

As the use of immunotherapy to treat cancer surges, clinicians must be aware of the risk of serious adverse cardiovascular effects such as myocarditis, arrhythmias, and atherosclerotic events. The rate of immune-related adverse events from the use of immune checkpoint inhibitor (ICI) therapy is 17% to 33% as single agents, increasing to as high as 50% when used in combination.

These effects can be extremely difficult to treat, even after discontinuation of therapy. “Although the recorded incidence of immunotherapy-induced myocarditis is rare at less than 1%, it can be quite serious, with up to a 50% mortality rate,” said Dr. Han Zhu, instructor of medicine, Stanford University School of Medicine, Stanford, CA.

Since the initial report of autopsy findings suggesting acute lymphocytic myocarditis in 2 patients treated with immunotherapy, “a wide spectrum of other ICI-associated cardiotoxicities have been characterized, including conduction disease ranging from atrial to ventricular tachyarrhythmias, as well as bradyarrhythmia, heart block, vasculitis, and pericardial disease, in addition to myocarditis,” she said.

Earlier this year, in a matched-cohort study, investigators at Harvard Medical School, Boston, MA, found a threefold increased incidence of cardiovascular events in patients after starting treatment with an ICI (hazard ratio 3.3; P < .001); and in their case-crossover analysis, the rate of cardiovascular events increased from 1.37 to 6.55 per 100 person-years at 2 years (adjusted hazard ratio 4.8; P < .001). Imaging study showed an increase in the rate of progression of total aortic plaque volume.1

The potentially fatal nature of ICI-associated cardiotoxicity and its often late presentation has prompted investigation of the potential utility of biomarker screening in early identification of cardiotoxicity. Sarocchi et al found one case of subclinical myocarditis among 59 patients with non-small-cell lung cancer who underwent serial measurement of troponin levels.2 Investigators at Memorial Sloan Kettering Cancer Center described their experience with myocarditis surveillance through the use of serial screening of troponin in 76 asymptomatic patients with advanced melanoma who were being treated with a combination of ICIs, none of whom developed myocarditis.3

Stanford has developed its own monitoring algorithm for patients receiving single-agent and dual-agent immunotherapy. High-sensitivity troponin measures are performed at every dose of immunotherapy for up to 10 cycles, based on a median time to immune event of 2.5 to 8.6 weeks, as reported by the VigiBase study authors.4

“Importantly, we have a cardio-oncology rapid troponin response team consisting of a cardiologist, myself, a medicine resident, and an oncologist to triage positive troponins that could be due to other causes, such as supply-demand mismatch and the patient’s underlying complex medical disease,” said Dr. Zhu. “As such, we actually have caught some cases of smoldering myocarditis with this algorithm.”

ICIs activate T cells, so treatment of myocarditis is targeted toward immunosuppression. Corticosteroids remain the first line of therapy, although they suppress the immune system nonspecifically and therefore lead to side effects, said Dr. Zhu. Second-line agents are targeted towards T cells and include tacrolimus, mycophenolate mofetil, antithymocyte globulin, and infliximab, and others are under study, notably abatacept, which blocks CD80 and CD86 on antigen-presenting cells.

References

  1. Drobni ZD, Alvi RM, Taron J, et al. Association between immune checkpoint inhibitors with cardiovascular events and atherosclerotic plaque. Circulation 2020 Oct 2. doi:10.1161/CIRCULATIONAHA.120.049981. Published online ahead of print.
  2. Sarocchi M, Grossi F, Arboscello E, et al. Serial troponin for early detection of nivolumab cardiotoxicity in advanced non-small cell lung cancer patients. Oncologist 2018; 23(8):936–942.
  3. Lee Chuy K, Oikonomou EK, Postow MA, et al. Myocarditis surveillance in patients with advanced melanoma on combination immune checkpoint inhibitor therapy: the Memorial Sloan Kettering Cancer Center experience. Oncologist 2019; 24:e196–197. doi:10.1634/theoncologist.2019-0040
  4. Salem JE, Manouchehri A, Moey M, et al. Cardiovascular toxicities associated with immune checkpoint inhibitors: an observational, retrospective, pharmacovigilance study. Lancet Oncol 2018; 19(12):1579–1589. doi:10.1016/S1470-2045(18)30608-9

Dr. Zhu has disclosed no relevant relationships.

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