Immune Checkpoint Inhibitor Therapy and Risk of Venous Thromboembolism

SUMMARY: The Center for Disease Control and Prevention (CDC) estimates that approximately 1-2 per 1000 individuals develop Deep Vein Thrombosis (DVT)/Pulmonary Embolism (PE) each year in the United States, resulting in 60,000-100,000 deaths. Venous ThromboEmbolism (VTE) is the third leading cause of cardiovascular mortality, after myocardial infarction and stroke. Ambulatory cancer patients initiating chemotherapy are at varying risk for Venous Thromboembolism (VTE), which in turn can have a substantial effect on health care costs, with negative impact on quality of life.

Approximately 20% of cancer patients develop VTE and about 20% of all VTE cases occur in patients with cancer. Cancer patients have a 4-7 fold increased risk of thrombosis, compared with those without cancer, and patients with cancer and VTE are at a markedly increased risk for morbidity and mortality. The etiology of thrombosis in cancer is multifactorial, and the vascular system is an important interface between the malignant cells and their systemic and external environments. Genetic alterations in malignant cells, as they respond to their microenvironment, can result in inflammation, angiogenesis, and tissue repair. This in turn leads to the local and systemic activation of the coagulation system. It has been postulated that the procoagulant effect of malignant cells may be related to the release of soluble mediators such as G-CSF into the circulation or by the shedding of procoagulant Extracellular Vesicles (EVs) harboring Tissue Factor. Previously published studies had entertained the notion that certain oncogenic mutations may deregulate hemostatic genes (coagulome) in cancer cells.
Immune Checkpoint Inhibitors (ICIs) have revolutionized cancer management. They bind to either PD-1 receptor or its ligand PD-L1 and block their interaction, thereby reversing the PD-1 pathway-mediated inhibition of the immune response and unleashing the tumor-specific effector T cells. This can however be accompanied by various off-target manifestations of autoimmunity induced by immune checkpoint inhibitors with resulting systemic inflammation on the hemostatic system. The risk of Venous ThromboEmbolism (VTE) and Arterial ThromboEmbolism (ATE) associated with ICIs is currently unclear. The goal of this study was to quantify the risk of VTE/ATE in patients with cancer, treated with ICIs, explore clinical impact, and investigate potential clinical risk factors.

The authors conducted a single-center, retrospective cohort study at the Medical University of Vienna, Austria, and included 672 patients with histologically confirmed cancer, who were treated with one or more doses of an Immune Checkpoint Inhibitor (Nivolumab, Pembrolizumab, Ipilimumab, Atezolizumab, or Avelumab), between 2015 and 2018. Patients received a median of 7 cycles of therapy. About a third of patients (30.4%) had Malignant Melanoma, whereas 24% had Non Small Cell Lung Cancer, 11% had Renal Cell Carcinoma, 10.4% had Head and Neck Squamous Cell Carcinoma and 5% had Urothelial cancer. Majority of patients (86%) had advanced disease at the time of ICI initiation. The median patient age was 64 years, 39% were female and most patients had an ECOG Performance Status of 0 or 1. Approximately 13% of patients had a history of VTE prior to the initiation of ICI therapy. Approximately 9% of patients had a history of ATE, and was associated with the current cancer diagnosis in 2.2% of the total cohort. At the time of ICI therapy initiation, 16.5% received continuous anticoagulation and 20% received antiplatelet therapy. The Primary outcomes of the study were cumulative incidence rates of VTE and ATE. Secondary outcomes included the association of VTE/ATE with Overall Survival (OS), Progression Free Survival (PFS), and radiological Disease Control Rate (DCR). The median follow up was 8.5 months.

It was noted that the cumulative incidences of VTE and ATE during ICI therapy were 12.9% and 1.8% respectively. The occurrence of VTE was associated with increased mortality with shorter OS. The median OS after the occurrence of VTE was 11.6 months compared with 25.5 months in those without VTE (P<0.001). The researchers noted that the number of fatal Pulmonary Embolisms were not high (N=2) in this study, suggesting that the impact of VTE goes beyond direct VTE-related mortality. The diagnosis of VTE was further associated with shorter PFS. Median PFS after VTE was 1.7 months compared with 6.7 months in those without VTE (P<0.001). The occurrence of ATE was not associated with risk of mortality or early progression of disease. However, this could have been due to relatively low number of ATE events and potential lack of statistical power. Therefore, definite conclusions cannot be drawn. Prior history of VTE predicted VTE occurrence. Distant metastasis was associated with VTE risk, although this was not statistically significant. The researchers did not find association of VTE with ECOG Performance Status or Khorana score, and the rates of VTE were comparable between tumor types and different immune Checkpoint Inhibitors. No association with VTE risk was observed for patients undergoing continuous anticoagulation or anti-platelet therapy at baseline.

It was concluded that despite the limitations of this study, patients with cancer undergoing treatment with Immune Checkpoint inhibitors are at a high risk of developing thromboembolic complications, especially VTE, and VTE occurrence was associated with increased mortality. The authors added that further studies are needed to better understand the risk of VTE and ATE associated with ICIs, and thus improve patient care by preventing thromboembolic complications.

Incidence, risk factors, and outcomes of venous and arterial thromboembolism in immune checkpoint inhibitor therapy. Moik F, Chan WE, Wiedemann S, et al. Blood.2021;137:1669-1678.