Immune checkpoint inhibitors (ICIs) are a type of immunotherapy that revolutionized cancer treatment and, in recent years, have become a mainstay of therapy. They are widely used to treat various cancers, including non-small-cell lung cancer, melanoma, renal cell carcinoma, and head and neck cancer [1]. ICIs are monoclonal antibodies that target proteins that negatively regulate the immune system, including programmed cell death (PD-1) and cytotoxic T-ymphocyte-associated antigen 4 (CTLA-4) [1].
One of the advantages of ICIs is that they have a durable effect, continuing to work even after treatment has ended. However, with the post-marketing use of ICIs, the concern of thrombosis events related to these drugs has emerged.
ICI and thrombosis
The incidence of venous thromboembolism in patients receiving ICIs varies depending on the specific drug and cancer type but is around 1 and 10% [1,2].
A recent review summarized the results of 27 cohort studies showing that venous thromboembolism (VTE) incidence can vary depending on the type of cancer, concurrent cancer therapies, and follow-up duration. In general, the incidence is about 5–8% at 6 months and 10–15% at 12 months [2].
In additition, the exposure to ICIs can be prolonged, with the risk of thrombosis accumulating over time. A study showed that the thrombosis rate in patients with metastatic renal cell carcinoma continued to increase during the entire ICI treatment duration, lasting up to 30 months [3,4]. This is a peculiar characteristic; in fact, the risk of VTE is generally higher within the first 6 months of treatment with chemotherapy.
Conflicting results exist regarding the risk of VTE and the use of ICI in association with chemotherapy. It is unclear if the combined use of ICI with chemotherapy is associated with an increased risk of VTE compared to ICI alone or chemotherapy alone [5,6]. It must be underlined that a fair comparison of the risk of thrombosis subsequent to the use of ICI alone, chemotherapy alone, or ICI in combination with chemotherapy might not be straightforward because the baseline characteristics of these patients greatly differ.
The exact mechanism by which ICIs increase the risk of thrombosis is not fully understood. However, ICIs can cause inflammation and damage blood vessels, contributing to developing thrombosis [7,8].
Biomarkers for thrombosis using ICIs
Identifying biomarkers of thrombosis in patients treated with ICIs is an important area of research, as it could help identify patients at higher risk for developing thrombosis and allow for earlier intervention to prevent complications.
Several biomarkers have been studied in relation to thrombosis in patients receiving ICIs, including C-reactive protein, the number of total myeloid suppressor cells, and inflammatory cytokines.
A study analyzed pre-ICI blood samples from 15 individuals on ICIs who subsequently developed VTE compared to 10 individuals on ICIs who did not develop VTE [1,6]. Patients who developed VTE showed a significant increase in total myeloid-derived suppressor cells and elevated levels of inflammatory biomarkers, including CXCL8 (chemokine ligand), soluble vascular cell adhesion molecule 1, and clustering of other inflammatory cytokines, including IL-1β, IL-6 and TNF [1].
While biomarkers can provide important information about the risk of thrombosis in patients receiving ICIs, they should be used in conjunction with clinical assessment and other risk factors to determine the most appropriate course of treatment and monitoring for each patient.
Risk factors for VTE during ICI treatment
Several risk factors have been associated with an increased risk of thrombosis in patients using ICIs for cancer treatment.
They can be patient-related, such as cancer type and stage, history of VTE, gender, and age, or treatment-related, such as type of ICI, and concomitant treatment, such as chemotherapy.
Patients with advanced-stage cancer, older patients, or with a previous history of thrombosis are at higher risk of thrombosis. Also, patients with other medical conditions, such as cardiovascular disease or diabetes, may see their thrombosis risk increased. Finally, some types of ICIs might be associated with a higher risk of VTE. As previously said, the risk could further increase if ICIs are combined with chemotherapy [2].
No risk prediction models are available for risk stratification of patients with cancer receiving ICIs. Although the Khorana score is one of the most validated risk models for cancer patients, it has some limitations. Conflicting results exist on the utility of this score in accurately predicting thrombosis in patients receiving ICIs. For this reason, developing a specific risk prediction model for this population is of utmost importance [2].
Conclusion
Overall, while ICIs represent an important advancement in cancer treatment, it is important to carefully assess each patient’s risk factors for thrombosis before starting treatment with ICIs and to monitor patients closely during treatment for signs and symptoms of thrombotic events. In addition, healthcare providers should be aware of the potential risk of thrombosis in patients receiving ICIs and take appropriate measures to prevent and manage these complications.
Also, it is known that VTE symptoms affect how cancer patients perceive their disease and CAT. This should be considered when communicating with cancer patients about the risk of their treatment.
References
- Wang TF, Khorana AA, Carrier M. Thrombotic Complications Associated with Immune Checkpoint Inhibitors. Cancers (Basel). 2021;13(18):4606.
- Wang T-F, Carrier M. Immune Checkpoint Inhibitors-Associated Thrombosis: Incidence, Risk Factors and Management. Current Oncology. 2023;30(3):3032-3046. https://doi.org/10.3390/curroncol30030230
- Sheng IY, Gupta S, Reddy CA, et al. Thromboembolism in Patients with Metastatic Renal Cell Carcinoma Treated with Immunotherapy. Target Oncol. 2021;16(6):813-821. doi: 10.1007/s11523-021-00852-z.
- Sheng IY, Gupta S, Reddy CA, et al. Thromboembolism in patients with metastatic urothelial cancer treated with immune checkpoint inhibitors. Target Oncol. 2022;17(5):563-569. doi: 10.1007/s11523-022-00905-x.
- Sussman TA, Li H, Hobbs B, et al. Incidence of thromboembolism in patients with melanoma on immune checkpoint inhibitor therapy and its adverse association with survival. J Immunother Cancer. 2021;9(1):e001719. doi: 10.1136/jitc-2020-001719.
- Roopkumar J, Swaidani S, Kim AS, et al. Increased Incidence of Venous Thromboembolism with Cancer Immunotherapy. Med (N Y). 2021;2(4):423-434. doi: 10.1016/j.medj.2021.02.002.
- Kunimasa K, Nishino K, Kimura M, et al. Pembrolizumab-induced acute thrombosis: A case report. Medicine (Baltimore). 2018;97(20):e10772. doi: 10.1097/MD.0000000000010772.
- Cochain C, Chaudhari SM, Koch M, et al. Programmed cell death-1 deficiency exacerbates T cell activation and atherogenesis despite expansion of regulatory T cells in atherosclerosis-prone mice. PLoS One. 2014;9(4):e93280. doi: 10.1371/journal.pone.0093280.