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Immune Checkpoint Inhibitors and Venous Thromboembolism: The More Things Change…Funding Dr. Khorana acknowledges research support from the National Heart, Lung and Blood Institute (U01HL143402; R01HL164516) and the Sondra and Stephen Hardis Chair in Oncology Research.
People with cancer are known to have a high risk of thromboembolism, (and, paradoxically, bleeding) and much work has been directed to understanding its epidemiology, outcomes, and underlying pathophysiology. Treatment of cancer itself—both locoregional and systemic—has been the focus of much of this work. Systemic therapy against cancer is currently in the midst of a paradigm shift. To say that immunotherapy—in particular, immune checkpoint inhibitor (ICI) therapy—has transformed the systemic therapy of cancer is an understatement. The advent of this class of drugs—which works by enhancing antitumor immunity secondary to blocking down-regulators of the immune response such as programmed cell death 1 (PD-1) or its ligand, programmed cell death ligand 1 (PD-L1), and cytotoxic T-lymphocyte antigen 4 (CTLA-4)—has substantially increased survival and cure rates in people with various stages and types of cancers. All told, regulatory authorities have approved 90 indications for at least 11 agents worldwide, ranging from neoadjuvant and adjuvant therapy in curative settings to palliative (but life-extending) treatment in metastatic settings.  Yet, these agents are not without toxicity. By creating a pro-inflammatory milieu, ICI therapy is known to be associated with inflammatory or autoimmune side effects that affect multiple organ systems and are together known as immune-related adverse events (IRAEs).  Although initial toxicity reports did not include vascular effects, emerging data from various groups focused on hematologic toxicities have pointed to a high rate of an old complication associated with these new agents: venous thromboembolism (VTE).
In this issue of the journal, le Sève et al buttress the existing data with interesting new information. The investigators conducted a cohort study of 374 cancer patients (mostly with lung cancer or melanoma) receiving ICI therapy (mostly single-agent nivolumab) at their institution. They found a high rate of VTE (13.4%). Of note, because ICI therapy substantially increases survival, rates of VTE should be considered by time interval because exposure time is much longer than with traditional treatments. The 1-year cumulative incidence of VTE was also high in this study, at 12.2%. Two findings are of particular interest. First, the authors report a substantially increased risk of VTE in patients receiving doublet immunotherapy (1-year cumulative incidence: 29.3%, adjusted sub-hazard ratio [SHR]: 3.6). Second, the authors also found an increased risk associated with IRAEs; that is, if patients also developed other immune-related toxicity, they were more likely to get VTE (1-year cumulative incidence: 17.4%, adjusted SHR: 2.2). These findings were statistically significant despite the small sample size of these subgroups, e.g., only 21 patients received doublet ICI therapy.
How do these findings stack up against what is known about VTE risk with ICI therapy? Several research groups, including ours, have previously published rates of VTE (and some with arterial events) in association with ICI therapy; rates in the current article are consistent with these studies (typically 10–15% at 1 year). A recent meta-analysis of randomized trials concluded there was no significant increase in the overall risk of VTE in patients treated with ICIs; however, there was the risk of VTE with some regimens, e.g., PD-L1 inhibitors and CTLA-4 inhibitor combination therapy and pulmonary thromboembolism in lung cancer patients. Also, PD-L1 inhibitors were associated with a significant increase in arterial thromboembolism.
It should be noted that VTE incidence in cohort studies is much higher than reported in the original randomized trials of ICI therapy. This points to a major fault in the adverse event collection system of cancer trials. VTE appears to be systematically under-reported and is, therefore, not flagged until cohort studies are conducted after drug approval. Better methods of collection of VTE as a potential toxicity of cancer drugs need to be developed to avoid this situation in the future. A related question, not answered by the current or several prior studies, is whether the high rates of VTE observed in association with ICI therapy are higher than, or similar to, what patients would experience with non-ICI therapy. This question is hard to answer precisely because of the success of ICI therapy; prior non-ICI agents did not substantially improve survival and therefore time on treatment was far less. In addition, there are no good control cohorts for comparison since ICI therapies have become a new standard of care for several of these settings. Data arguing against a higher risk come from a recent analysis of administrative claims data in lung cancer where 6-month incidence of VTE was 8.1% for ICI-only therapy versus 10.9% for chemotherapy-only and 12.8% for ICI with chemotherapy. Regardless of whether rates are higher or lower than chemotherapy, however, there is no question that overall incidence is quite substantial and prevention efforts are needed.
Are there subgroups of patients receiving ICI therapy that are at higher risk of VTE, and therefore could be targeted for thromboprophylaxis in future studies? The data for risk factors in this unique population are inconsistent given different stages and types of cancers as well as heterogenous regimens studied. Potential risk factors that have been identified include prior history of VTE (also flagged in this study), smoking status, age, and stage. Doublet immunotherapy has been identified as a risk factor in one prior study, as in the current one, but not in others. Formal risk prediction tools are available and validated for prediction of VTE in cancer patients receiving systemic therapy. One of these, the Khorana score originally developed to predict risk of VTE on chemotherapy, has been evaluated in some studies to see if it is also predictive of immunotherapy-associated VTE. Two of the largest cohorts did find such an association (e.g., HR of 1.54 (95% confidence interval: 1.14–2.09) for Khorana score ≥2 in a study of 2,854 patients by Gong et al, but other studies have not.
VTE with ICI therapy may be driven by inflammation, and the findings by le Sève et al in the current article seem to suggest this as well. The association noted by them with both doublet therapy (more likely to cause autoimmune toxicity) and with IRAEs (evidence for immune activation) points to a thromboinflammatory phenomenon. Further support for this hypothesis comes from the finding that a “flare” in levels of the acute phase reactant, C-reactive protein, was associated with increased VTE (17.5 vs. 2.9% in those without a flare; SHR: 3.6). Our group has previously published pilot data indicating that elevated pretreatment levels of myeloid-derived suppressor cells and interleukin-8 were associated with VTE while receiving ICI therapy; ongoing studies to evaluate mechanisms of immunotherapy-associated thrombosis should hopefully shed more light on this area.
The findings of the article by le Sève et al thus further highlight this emerging area of toxicity associated with ICI therapy—a century-plus-old problem for brand-new drugs. Many unanswered questions remain, however ([Box 1]). The association of VTE with worsened survival while on ICI therapy, racial and ethnic disparities as seen in similar settings, the role of primary prevention using anticoagulants, the impact of anticoagulants on bleeding risk and whether existing bleeding scores apply (particularly given high rates of colitis and pneumonitis as IRAEs with ICI therapy), mechanisms underlying venous and arterial thromboembolism while on ICI therapy—these are all areas needing careful and thoughtful study. It should not escape our attention that these were also all areas needing careful study for the prior generation of anticancer treatments including hormonal and chemotherapy. As French satirist Alphonse Karr said in another century: plus ça change, plus c'est la même chos e. The more things change, the more they stay the same.
Box 1. Unanswered questions regarding immunotherapy-associated thromboembolism
Is the risk of VTE the same across different types of ICI therapies?
Is the risk of VTE higher with ICI therapy in comparison to chemotherapy?
Are there racial and ethnic disparities in immunotherapy-associated thrombosis?
What are the mechanisms underlying VTE and arterial events?
Can we identify patients initiating ICI therapy at high risk for subsequent VTE using clinical variables or risk assessment tools?
Can we identify patients initiating ICI therapy at high risk for subsequent VTE using biomarkers?
Will high-risk patients benefit from targeted thromboprophylaxis?
Will thromboprophylaxis have the same risk/benefit ratio as with chemotherapy, or will bleeding be a greater risk in patients on ICI therapy?
What predicts for bleeding risk on ICI therapy?
Why is immunotherapy-associated thrombosis also associated with worsened survival?
Will anticoagulant thromboprophylaxis improve survival on ICI therapy?
Received: 07 June 2023
Accepted: 07 June 2023
Accepted Manuscript online:
03 July 2023
Article published online:
18 July 2023
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