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Tumor cells evade immune destruction by activating immune checkpoint receptor proteins including cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1) found on T cells, and programmed death ligand 1 (PD-L1) found on tumor cells. A type of novel anticancer therapy termed “immune checkpoint inhibitors (ICIs)” involves monoclonal antibodies that specifically target these proteins and prevent immune escape from tumor cells. Immune checkpoint inhibitors (ICIs) target programmed cell death (PD) 1 receptor and its ligand PD-L1, and have become an integral part of treatment regimens in many cancers including lung cancer, renal cell carcinoma, melanoma, and more. Cancer is associated with a significantly increased risk of venous thromboembolism compared to non-cancer patients, and the risks increase further with anticancer therapies including ICIs. Cancer-associated thrombosis can lead to hospitalizations, delayed cancer treatment, and mortality.
- immune checkpoint inhibitors
- thrombosis
- cell death
1. Introduction
Tumor cells evade immune destruction by activating immune checkpoint receptor proteins including cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1) found on T cells, and programmed death ligand 1 (PD-L1) found on tumor cells. A type of novel anticancer therapy termed “immune checkpoint inhibitors (ICIs)” involves monoclonal antibodies that specifically target these proteins and prevent immune escape from tumor cells. Since the approval of the first ICI (ipilimumab) in 2011, seven ICIs have been approved in Canada and the United States in approximately 20 different malignancies (Table 1), including ipilimumab (anti-CTLA-4), nivolumab, pembrolizumab, cemiplimab (anti-PD-1), and atezolizumab, durvalumab, avelumab (anti-PD-L1). As such, patients eligible for ICI treatment significantly increased from 1.5% in 2011 to 43.6% in 2018 [1]. Sustained responses and significant improvement in survival have been seen with these novel therapies, and they have become the mainstay of therapies in many cancers such as melanoma, lung cancer, renal cell carcinoma (RCC), and more [2].
Table 1.
Summary of approved immune checkpoint inhibitors (and their indications).
| Immune Checkpoint Inhibitors | Target | Approved Indication |
|---|---|---|
| Ipilimumab | CTLA-4 | Melanoma NSCLC RCC Colorectal cancer Malignant pleural mesothelioma |
| Pembrolizumab | PD-1 | Melanoma NSCLC Urothelial carcinoma RCC Bladder cancer Esophageal/esophagogastric junction cancer Colorectal cancer Endometrial cancer Cervical cancer Breast cancer Head and neck squamous cell carcinoma Hodgkin lymphoma Primary mediastinal B cell lymphoma |
| Nivolumab | PD-1 | Melanoma NSCLC RCC Head and neck squamous cell carcinoma Classical Hodgkin lymphoma Hepatocellular carcinoma |
| Cemiplimab | PD-1 | NSCLC Cutaneous squamous cell carcinoma Cutaneous basal cell carcinoma Cervical cancer |
| Atezolizumab | PD-L1 | NSCLC Small cell lung cancer Urothelial carcinoma |
| Avelumab | PD-L1 | Urothelial carcinoma Merkel cell carcinoma |
| Durvalumab | PD-L1 | NSCLC Urothelial carcinoma |
Mostly approved for unresected or metastatic cancers, refer to individual monographs for detailed approval indications for each cancer. Abbreviations: NSCLC: non-small cell lung cancer; RCC: renal cell carcinoma.
Although thrombosis was not raised as a major concern in initial randomized controlled trials (RCTs) leading to the approval of ICIs, reports of thromboembolic disease had emerged from post-marketing wide use of these agents. Cancer-associated thrombosis is a known phenomenon, and it is estimated that 20% of cancer patients will develop thrombosis during their cancer journey [3]. It can result in hospitalizations, delayed cancer treatment, significant morbidity, and mortality [4][5][4,5]. Patients often experience psychosocial and financial distresses from the diagnosis of thrombosis as well [6][7][6,7]. Therefore, the optimal prevention and treatment strategies for cancer-associated thrombosis are crucial in the care of cancer patients.
2. Mechanism of Thrombosis and Immunotherapy
While the exact mechanisms of ICI-associated thrombosis remain unclear, studies have made strides to understand them. Programmed cell death protein 1 is crucial in downregulating pro-atherogenic T cell responses, so PD-1 antibodies can exacerbate atherosclerotic inflammatory vascular lesions [8][9]. Studies have shown that ICIs are found to be associated with increased T cell activation and endothelial inflammation, leading to thrombosis formation and accelerated atherosclerosis [9][10][10,11]. Similar to other immune-related adverse events associated with ICIs such as colitis and pneumonitis, ICIs release the break on immunoregulatory pathways, lead to an increase in inflammation and related cytokines, activate blood and endothelial cells, as well as release of neutrophil extracellular traps (NETs), and eventually result in thrombosis [11][12].3. Incidence of Thrombosis in Patients Receiving Immune Checkpoint Inhibitors
Initial RCTs investigating the efficacy of ICIs as anticancer treatment did not report thrombosis as a major adverse event of concern. An initial meta-analysis of these RCTs showed a modest rate of VTE at 2.7% (95% confidence interval [CI] 1.8–4.0) and an arterial thrombosis (ATE) rate of 1.1% (95% CI 0.5–2.1) [12][13]. Another meta-analysis of RCTs and prospective studies of ICI use in patients with melanoma and non-small cell lung cancer (NSCLC) also reported similar rates (VTE rates: 1.5% in melanoma and 1.9% in NSCLC) [13][14]. Most recently, an updated meta-analysis showed no significantly increased risk of VTE (odds ratio [OR] 0.99, 95% CI 0.82–1.19) in patients treated with ICIs compared to non-ICI regimens [14][15]. However, all of these meta-analyses suffered from the possibility of underreporting of thrombosis events in RCTs in the first place. Solinas et al. excluded 40% of the eligible RCTs from analysis as they did not specifically report rates of thrombosis [12][13]. In addition, in these studies, thrombosis events were reported as adverse events based on the Common Terminology Criteria for Adverse Events (CTCAE) criteria instead of planned outcomes, and adverse events were often only reported if they were over certain percentages. Significant underreporting of thrombosis events had been shown in previous oncology RCTs with focus on efficacy of cancer therapies compared to thromboprophylaxis trials, which requires close attention for data interpretation [15][16].
Since the approval and wide clinical use of various ICIs, occurrences of venous and/or arterial thromboses are increasingly reported. Table 2 summarized the results of 27 cohort studies reported to date, with the majority being retrospective cohorts from single centers. Most (80–100%) patients had metastatic cancer, with the most common cancers including NSCLC, melanoma, and RCC. All studies included a variety of different ICIs available in clinical care. The incidence of thrombosis differed widely among studies, due to diverse types of underlying malignancies, concurrent cancer therapies (such as chemotherapy), and variable follow-up durations. In general, the incidence of VTE was 5–8% at 6 months and 10–15% at 12 months (Table 2). Overall, the rates reported in these retrospective cohort studies were higher than those reported from RCTs (1–2% in meta-analyses) [12][13][13,14], but not considerably higher when considering the 6-month risks of VTE of 9–10% in ambulatory cancer patients with Khorana score of ≥ 2 receiving chemotherapy [16][17]. However, given the efficacy of ICIs, the exposure of ICIs can be prolonged, and the risks of thrombosis can continue to accumulate. Sheng et al. showed that the thrombosis rate did not plateau until approximately 30 months in patients with metastatic RCC and 36 months in those with metastatic urothelial cancer [17][18][18,19]. Therefore, as patients continue ICIs, the risks of thrombosis can continue to increase. This is worth noting as compared to chemotherapy, for which the highest risk of thrombosis is typically seen within the first 6 months.
Table 2. Summary of incidence rates of venous and arterial thrombosis from retrospective studies of cancer patients receiving immune checkpoint inhibitors (studies missing follow-up durations were not included).
| Study | Country | N | Type of Cancer | Stage IV | Follow-up [Median (IQR)] | VTE Incidence % (95% CI) |
ATE Incidence % (95% CI) |
|---|---|---|---|---|---|---|---|
| 47% | |||||||
| N/A | |||||||
| 6 mo: |
44][43,44,45]. It is interesting to note that the rates of thrombosis appear to be numerically lower in the population studies compared to the above-mentioned retrospective studies, with 6-month VTE rate of 2–4% and 4–7% at 12 months. In these population studies, outcomes were identified by ICD10 codes +/− imaging codes (as compared to individual chart review in retrospective studies), which could account for the difference in event rates. In addition, all three studies were from a single country (Danish registry), as compared to various countries from cohort studies (Table 2).
Table 3.
Summary of incidence of VTE and ATE from population cohort studies (all from Danish registries).
| Study | N | Type of cancer | Follow-up (mo) | VTE (%), (95% CI) | ATE (%), (95% CI) | |||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Hegde et al. 2017 [19][20] Abstract | USA | 76 | Lung | |||||||||
| Mulder et al. 2021 [43][ | N/A | 44] | 370 | All cancers | 610.8 mo | 18.4 | 2.6 | |||||
| 4.1 (2.3–6.7) | N/A | Ibrahimi et al. 2017 [20][21] Abstract |
USA | 154 | Lung 20.8% Melanoma 20.1% Ovarian 12.3% |
92% | 7 mo (198 days) | 10.4 | 0 | |||
| Bar et al. 2019 [21][22] | Israel | 1215 | All cancers Melanoma 40.5% Lung 28.7% |
N/A | 12 mo | AVE (MI, stroke, PE, DVT) 6 mo: 4.9 12 mo: 5.8 |
||||||
| Nichetti et al. 2019 [22][23] | Italy | 217 | NSCLC | 95.4% | 37.8 mo | 7.4 | 6.5 | |||||
| Ando et al. 2020 [23][24] | Japan | 122 | Lung, kidney, stomach, urothelial, melanoma | N/A | N/A Time to thrombosis 90 days (range 6–178) |
4.1 | 4.9 | |||||
| Drobni et al. 2020 [24][25] | USA | 2842 | All cancers NSCLC 28.8% Melanoma 27.9% |
N/A | 2 years | N/A | Composite: 5.35/100 person-yrs MI: 2.49 Stroke: 2.08 |
|||||
| Deschênes-Simard et al. 2021 [25][26] | Canada | 593 | NSCLC | 87.2% | 12.7 (4.9–22.7) mo | 9.9 (7.5–12.3) 76.5 (59.9–97.8) per 1000 person-years |
1.3 | |||||
| Gong et al. 2021 [26][27] | USA | 2854 | All cancers NSCLC 28.4% Melanoma 28.2% |
N/A | 194 days (IQR 65–412) | 6 mo: 7.4 12 mo: 13.8 |
N/A | |||||
| Gutierrez-Sainz et al. 2021 [27][28] | Spain | 229 | Lung 48% Melanoma 23.6% RCC 11.8% |
96.5% | 9.8 mo | 7 (4–10) | N/A | |||||
| Guven et al. 2021 [28][29] | Turkey | 133 | RCC 26.3% Melanoma 24.1% NSCLC 18.8% |
100% | 10.1 (5.8–18.5) mo | 11.3 | N/A | |||||
| Haist et al. 2021 [29][30] | Germany | 280 | Melanoma | 100% | 28 mo (95% CI 23.4–32.6) | 12.5 | 4.3 | |||||
| Hill et al. 2021 [30 | (a) 7.6 (4.3–12.2) | (b) 9.9 (5.8–15.3) | (c) 9.4 (4.8–15.8) 12 mo: (a) 9.0 (5.3–14.0) (b) 12.8 (7.8–19.0) (c) 12.2 (6.8–19.2) |
N/A | ||||||||
| 12 | 7.1 (4.2–11.1) | |||||||||||
| Moik et al. 2021 [43][44] Abstract | Icht et al. 2021 [31][32] | Israel | 176 | NSCLC | 85.8% | 6 mo (187 days) | 4.5 (2.1–8.3) | N/A | ||||
| 3259 | All cancers | 6 | 3.9 (3.3–4.7) | 1.3 (0.9–1.8) | ||||||||
| 12 | 5.7 (4.9–6.6) | 2.2 (1.7–2.8) | ][31] | USA | 435 (a) ICI: 171 |
Kewan et al. 2021 [32][33] | USA | 552 | All cancers NSCLC 47.3% |
100% | 12.1 mo | 12.1 |
| 24 | 7.3 (6.2–8.4) | (b) ICI+chemo: 157 (c) chemo then durvalumab: 107 |
NSCLC | 1.3 | ||||||||
| 3.1 (2.4–3.8) | Madison et al. 2021 [33][34] ^ | USA | 6127 | Lung | N/A | 6 mo | 6.3 | 2.6 | ||||
| Moik et al. 2021 [34][35] | Austria | 672 | Melanoma 30.4% NSCLC 24.1% RCC 11% |
85.8% | 8.5 mo | 6 mo: 5.0 (3.4–6.9) 12mo: 7.0 (5.1–9.3) Overall: 12.9 (8.2–18.5) |
6 mo: 1.0 (0.4–2.0) 12 mo: 1.8 (0.7–3.6) Overall 1.8 (0.7–3.6) |
|||||
| Roopkumar et al. 2021 | USA | 1686 | Lung 49.6% Melanoma 13.2% | 90.3% | 438 days (range 7–1971) | 6 mo: 7.1 12 mo: 10.9 Overall: 24 |
N/A | |||||
| Sheng et al. 2021 [17][18] | USA | 351 | RCC | 100% | 12.8 mo | 11 | 2 | |||||
| Total thromboembolism: 6 mo: 4.4 (2.6–6.9) 12 mo: 9.8 (6.8–13.4) |
||||||||||||
| Sussman et al. 2021 | USA | 228 | Melanoma | 81.1% | 27.3 mo | 6 mo: 8.0 (4.9–12.0) 12 mo: 12.9 (8.9–17.7) |
6 mo: 2.2 (0.8–4.8) 12 mo: 4.5 (2.3–7.8) |
|||||
| Alma et al. 2022 [35][36] | France | 481 | Lung | 86% | 9.8 mo | 9.8 | N/A | |||||
| Bjornhart et al. 2022 [36][37] | Denmark | 146 prospective (A) * | NSCLC | 87% | 16.5 mo | 6 mo: 13.0 12 mo: 14.4 Overall: 14 |
N/A | |||||
| 426 retrospective (B) | 6 mo: 4.9 12 mo: 5.6 Overall: 6 |
|||||||||||
| Canovas et al. 2022 [37][38] | Spain | 665 | Lung | 91.2% | 14 mo | 6.9 | 1.5 | |||||
| All thrombosis: 8.4 (6.23–10.6) | ||||||||||||
| [38][39] | Japan | 120 | Lung | 62.5% | within 6 mo | 2.5 | 4.2 | |||||
| Khorana et al. 2023 [39][40] ^ | USA | (a) ICI: 605 (b) ICI+chemo: 602 |
NSCLC | 100% | 9.1 mo | 6 mo: (a) 8.1 (b) 12.8 12 mo: (a) 13.5 (10.6–16.5) (b) 22.4 (20.2–24.5) |
N/A | |||||
| May et al. 2022 abstract | ||||||||||||
| Overvad et al. 2022 [44][45] | 3946 | All cancers | 6 | 2.6 | 1.3 | 291 | Melanoma | 82.5% | 17 mo | 4.8 | 1.0 | |
| [40][41] ^ | USA | 1823 | All cancers | N/A | 6 mo | 7.3 | ||||||
| 12 | 3.8 | 1.9 | All thrombosis: 5.8 (3.34–9.18) | |||||||||
| N/A | ||||||||||||
| Endo et al. 2022 | Sanfilippo et al. 2022 abstract [41][42]^ | USA | 1754 | All cancers | 77.9% | 6 mo | 4.1 | N/A | ||||
| Sheng et al. 2022 [18][19] | USA | 279 | Urothelial | 100% | 5.6 mo | 13 | 2 | |||||
| Total thromboembolism: 6 mo: 9.1 (6.0–13.0) 12 mo: 13.6 (9.6–18.4) |
||||||||||||
* A prospective cohort employed screening-detected VTE by computed tomography venography and pulmonary angiography. ^ Outcomes identified by ICD codes. Gong: VTE after ICI compared to pre, HR 4.98 (3.65–8.59). Abbreviations: ATE—arterial thrombosis; AVE—arterial event; CI—confidence interval; DVT—deep vein thrombosis; ICI—immune checkpoint inhibitor; MI—myocardial infarction; mo—months; N/A—not available; NSCLC—non-small cell lung cancer; PE—pulmonary embolism; RCC—renal cell carcinoma; USA—United States of America; VTE—venous thromboembolism.
In addition to retrospective cohort studies, three Danish population cohort studies reported the incidence of thrombosis in patients on ICIs (Table 3) [42][43][
Abbreviations: ATE—arterial thrombosis; CI—confidence interval; mo—months; VTE—venous thromboembolism.
Whether ICI combinations or combined ICI and chemotherapy would be associated with an increased risk of VTE (compared to single ICI or chemotherapy alone) is also an area of debate. Sussman et al. showed that ICI combinations were associated with a higher risk of VTE compared to single agent ICI [45][46]. A recent meta-analysis also showed that compared to mono-ICI, combined ICIs were associated with an increased risk of VTE and myocardial infarction in those with NSCLC [13][14]. However, another study showed that combined ICIs were not associated with higher risks [46][47]. Similarly, some studies showed an increased risk of ICI–chemotherapy combination compared to chemotherapy alone [30][41][31,42], while others showed similar rates of thrombosis in patients receiving ICI alone, chemotherapy alone, or combination [21][22]. Most recently, in the analysis of an oncology database of 2299 patients with stage IV NSCLC, first-line ICI-based regimens were associated with a 26% reduction in the risk of VTE compared to chemotherapy-based regimens, while the risks were comparable between ICI/chemo versus chemotherapy alone [39][40]. It is worth noting that a fair comparison of the risks of thrombosis associated with combination of chemotherapy and ICIs to ICI alone or chemotherapy alone could be challenging, as the baseline characteristics of these patients commonly differ significantly.
Data on the incidence or arterial thrombosis were even more scant, with rates within 1-2% over a follow-up period of 6 to 17 months (Table 2). A recent meta-analysis showed an increased risk of arterial thrombosis (OR 1.58, 95% CI 1.21–2.06) associated with ICI regimens [14][15]. In a matched cohort study of 2842 patients, Drobni et al. revealed that there was a three-fold increased risk of cardiovascular events after the start of ICIs compared to other anticancer therapies. The risks were similarly increased when they compared before and after ICI use in the same patients [24][25]. They also found ICI to be associated with a > three-fold higher rate of progression of total aortic plaque volume, which can be attenuated with concomitant use of corticosteroids or statins [24][25].