Immune Checkpoint Inhibitors May Increase Thromboembolism Risk

Patients with cancer who are treated with immune checkpoint inhibitors are at an increased risk of developing venous thromboembolism (VTE) and arterial thromboembolism (ATE), and these events appear to adversely affect survival outcomes, according to a study published in Blood.

“The high rates of thrombosis we observed can help raise awareness for clinicians treating patients with immune checkpoint inhibitors,” lead author Florian Moik, MD, of the Medical University of Vienna in Austria, told ASH Clinical News. “Given the possibility for long-term survival with this effective novel treatment strategy, the identification of potentially life-threatening thrombotic events is of utmost importance.”

For this study, Dr. Moik and colleagues conducted a retrospective review of patients with cancer treated at the Vienna General Hospital. Participants were identified using an in-house pharmacy prescription program, were ≥18 years of age, and had received at least one dose of an immune checkpoint inhibitor between 2015 and 2018.

The primary outcomes were the occurrence of a VTE or ATE during treatment with an immune checkpoint inhibitor. Secondary objectives included the assessment of how VTE and ATE affected the rates of overall survival (OS) and progression-free survival (PFS).

Of the 672 patients included in the analysis, most received an immune checkpoint inhibitor as part of routine care (n=580), while the remaining 92 patients were treated in the context of an open-label or single-arm clinical trial (n=92). The median age at time of therapy initiation was 64 years, and 38.7% of the patient population were women. Most (92.4%) of the cohort had an Eastern Cooperative Oncology Group Performance Status score of 0 or 1 and the median Charlson Comorbidity Index score was 8.

Cancer diagnoses in the overall study cohort included:

  • malignant melanoma (n=204)
  • non-small cell lung cancer (n=162)
  • renal cell carcinoma (n=74)
  • head and neck squamous cell carcinoma (n=70)
  • urothelial cancer (n=33)

The most frequently prescribed immune checkpoint inhibitors were nivolumab (n=282) and pembrolizumab (n=269), followed by ipilimumab (n=45), ipilimumab plus nivolumab (n=40), atezolizumab (n=30), and avelumab (n=6).

A total of 85 participants (12.6%) had a history of VTE (mostly associated with the current cancer diagnosis) before starting immune checkpoint inhibitor therapy. In addition, 62 patients (9.2%) had a history of ATE; in 15 of these patients, ATE was associated with the current cancer diagnosis.

“The identification of potentially life-threatening thrombotic events is of utmost importance.”

—Florian Moik, MD

During a median follow-up period of 8.5 months, investigators observed 47 VTE events, for a cumulative VTE incidence of 12.9% during immune checkpoint inhibitor treatment. Deep vein thrombosis and pulmonary embolism were the most common types of VTE. The median time from the start of therapy to VTE was 4.2 months.

Nine ATE events were recorded. Cumulative incidences of ATE at 3, 6, 12, and 24 months were 0.6%, 1.0%, 1.3%, and 1.8%, respectively. Types of ATE events included acute coronary syndrome (n=4), ischemic stroke (n=3), and acute vascular occlusion (n=2). There was one confirmed fatal ATE, which was later determined to be ischemic stroke.

Over a median follow-up period of 23.1 months, 294 patients died. The median OS following a VTE was 11.6 months, compared with 25.5 months for patients without VTE (p<0.001), and patients who had a VTE had a significantly shorter OS (hazard ratio [HR] = 3.09). VTE also was associated with a significantly shorter median PFS (1.7 vs. 6.7 months; HR=3.63; p<0.001).

However, the authors did not find an association between ATE and the risk of mortality (HR=0.79) or early disease progression (HR=0.64), possibly because these events were so rare (n=9). Exploratory analyses into potential risk factors of VTE included history of VTE, sex, and anticoagulation at baseline (TABLE).

The investigators also observed similar rates of VTE and ATE among patients with different tumor types. “This might be explained by either the underlying risk profile of patients in our cohort, with mostly advanced disease, or suggest a pro-thrombotic class effect of immune checkpoint inhibitors that influences the risk of thrombosis irrespective of underlying tumor type,” said Dr. Moik.

Limitations of this study included its retrospective design and the lack of a comparator arm comprising patients with cancer who were not treated with immune checkpoint inhibitors.

Dr. Moik and corresponding study author Cihan Ay, MD, also from the Medical University of Vienna, emphasized the need for further investigation to “better characterize the risk of thrombosis under immune checkpoint inhibitors to identify risk factors and potential biomarkers that are able to stratify patients according to their underlying thrombotic risk.” Doing so, they concluded, could assist in better selection of patients who might benefit from future prophylactic treatment with anticoagulation.

The authors report no relevant conflicts of interest.


Moik F, Chan WE, Wiedemann S, et al. Incidence, risk factors and outcomes of venous and arterial thromboembolism in immune checkpoint inhibitor therapy. Blood. 2020 October 16. [Epub ahead of print]