Immune checkpoint inhibitors linked to high thromboembolism risk in patients with cancer
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Patients with cancer may be at high risk for venous thromboembolism and arterial thromboembolic events while undergoing treatment with immune checkpoint inhibitors, according to study results published in Blood.
Researchers also noted an association of VTE with increased risk for mortality, researchers noted.
“Immune checkpoint inhibitors are increasingly used in clinical practice to treat different types of cancer. Recent data from small cohort studies and case reports suggest a substantial thrombotic risk in these patients,” Cihan Ay, MD, associate professor of medicine and hemostaseology at Medical University of Vienna in Austria, told Healio. “Given the mostly advanced disease stage and level of pretreatment in patients treated with immune checkpoint inhibitors, a considerable underlying prothrombotic propensity is expected. Surprisingly, the large-scale clinical trials evaluating immune checkpoint inhibitors did not provide information on risk for VTE or arterial thromboembolism.”
Ay and colleagues conducted a single-institution, retrospective study of 672 adults with cancer (median age, 64 years; 61.3% men) who received immune checkpoint inhibitor treatment between 2015 and 2018 at Vienna General Hospital in Austria. About one-third of patients (30.4%) had melanoma, whereas 24.1% had non-small cell lung cancer, 11% had renal cell carcinoma and 10.4% had head and neck squamous cell carcinoma. Most patients (92.4%) had an ECOG performance status of 0 or 1, and 86% had stage IV disease.
Researchers culled data on the incidence and clinical consequences of VTE and arterial thromboembolism and explored potential clinical risk factors to identify those at high risk for events.
Among 85 patients (12.9%) who had a history of VTE before initiation of immune checkpoint inhibitor therapy, 65 experienced a prior VTE associated with their current cancer diagnosis. Sixty-two patients (9.2%) had a history of arterial thromboembolism, which for 15 patients was associated with the current cancer diagnosis.
At the time of immune checkpoint inhibitor initiation, 16.5% of patients received continuous anticoagulation and 19.8% received antiplatelet therapy.
Cumulative incidence rates of VTE and arterial thromboembolism served as the primary outcome.
Median follow-up was 8.5 months.
Researchers observed 47 VTE events, for a cumulative incidence of 12.9% (95% CI, 8.2-18.5), and nine arterial thromboembolic events, for a cumulative incidence of 1.8% (95% CI, 0.7-3.6), during immune checkpoint inhibitor therapy.
The occurrence of VTE appeared associated with a high risk for mortality (transition HR = 3.09; 95% CI, 2.07-4.6). In addition, having a prior history of VTE predicted VTE recurrence (subdistribution HR = 3.69; 95% CI, 2-6.81). Distant metastasis also appeared associated with risk for VTE (subdistribution HR = 1.71; 95% CI, 0.62-4.73), but the difference did not reach statistical significance.
“The occurrence of VTE was associated with a more than threefold increase in mortality and a 3.6-fold increased risk for cancer progression,” Ay said. “This association seems to go beyond direct thromboembolism-related mortality, as the number of fatal events was low, indicating a potential role of VTE as an indicator for more aggressive clinical course of disease during immune checkpoint inhibitor therapy.”
VTE and arterial thromboembolism also frequently led to delays or discontinuation of immune checkpoint inhibitor therapy, and anticoagulation treatment of VTE was characterized by substantial risk for recurrent thrombotic and hemorrhagic events, Ay added.
“In addition, a prior history of VTE was identified as a risk factor for future VTE under immunotherapy, but other known risk factors such as age, sex, tumor type and stage did not stratify thrombotic risk in these patients,” Ay said. “Importantly, the established risk-prediction model for patients receiving outpatient chemotherapy, the Khorana score, did not predict thrombosis risk in this cohort, suggesting the clinical need for immunotherapy-specific risk stratification tools in the future.”
Future research should aim to identify high-risk subgroups that may benefit from prophylactic anticoagulation, according to Ay. A potential causal role of immune checkpoint inhibitors in the induction of a hypercoagulable state also should be investigated, he told Healio.
“The occurrence of VTE might be an indicator of more aggressive cancer phenotypes characterized by impaired survival times,” Ay said. “An increased risk for disease progression and VTE and arterial thromboembolism have a detrimental impact on the clinical course of patients treated with immune checkpoint inhibitors.”
To date, the question remains whether the observed thrombotic risk reflects a causal prothrombotic effect of immune checkpoint inhibitors or rather represents the underlying thrombotic risk profile of patients treated with these agents, Ay added.
“However, irrespective of potential causality, the identification of secondary contributors to morbidity and mortality is of utmost importance in this emerging patient population, especially given the possibility of ongoing treatment response and survival despite oftentimes advanced cancer stage with this novel anticancer treatment,” Ay said.
The findings suggest phase 2 and phase 3 trials of immune checkpoint inhibitors should be reevaluated for safety, with a specific focus on risk for VTE and arterial thromboembolism, according to an accompanying editorial by Jan Beyer-Westendorf, MD, head of the thrombosis research unit at the Center for Vascular Medicine at University Hospital Dresden in Germany.
“ [Ay and colleagues] spotlight an important and underestimated safety issue of immune checkpoint inhibitors,” Beyer-Westendorf wrote. “Readers and prescribers are encouraged not only to study this article carefully but to include the question of thromboembolism in their daily treatment considerations and to invest further research into this important topic.”
For more information:
Cihan Ay, MD, can be reached at Medical University of Vienna, Waehringer Guertel 18-20, A-1090, Vienna, Austria; email: cihan.ay@meduniwien.ac.at.
References:
Beyer-Westendorf J, et al. Blood. 2021;doi:10.1182/blood.2020009480.
Moik F, et al. Blood. 2021;doi:10.1182/blood.2020007878.
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