Incidence of thromboembolism in patients with melanoma on immune checkpoint inhibitor therapy and its adverse association with survival

Abstract

Background: Thromboembolism (TE) in cancer significantly contributes to morbidity and mortality. Little is known about the incidence of arterial TE (ATE) and venous TE (VTE) in patients with melanoma on immune checkpoint inhibitor (ICI) therapy.

Methods: We conducted a retrospective cohort study of patients with melanoma receiving ICI from July 2015 through December 2017 at the Cleveland Clinic. TE, including VTE events of deep venous thrombosis, pulmonary embolism, visceral vein thrombosis, and ATE events of myocardial infarction, stroke, peripheral arterial embolism, or transient ischemic attack after ICI initiation were identified. Overall survival (OS) from ICI initiation was estimated by Kaplan-Meier and Cox hazard models; associations between TE, ICI regimen, and clinical risk factors were evaluated using log-rank test.

Results: The study population comprised 228 patients with median age of 65 years (23-91 years), 67% male, and median follow-up of 27.3 months. Pembrolizumab was most commonly used (38.7%), followed by combination of ipilimumab plus nivolumab (29.4%), ipilimumab (20%), and nivolumab (12.3%). Most had stage IV disease (81.1%) and 11% had brain metastases (BM) at treatment initiation. Fifty-one TE events occurred in 47 patients (20.6%), including 37 (16.2%) VTE and 14 (6.1%) ATE. Cumulative incidence of TE after ICI initiation was 9.3% (95% CI: 6.0% to 13.6%) at 6 months, and 16.0% (95% CI: 11.6% to 21.2%) at 12 months. The 6-month and 12-month VTE cumulative incidence rates were higher with combination ICI than single agent (16.7% vs 5.0% and 21.3% vs 9.5%, respectively; p=0.02). Risk factors significantly associated with VTE in multivariate analysis included combination ICI (HR 2.70; 95% CI: 1.28 to 5.70; p=0.009), Khorana Score ≥1 (HR 2.24; 95% CI: 1.06 to 4.74; p=0.03), history of coronary artery disease (HR 2.71; 95% CI: 1.16 to 6.29); p=0.02), and anticoagulation at treatment start (HR 4.14; 95% CI: 1.60 to 10.7; p=0.003). Of patients without BM, OS was worse in patients with TE compared with those without (2-year OS 50.8% vs 71.3%; HR 2.27; 95% CI: 1.36 to 3.79; p=0.002), when adjusted for age and stage.

Conclusions: ICI is associated with a high incidence of TE in patients with melanoma, with higher rates with combination therapy; TE is associated with substantial worsening of survival. Further studies are needed to identify pathophysiology, biomarkers, and preventive approaches.

Keywords: immunotherapy; inflammation; melanoma.

Figure 1

Cumulative incidence function graphs of (A) TE at 3 months, 6 months, 9 months, and 12 months of ICI initiation with 95% CIs; (B) VTE at 3 months, 6 months, 9 months, and 12 months of ICI initiation with 95% CIs; and (C) ATE at 3 months, 6 months, 9 months, and 12 months of ICI initiation with 95% CIs. ATE, arterial thromboembolism; CIF, cumulative incidence function; ICI, immune checkpoint inhibitor; TE, thromboembolism; VTE, venous thromboembolism.

Figure 2

Cumulative incidence of VTE using Fine and Gray method with death as a competing risk for factors associated with VTE in univariate analysis (A) stratified by ICI regimen of either single or doublet ICI therapy (p=0.02); (B) stratified by Khorana Score of 0 or ≥1 at treatment initiation (p=0.03); and (C) stratified by the presence or the absence of CAD history (p=0.06). CAD, coronary artery disease; CIF, cumulative incidence function; ICI, immune checkpoint inhibitor; mo, months; TE, thromboembolism; VTE, venous thromboembolism.

Figure 3

Kaplan-Meier curves for OS of melanoma patients after ICI initiation. (A) OS in patients without brain metastases (n=185) stratified by the presence or the absence of TE (p<0.001). (B) OS in patients with brain metastases (n=43) stratified by the presence or the absence of TE (p=0.96). ICI, immune checkpoint inhibitor; OS, overall survival; TE, thromboembolism.