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Abstract
Background Little is known about rates of arterial thromboembolism (ATE) and venous thromboembolism (VTE) in patients with melanoma on ICI. We assessed incidence and outcomes of ATE and VTE in patients with melanoma receiving ICI.
Methods We conducted a retrospective cohort study of patients with melanoma receiving ICI from July 2015 through December 2017 at Cleveland Clinic. TE including VTE events of deep venous thrombosis (DVT), pulmonary embolism (PE), visceral vein thrombosis (VVT), and ATE events of myocardial infarction (MI), stroke, or transient ischemic attack (TIA) 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 65 (23–91) years, 67% male, and median follow up 27.3 months. Pembrolizumab was most commonly used (38.7%), followed by combination 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. Of VTE, DVT comprised 46.0%, PE 24.3%, DVT+PE 21.6%, VVT 5.4%, and DVT+VVT 2.7%. Of ATE, stroke comprised 57.2%, MI 35.7%, and TIA 7.1%. Of all TE events, 72% resulted in hospitalization and 19% resulted in clot-related mortality. Cumulative incidence of TE after ICI initiation was 9.3% (95%CI,6.0–13.6%) at 6 months, and 16.0% (95%CI,11.6–21.2%) at 12 months. The 6- and 12-month VTE cumulative incidence rates were 8.0% (95%CI,4.9–12.0%), and 12.9% (95%CI,8.9–17.7%), respectively. The 6- and 12-month ATE cumulative incidence rates were 2.2% (95%CI,0.84–4.8%), and 4.5% (95%CI,2.3–7.8%), respectively. The 6- 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) (figure 1). Risk factors associated with VTE in univariate analysis included BM, stage IV disease, combination ICI, and Khorana score ≥1 (p<0.05 for all). In multivariate analysis, combination ICI (HR 2.21; [95%CI,1.04–4.72]; p=0.04) and Khorana score ≥1 (HR 2.48; [95%CI,1.18–5.20]; p=0.02) remained significantly associated with VTE.Of patients without BM, OS was worse in patients with TE compared to those without (3-year OS 34.9% vs. 62.9%; HR 1.84; [95%CI,1.16–2.93]; p<0.001), when adjusted for age, stage, and Khorana score (figure 2).
Cumulative incidence of VTE, stratified by ICI*Death before VTE was considered a competing risk in CIF estimation
OS in patients without BM stratified by TE status
Conclusions ICI is associated with a high incidence of TE in patients with melanoma; TE is associated with substantial worsening of survival.
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