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

Abstract

BackgroundThromboembolism (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.MethodsWe 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.ResultsThe 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.ConclusionsICI 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.

Anticoagulation with Factor Xa Inhibitors Is Associated with Improved Overall Response and Progression-Free Survival in Patients with Metastatic Malignant Melanoma Receiving Immune Checkpoint Inhibitors—A Retrospective, Real-World Cohort Study

“…However, our data are consistent with previous studies and randomized phase III trials [32], which found no association of concomitant AC with prolonged survival in patients with NSCLC [16] or other advanced solid cancer entities [19,21]. Although the cancer-specific risk of VTE in the pre-ICI era was found to be smaller in melanoma patients [33], melanoma patients treated with ICI show similar rates of TEE-and VTE-associated mortality as compared to patients with other advanced cancers [27,34,35], providing a biological rationale for AC therapy [21].…”

“…However, given the strong heterogeneity of patients in terms of the primary tumor localization, the question as to whether the use of AC in general and the application of FXa or thrombin inhibitors more specifically might impact the outcome of ICI treatment might be better addressed in defined tumor entities with unmet clinical needs in improvements of ICI therapy. The exigency to comprehensively analyze the clinical wirings between the use of (different) anticoagulants and ICI in patients with advanced melanoma is highlighted when taking into account the increased risk of thromboembolic events (TEE) in patients treated with ICI and the TEE-associated adverse survival [21].…”

Thrombotic Complications Associated with Immune Checkpoint Inhibitors

“…The references in the relevant articles were also manually searched for related studies. Overall, 18 retrospective studies reporting incidences and/or outcomes of venous and/or arterial thrombosis in patients on ICIs [ 1 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 ] and 4 additional relevant systematic reviews and meta-analyses [ 24 , 25 , 26 , 27 ] were identified and included in this review.…”

“…In patients receiving ICIs, several studies have shown that the occurrence of thrombosis was associated with worsening survival [10,11,[20][21][22] while others have not [14][15][16] (Table 2). Possible explanations of worse survival in patients who developed VTE include that thrombosis is an indicator for more advanced cancer stage, worse prognosis, poorer performance status, and/or thrombosis or anticoagulation-related mortality.…”

Pulmonary Toxicities Associated With the Use of Immune Checkpoint Inhibitors: An Update From the Immuno-Oncology Subgroup of the Neutropenia, Infection & Myelosuppression Study Group of the Multinational Association for Supportive Care in Cancer

“…Pulmonary embolism (PE) is more common in melanoma patients treated with ICIs (Sussman et al, 2021). Furthermore, it appears to be more prevalent in patients treated with combination checkpoint inhibition in comparison with single-agent therapy.…”