Department of Hematology and Oncology, Taussig Cancer Institute, Cleveland Clinic Foundation, Cleveland, Ohio, USA.
Department of Population Health, Dell Medical School, The University of Texas at Austin, Austin, Texas, USA.
J Immunother Cancer. 2021 Jan;9(1). doi: 10.1136/jitc-2020-001719.
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.
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.
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.
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.
癌症导致的血栓栓塞（TE）显著增加发病率和死亡率。目前关于接受免疫检查点抑制剂（ICI）治疗的黑色素瘤患者动脉 TE（ATE）和静脉 TE（VTE）的发生率知之甚少。
我们对 2015 年 7 月至 2017 年 12 月在克利夫兰诊所接受 ICI 治疗的黑色素瘤患者进行了回顾性队列研究。确定了 ICI 治疗开始后发生的 TE 事件，包括深静脉血栓形成、肺栓塞、内脏静脉血栓形成和 ATE 事件（心肌梗死、中风、外周动脉栓塞或短暂性脑缺血发作）。通过 Kaplan-Meier 和 Cox 风险模型估计 ICI 开始后的总生存（OS）；使用对数秩检验评估 TE、ICI 方案和临床危险因素之间的关系。
研究人群包括中位年龄为 65 岁（23-91 岁）的 228 名患者，其中 67%为男性，中位随访时间为 27.3 个月。最常使用的是 pembrolizumab（38.7%），其次是 ipilimumab 联合 nivolumab（29.4%）、ipilimumab（20%）和 nivolumab（12.3%）。大多数患者患有 IV 期疾病（81.1%），11%的患者在治疗开始时存在脑转移（BM）。47 名患者（20.6%）发生了 51 次 TE 事件，包括 37 次（16.2%）VTE 和 14 次（6.1%）ATE。ICI 治疗开始后 6 个月 TE 的累积发生率为 9.3%（95%CI：6.0%至 13.6%），12 个月时为 16.0%（95%CI：11.6%至 21.2%）。联合 ICI 与单药治疗相比，6 个月和 12 个月的 VTE 累积发生率更高（16.7%比 5.0%和 21.3%比 9.5%；p=0.02）。多变量分析中，与 VTE 显著相关的危险因素包括联合 ICI（HR 2.70；95%CI：1.28 至 5.70；p=0.009）、Khorana 评分≥1（HR 2.24；95%CI：1.06 至 4.74；p=0.03）、冠状动脉疾病史（HR 2.71；95%CI：1.16 至 6.29；p=0.02）和治疗开始时抗凝（HR 4.14；95%CI：1.60 至 10.7；p=0.003）。在没有 BM 的患者中，与无 TE 的患者相比，TE 患者的 OS 更差（2 年 OS 50.8%比 71.3%；HR 2.27；95%CI：1.36 至 3.79；p=0.002），但在调整年龄和分期后。
ICI 与黑色素瘤患者的 TE 发生率高相关，联合治疗的发生率更高；TE 与生存显著恶化相关。需要进一步研究以确定病理生理学、生物标志物和预防方法。
