Incidence of thromboembolism in patients with melanoma on immune checkpoint inhibitor therapy and its adverse association with survival.
Incidence of thromboembolism in patients with melanoma on immune checkpoint inhibitor therapy and its adverse association with survival.
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DOI：
10.1136/jitc-2020-001719
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发表时间：
2021-01
影响因子：
10.9
通讯作者：
Khorana AA
中科院分区：
文献类型：
--
作者：
Sussman TA;Li H;Hobbs B;Funchain P;McCrae KR;Khorana AA
癌症中的血栓栓塞症(TE)极大地增加了发病率和死亡率。关于接受免疫检查点抑制剂(ICI)治疗的黑色素瘤患者发生动脉TE(ATE)和静脉TE(VTE)的情况知之甚少。我们对2015年7月至2017年12月在克利夫兰诊所接受ICI的黑色素瘤患者进行了一项回顾性队列研究。包括深静脉血栓形成、肺栓塞、内脏静脉血栓形成的VTE事件，以及ICI后心肌梗死、卒中、外周动脉栓塞或短暂性脑缺血发作的ATE事件。用Kaplan-Meier和Cox风险模型估计ICI开始后的总生存期(OS)；用LOG-RANK检验评估TE、ICI方案和临床危险因素之间的相关性。研究人群包括228名患者，中位年龄为65岁(23-91岁)，其中67%为男性，中位随访时间为27.3个月。Pembrolizumab最常用(38.7%)，其次是ipilimumab+nivolumab(29.4%)、ipilimumab(20%)和nivolumab(12.3%)。大多数人在治疗开始时有IV期疾病(81.1%)和11%的人有脑转移(BM)。其中47例(20.6%)发生51次TE事件，其中37例(16.2%)发生VTE，14例(6.1%)发生ATE。ICI后6个月和12个月的累积TE发生率分别为9.3%(95%CI：6.0%~13.6%)和16.0%(95%CI：11.6%~21.2%)。联合用药6个月和12个月VTE累积发生率分别为16.7%比5.0%和21.3%比9.5%(P=0.02)。多因素分析显示，合并ICI(HR 2.70；95% CI：1.2 8~5.70；p=0.009)、Khorana评分≥1(HR 2.2 4；95% CI：1.0 6~4.74；p=0.0 3)、冠状动脉病史(HR 2.71；95% CI：1.16~6.2 9)、治疗开始时抗凝(HR 4.14；95%CI：1.6 0~10.7；p=0.003)与VTE显著相关。在无BM的患者中，在调整年龄和分期后，有TE的患者的OS比无BM的患者更差(2年OS 50.8%比71.3%；HR 2.27；95% CI：1.363.79；p=0.002)。ICI与黑色素瘤患者的TE发生率高有关，联合治疗的发生率更高；TE与存活率的显著恶化有关。需要进一步的研究来确定病理生理学、生物标记物和预防方法。
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.
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影响因子：
82.9
作者：
Koelwyn GJ;Newman AAC;Afonso MS;van Solingen C;Corr EM;Brown EJ;Albers KB;Yamaguchi N;Narke D;Schlegel M;Sharma M;Shanley LC;Barrett TJ;Rahman K;Mezzano V;Fisher EA;Park DS;Newman JD;Quail DF;Nelson ER;Caan BJ;Jones LW;Moore KJ
通讯作者：
Moore KJ
影响因子：
3.4
作者：
Ando, Yosuke;Hayashi, Takahiro;Imaizumi, Kazuyoshi
通讯作者：
Imaizumi, Kazuyoshi
影响因子：
45.3
作者：
Key, Nigel S.;Khorana, Alok A.;Falanga, Anna
通讯作者：
Falanga, Anna
影响因子：
11.5
作者：
Khorana, Alok A.;Ahrendt, Steven A.;Taubman, Mark B.
通讯作者：
Taubman, Mark B.
影响因子：
6.2
作者：
Khorana, Alok A.;Francis, Charles W.;Lyman, Gary H.
通讯作者：
Lyman, Gary H.