Incidence, predictors and prognostic significance of thromboembolic disease in patients with advanced ALK-rearranged non-small cell lung cancer

Abstract

Incidence, predictors and prognostic significance of thromboembolic disease in patients with advanced ALKrearranged non-small cell lung cancer To the Editor: Thromboembolic disease is fairly common in patients with lung cancer [1-3]. This incidence seems to be higher in patients with lung adenocarcinomas [4], with approximately 15% of those with advanced stage disease developing venous thromboembolisms (VTE) during the whole course of their disease [5-7]. Pulmonary adenocarcinomas are a heterogeneous group of diseases that can be stratified according to the presence of major oncogenic driver alterations. Anaplastic lymphoma kinase (ALK) rearrangements are detected in approximately 4% of these cases [8]. Isolated reports have suggested that patients bearing ALK-rearranged tumours might have a higher than expected incidence of thromboembolisms [9, 10]. In the present study, we have analysed the incidence, predictors and prognostic significance of thromboembolic events in a large, multi-institutional and homogeneous cohort of advanced stage patients with ALK-rearranged lung cancers from Spain and Portugal. Our primary objective was to estimate the incidence of thromboembolic events and their association with overall survival in these patients. A centralised institutional ethics committee approval at the 12 de Octubre University Hospital valid for all Spanish centres, and an institutional ethics committee approval at the Portuguese Institute of Oncology of Porto, were obtained before the study was initiated. We retrospectively selected all consecutive patients diagnosed with advanced stage (stages III and IV) ALK fusion positive non-small cell lung cancers (NSCLCs) between January 2012 and December 2016. Data were contributed by 29 Medical Centres from Spain and one from Portugal. ALK positivity was determined according to local standard protocols in each institution. We excluded patients with neuroendocrine tumours and patients on therapeutic doses of anticoagulants prior to advanced stage cancer diagnosis. We defined a thromboembolic event as any venous or arterial thromboembolism, documented by imaging studies, that occurred at the time or after advanced stage cancer diagnosis. In addition to thromboembolic events, collected during the whole patients' follow-up period, we collected baseline information (within 1 month of advanced stage cancer diagnosis) of several clinical and analytical variables of interest. We included 241 ALK-rearranged NSCLCs in this study. The median age was 56 years (range 17-84 years). Half of the patients were never smokers (52%), and most had stage IV pulmonary adenocarcinomas (n=204, 85%). Baseline brain and liver metastasis were detected in 22% and 25% of the patients, respectively. 17 patients (7%) and 185 patients (77%) had high and intermediate Khorana risk scores (KRS) [11] respectively. The median follow-up of our study population was 19 months (range 0-59 months), and 127 (53%) of the patients died. The median follow-up of alive patients was 30 months (range 4-49 months). The est...

Impact of ALK Rearrangement on Venous and Arterial Thrombotic Risk in NSCLC

“…A 2018 study, including 241 patients with ALK rearrangement collected from 30 centers in Spain and Portugal but without a control or comparator group (and therefore no risk analysis), reported a VTE rate of 30%. 23 One previous study did perform survival analysis as we did but included just 33 patients with the ALK rearrangement. 22 This study reported a VTE rate of 27% in patients with ALK rearrangement with an SHR for VTE of 2.47 (95% CI: 1.04-5.90) relative to other patients with NSCLC.…”

“…Several case reports of severe hypercoagulable states in ALK-rearranged NSCLC have been published, [14][15][16] describing severe decompensated disseminated intravascular coagulation with thrombosis or recurrent venous and arterial events despite escalating anticoagulant and antiplatelet regimens. Previous observational studies have also specifically evaluated the risk of VTE in ALK-rearranged NSCLC [17][18][19][20][21][22][23] with highly variable and conflicting results, although each of these studies had several important limitations, including one or more of small sample sizes, lack of time-to-event (survival) analysis, lack of a control group, and failure to control for critical covariates, confounders, and the competing risk of death. In addition, none of these studies evaluated the separate and distinct risk of arterial thrombosis.…”

Is There an Interplay between Immune Checkpoint Inhibitors, Thromboprophylactic Treatments and Thromboembolic Events? Mechanisms and Impact in Non-Small Cell Lung Cancer Patients

“…Similarly, in order to demonstrate a direct correlation between ICIs and TE events, a control arm of patients with similar characteristics not receiving immunotherapy would have been optimal. However, this comparison is hard to perform, since NSCLC patients treated with chemotherapy are at even higher risk of TE events, as are patients with driver mutations receiving targeted therapies [54][55][56]. Moreover, if tested, lower rates of PD-L1 positivity would be found in these populations, as this might represent the reason to omit ICIs.…”

SEOM clinical guideline of venous thromboembolism (VTE) and cancer (2019)

“…Incidence of thrombosis in these patients varies widely, so it is important to identify patients at higher risk of developing VTE whom prophylaxis may be beneficial. Recently, VTE incidence over 30% have been described in pancreatic cancer [17,18] and specific molecular subtypes of non-small cell lung cancer (NSCLC) with ROS-1 [19] and ALK rearrangement [20,21]. Cancer patients are usually unaware of VTE risk [22].…”