Association of ALK rearrangement and risk of venous thromboembolism in patients with non-small cell lung cancer: A prospective cohort study

Dou, Feifei; Zhang, Yuan; Yi, Jiawen; Zhu, Min; Zhang, Shu; Zhang, Di; Zhang, Yuhui

doi:10.1016/j.thromres.2019.12.009

Cited by 37 publications

(38 citation statements)

References 40 publications

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“…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. The previous study with the highest number of patients with ALK rearrangement (193 total) that included a control group did not perform time-to-event analysis, evaluate patients over the full course of their disease (events from the first 90 d from diagnosis only were included), account for the competing risk of death, or control for several VTE risk factors such as obesity, thrombophilia, thrombogenic chemotherapy, and others.…”

Section: Discussionmentioning

confidence: 66%

“…Given the high death rate in patients with advanced-stage lung cancer, accounting for the competing risk of death is critical; otherwise, biased thrombosis risk estimates may be derived. Most previous studies were small retrospective cohorts (17-70 patients with the ALK rearrangement) [17][18][19][20][21][22] that did not employ survival analysis or control for the competing risk of death. Although some of these studies found elevated VTE rates in the 42% to 47% range, others reported rates as low as 8% to 17%.…”

Section: Discussionmentioning

confidence: 99%

“…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.…”

Section: Introductionmentioning

confidence: 99%

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

Al‐Samkari

Leiva

Dagogo‐Jack

et al. 2020

Journal of Thoracic Oncology

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Introduction: Clinical venous thromboembolism (VTE) risk prediction scores, such as the Khorana Risk Score, perform poorly in NSCLC, possibly because the tumor molecular subtype is omitted. Previous studies suggest a possible increased VTE risk in ALK-rearranged NSCLC, but data are conflicting. Methods: We performed a retrospective cohort study of patients with advanced-stage NSCLC diagnosed between 2009 and 2019. Multivariable, time-to-event analyses modeling the risk of first venous or arterial thrombosis in ALK and non-ALK NSCLC groups, controlling for covariates known to impact thrombosis risk (15 in VTE model and 17 in arterial thrombosis model), were performed using Cox proportional hazards regression and competing-risks regression. Multivariable negative binomial regression modeled the total VTE rate. Results: A total of 422 patients with ALK-rearranged and 385 patients with non-ALK-rearranged NSCLC were included. Patients with an ALK rearrangement were younger, had better performance status, and had lower rates of most thrombotic risk factors but had significantly higher rates of initial VTE (42.7% versus 28.6%, p < 0.0001), recurrent VTE (13.5% versus 3.1%, p < 0.0001), and similar rates of arterial thrombosis (5.0% versus 4.4%, p ¼ 0.71) compared with non-ALK NSCLC. VTE risk attributable to ALK was significant (Cox model: hazard ratio 3.70, [95% confidence interval [CI]: 2.51-5.44, p < 0.001], competing risks: subhazard ratio 3.91 [95% CI: 2.55-5.99, p < 0.001]). Negative binomial modeling revealed higher VTE rates in patients with an ALK rearrangement (incidence rate ratio 2.47 [95% CI: 1.72-3.55, p < 0.001]). The OR for recurrent VTE was 4.85 (95% CI: 2.60-9.52, p < 0.001). Arterial thrombosis risk attributable to ALK was significant (Cox model: hazard ratio 3.15 [95% CI: 1.18-8.37, p ¼ 0.021], competing risks: subhazard ratio 2.80 [95% CI: 1.06-7.43, p ¼ 0.038]). Conclusions: In time-to-event analyses controlling for thrombosis risk factors, the ALK rearrangement conferred a fourfold increase in VTE risk and a threefold increase in arterial thrombosis risk in NSCLC. These patients may benefit from pharmacologic thromboprophylaxis.

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Section: Discussionmentioning

confidence: 66%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Al‐Samkari

Leiva

Dagogo‐Jack

et al. 2020

Journal of Thoracic Oncology

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“…In the study of Zer et al, the rate of VTE in an ALK-rearranged cohort was 3 to 5 fold higher than previously reported in NSCLC population [ 16 ]. In the study of Dou et al, the presence of ALK rearrangement was associated with increased risk of VTE in patients with NSCLC [ 17 ]. In a most recent study, the time-to-event analyses indicated that the ALK rearrangement resulted in a 4-fold increase of VTE risk and 3-fold increase of arterial thrombosis risk in NSCLC [ 18 ].…”

Section: Discussionmentioning

confidence: 99%

“…These findings are consistent with our findings. To date, the possible reason why ALK causes VTE may be due to that the ALK rearrangement may increase the risk of VTE by enhancing tissue factor procoagulant activity via NF-κB signaling pathway, or by mucin abundance, or by heparin [ 16 , 17 ].…”

Section: Discussionmentioning

confidence: 99%

The association between pulmonary embolism and the cancer-related genomic alterations in patients with NSCLC

Xiong

Ding

et al. 2020

Respir Res

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To date, the association between the acute pulmonary embolism (PE) and the currently existing cancer-related genomic alterations in patients with non-small cell lung cancer (NSCLC) has been understudied. We reviewed patients with a confirmed histopathological diagnosis of NSCLC who underwent computed tomography pulmonary angiography (CTPA) and molecular tests including ALK, ROS1, EGFR, BRAF V600E as well as PD-L1 during the diagnosis of NSCLC, to explore the association between the genomic alterations and PE. The results showed that, for the patients with positive results of genomic alterations, the proportion of positive ALK (13.6%vs8.5%, P <0.001) and PD-L1 (24.7%vs19.9%, P = 0.001) in PE group were more than those in Non-PE group. The patients with positive ALK and PD-L1 had the most (19.0%) and second most (15.4%) incidence of PE among all the patients being studied. A multivariate Logistic regression analysis showed that the positive ALK [1.685(1.065–2.215)( P <0.001)] and PD-L1[1.798(1.137–2.201)( P <0.001)] were correlated with the occurrence of PE. The positive results of ALK and PD-L1 genomic alterations may indicate an increased risk of pulmonary embolism in patients with NSCLC.

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Association of anticoagulant use with clinical outcomes from crizotinib in ALK‐ and ROS1‐rearranged advanced non‐small cell lung cancers: A retrospective analysis of PROFILE 1001

Tsui

Wang

et al. 2022

Cancer Medicine

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Background ROS1‐ and ALK‐rearranged advanced NSCLCs are associated with increased thromboembolic risk. We hypothesized that a prothrombotic phenotype offers an evolutionary advantage to subsets of these cancers. The impact of this phenotype could alter outcomes from targeted therapy. Methods In a retrospective analysis of ROS1‐ and ALK‐rearranged NSCLCs treated with crizotinib in a phase 1 trial, we compared progression‐free survival (PFS) and objective response rate (ORR) based on the history of anticoagulation use (a possible surrogate of thromboembolism) at baseline (within 90 days before study enrollment) or within 90 days of study treatment. Results Twelve out of 53 (22.6%) ROS1‐ and 39 out of 153 (25.5%) ALK‐rearranged NSCLCs received anticoagulation before or during the trial. Most ROS1 and ALK patients on anticoagulation received low‐molecular‐weight heparin (75% and 64.1%, respectively). In the ROS1‐rearranged group, the median PFS (95% CI) values were 5.1 (4.4–14.4) and 29.0 (16.5–48.8) months, and the ORR values were 41.7% (95% CI: 15.2 to 72.3) and 80.5% (95% CI: 65.1 to 91.2) among those with and without anticoagulation treatment, respectively. In the ALK‐rearranged group, the median PFS (95% CI) was 7.1 (5.4–7.7) and 12.0 (9.4–18.3) months, and the ORR was 41% (95% CI: 25.6 to 57.9) and 74.3% (95% CI: 65.3 to 82.1) among those with and without anticoagulation, respectively. Conclusions Anticoagulation (as a potential surrogate of a prothrombotic subset) in ROS1‐ and ALK‐rearranged NSCLCs may be associated with a lower PFS and ORR to crizotinib. ClinicalTrial.gov: NCT00585195.

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Association of ALK rearrangement and risk of venous thromboembolism in patients with non-small cell lung cancer: A prospective cohort study

Cited by 37 publications

References 40 publications

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

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

The association between pulmonary embolism and the cancer-related genomic alterations in patients with NSCLC

Association of anticoagulant use with clinical outcomes from crizotinib in ALK‐ and ROS1‐rearranged advanced non‐small cell lung cancers: A retrospective analysis of PROFILE 1001

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