Real-World Validation of the Khorana Risk Score in Predicting Thrombosis for Lung Cancer Patients Treated with Immune Checkpoint Inhibitors

Introduction

Lung cancer patients treated with immune checkpoint inhibitors (ICIs) experience an increased risk of venous and arterial thromboembolism. However, there is limited data available to guide the risk stratification or prediction of these serious adverse events. The Khorana risk score is computed based on five risk factors: cancer type, high pre-chemotherapy platelet count (≥ 350,000/μL), low hemoglobin level (<10 g/dL or use of RBC growth factors), high pre-chemotherapy white blood cell count (> 11,000/μL), and high body mass index (BMI ≥ 35 kg/m²). These factors are used to stratify patients receiving chemotherapy into low, intermediate and high thrombotic risk groups. In this study, we aimed to investigate the utility of the Khorana risk score in predicting the occurrence of thrombotic events among lung cancer patients receiving ICIs.

Methods

We conducted a retrospective cohort study using the TriNetX Global Collaborative Network, a de-identified, stratified database comprising data from over 120 million patients across more than 120 healthcare organizations. We identified lung cancer patients who received any type of immune checkpoint inhibitor (ICI) from January 2014 to July 2023. We calculated the Khorana risk score using laboratory values (hemoglobin, white blood cell count, and platelet levels) and BMI measured within two weeks before the first ICI administration. We divided the patients into two cohorts: the high Khorana risk score cohort (3 to 5) and the intermediate Khorana risk score cohort (1 or 2). We set the time of the first ICI administration as the index date and had a one-year follow-up. The primary outcome was venous thromboembolic events (VTEs), including deep vein thrombosis (DVT) and pulmonary embolism (PE). The secondary outcomes were arterial thrombosis, such as myocardial infarction and ischemic stroke, as well as all-cause mortality.

Results

Over the study period, we identified 5,174 lung cancer patients receiving ICIs, who were divided into 601 patients with high Khorana risk scores (3-5) and 4,573 with intermediate Khorana risk scores (1-2). The mean age (standard deviation) of each group was 64.7 (10.9) in the high Khorana risk score cohort and 67.1 (10.2) in the intermediate Khorana risk score cohort. The high Khorana risk score cohort consisted of more females (42% vs. 38%). The high Khorana risk score cohort had a higher proportion of Black or African American patients (13% vs. 10%) and fewer White patients (65% vs. 69%). BMI was similar in both cohorts (mean ± standard deviation, 25.6 ± 7.48 vs. 26.1 ± 5.83). Pembrolizumab was the most commonly used ICI in both cohorts (68% vs. 50%), followed by nivolumab (13% vs. 19%) and atezolizumab (13% vs. 17%). A high Khorana risk score was associated with a higher risk of VTE (HR: 1.24, 95% CI: 1.02-1.51, p-value: 0.035), mainly driven by an increased risk of DVT (HR: 1.33, 95% CI: 1.02-1.74, p-value: 0.038). The risk of PE was not statistically significant but indicated a higher risk in the high KS cohort (HR: 1.17, 95% CI: 0.91-1.50, p-value: 0.225). For the secondary outcomes, a high Khorana risk score demonstrated a higher risk for arterial thrombosis (HR: 1.48, 95% CI: 1.17-1.88, p-value: 0.001), mainly driven by ischemic stroke (HR: 1.64, 95% CI: 1.21-2.22, p-value: 0.001). There was a numerically increased risk for myocardial infarction, but it was not statistically significant (HR: 1.40, 95% CI: 0.99-1.99, p-value: 0.059). A high Khorana risk score was associated with increased mortality (HR: 1.61, 95% CI: 1.42-1.84, p-value < 0.001).

Conclusions

A high Khorana risk score (score ≥ 3) was associated with a higher risk of VTE and arterial thrombosis in lung cancer treated with ICIs and may be used to stratify patients with lung cancer treated with ICI therapy. Further studies are needed to explore how the Khorana score may be implemented clinically to predict the risk of ICI-associated thrombosis and identify patients who may benefit from prophylactic anticoagulation.