Khorana Risk Score for Thrombosis Prediction in Patients with Gynecologic Malignancies Using Immune Checkpoint Inhibitors - a Real-World Validation

Introduction

Immune checkpoint inhibitors (ICIs) are emerging as an important treatment option for various gynecologic malignancies. Unfortunately, ICIs are associated with an increased risk of venous thromboembolism (VTE) and arterial thromboembolism (ATE). Additionally, studies report that gynecological malignancies have a high risk of thrombosis. The Khorana risk score is a risk scoring system that predicts the risk of thrombosis after chemotherapy initiation. This risk scoring system is comprised of cancer type, obesity, elevated white blood cell and platelet count, and low hemoglobin level, measured before the initiation of chemotherapy. The Khorana risk score has been useful for assessing the risk of cancer-related thrombosis in chemotherapy but is understudied for patients with gynecological malignancies receiving immunotherapy. This study aims to validate the Khorana risk score in patients with gynecologic malignancies receiving ICIs using the TriNetX Global Collaborative Network, a stratified, de-identified global database comprising over 120 million patients across 120 healthcare organizations.

Methods

Within the database, we enrolled patients diagnosed with gynecological malignancies (malignancies of the vulva, vagina, uterus, and ovary) who received any ICIs from January 1, 2014, to July 19, 2023. We obtained the laboratory values and body mass index measured two weeks before ICI administration and calculated the Khorana risk score. We divided the patients into two cohorts: (1) a high Khorana risk score cohort, defined as a Khorana risk score of 3 to 5, and (2) an intermediate Khorana risk score cohort, defined as a Khorana risk score of 1 to 2. The first administration of ICI was set as the index date, and patients were followed for one year following ICI administration. The primary outcomes were VTE, defined as a composite outcome of deep vein thrombosis (DVT) and pulmonary embolism (PE), and ATE, defined as a composite of myocardial infarction and ischemic stroke. The secondary outcome was all-cause mortality.

Results

We identified 524 patients with gynecological malignancies, of whom 61 were in the high Khorana risk score (3-5) cohort and 463 were in the intermediate Khorana risk score (1-2) cohort. The mean age was higher in the intermediate Khorana risk score cohort than the high risk score cohort (58.1 vs. 62.8). The high-risk cohort had more Black or African American patients compared to the intermediate-risk cohort (23% vs. 12%) and fewer White patients (59% vs. 66%). BMI was higher in the high-risk cohort compared to the intermediate risk score cohort (30.2 vs. 27.6). Pembrolizumab was the most common ICI in both cohorts (92% vs. 77%), followed by nivolumab (16% vs. 15%). Compared to the intermediate-risk cohort, the high-risk cohort had a higher risk of VTE (HR: 2.60, 95% CI: 1.61-4.19, p < 0.001). Similar trends were seen for both PE (HR: 3.58, 95% CI: 2.02-6.34, p < 0.001) and DVT (HR: 2.37, 95% CI: 1.29-4.35, p = 0.004). The risk for ATE was not statistically significant but showed a tendency for higher risk in the high-risk cohort (HR: 2.31, 95% CI: 0.94-5.67, p = 0.059). Both stroke risk (HR: 2.08, 95% CI: 0.70-6.15, p = 0.176) and myocardial infarction risk (HR: 2.50, 95% CI: 0.52-12.08, p = 0.237) were elevated but not significant in the high-risk than the intermediate-risk cohort. The high-risk cohort demonstrated a higher risk of all-cause mortality (HR: 1.78, 95% CI: 1.17-2.71, p = 0.006).

Conclusions

Our study demonstrated that a high Khorana risk score of 3 or greater was associated with a higher VTE risk, all-cause mortality, and a tendency of higher ATE risk than those with a lower Khorana risk score in patients with gynecologic malignancies receiving ICIs. This suggests that the Khorana risk score may also be useful in stratifying thrombotic risk in gynecologic malignancies when administering ICIs. Further prospective studies are needed to explore the clinical implications of the Khorana risk score for this patient population.

No relevant conflicts of interest to declare.