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Immune Checkpoint Inhibitors and Venous Thromboembolism
Quick Takes
- Early increases in CRP during immune checkpoint inhibitor (ICI) therapy are linked to a higher risk of venous thromboembolism (VTE).
- CRP trajectories could serve as biomarkers for assessing VTE risk in cancer patients undergoing ICI therapy.
- This study highlights the intersection of cancer, inflammation, and hypercoagulability.
Study Questions:
Does an early rise in C-reactive protein (CRP) levels during immune checkpoint inhibitor (ICI) therapy predict the risk of venous thromboembolism (VTE) in cancer patients?
Methods:
This retrospective cohort study included 822 cancer patients undergoing ICI therapy from two academic centers. Patients were stratified based on CRP trajectories in the first 3 months of therapy, defining a CRP rise as a twofold increase from baseline. Competing risk and time-dependent analyses were performed to evaluate VTE incidence. The findings were validated across both the primary and external cohorts.
Results:
The study included a discovery cohort of 405 patients from the Medical University of Vienna and a validation cohort of 417 patients from the Medical University of Graz. The median age in the discovery cohort was 63 years, with 38.3% being female. A variety of cancers were represented, including melanoma (33.3%), non–small cell lung cancer (25.9%), and renal cell carcinoma (8.9%), with 91.3% of patients presenting with metastatic disease at the start of ICI therapy. Most patients received ICIs as second-line therapy, with a median of six therapy cycles.
Patients with a CRP rise in the discovery cohort (39.3%) demonstrated a cumulative VTE incidence of 19.9% (95% confidence interval [CI], 8.4–34.8) compared to 8.6% (95% CI, 3.1–17.6) in those without a CRP rise. After multivariable adjustment for age, sex, cancer type, disease stage, Eastern Cooperative Oncology Group (ECOG) performance status, and comorbidity burden, the subdistribution hazard ratio (sdHR) for VTE was 2.64 (95% CI, 1.06–6.62).
The validation cohort yielded consistent results. Patients with a CRP rise (40.3%) had a cumulative VTE incidence of 22.9% (95% CI, 9.7–39.3) compared to 10.8% (95% CI, 7.4–15.1) in those without. The sdHR for VTE after adjustment was 2.25 (95% CI, 1.03–4.94). Time-to-event analyses confirmed that the elevated VTE risk was not confounded by disease progression or other time-dependent factors.
Conclusions:
An early rise in CRP levels during ICI therapy is associated with a higher risk of VTE, suggesting that CRP trajectories might serve as valuable biomarkers in clinical practice for predicting thrombotic complications.
Perspective:
Given VTE's significant impact on cancer outcomes, identifying reliable biomarkers for thrombotic risk is crucial. The consistent relationship between CRP trajectories and VTE across multiple cohorts suggests potential clinical utility. However, in interpreting these findings, it is essential to acknowledge that CRP elevations may stem not only from ICI-induced immune modulation but also from underlying tumor progression.
While the observed early CRP rises could signal heightened thrombotic risk, the extent to which these changes are driven by ICIs versus advanced disease remains uncertain. Moreover, CRP is a nonspecific inflammatory marker influenced by a variety of clinical factors, and the current analysis is retrospective, limiting definitive causal inferences. Prospective studies are still needed to establish optimal CRP thresholds, understand underlying mechanisms, and distinguish between tumor progression versus ICI-related inflammation. As immunotherapy continues to evolve, leveraging biomarkers like CRP could help achieve more personalized risk assessment and prophylaxis strategies, ultimately improving patient outcomes.
Clinical Topics: Pulmonary Hypertension and Venous Thromboembolism, Vascular Medicine, Cardio-Oncology
Keywords: C-Reactive Protein, Cardio-oncology, Immune Checkpoint Inhibitors, Venous Thromboembolism
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