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CRP Levels May Help Stratify VTE Risk in Patients With Cancer on ICIs

January 30, 2025

February 2025

Ruth Jessen Hickman, MD

Ruth Jessen Hickman, MD, is a freelance medical and science writer based in Bloomington, Indiana.

C-reactive protein (CRP) levels may help identify patients on immune checkpoint inhibitors (ICIs) who are at increased risk of venous thromboembolism (VTE), according to results of a retrospective study of patients with cancer published in JACC: CardioOncology.1

Through a variety of mechanisms, patients with cancer have an increased risk of VTE, which can interrupt cancer treatment and cause mortality. Practitioners can employ a variety of risk stratification tools, such as the Khorana score, to help evaluate patients who might benefit from primary thromboprophylaxis. In the general population, VTE is associated with acute inflammation responses and increased CRP, and modest data suggest its potential utility as a biomarker predicting VTE. 2

ICIs have substantially improved cancer prognosis across a wide variety of cancer types. However, Cihan Ay, MD, the corresponding author of the retrospective study and a professor of hematology at the Medical University of Vienna, noted that multiple reports have documented a substantive increased risk of VTE in patients with cancer taking ICIs compared to those not on the therapy. It has been unclear if ICIs exert a prothrombotic effect or if this reflects different underlying patient risk profiles in patients who take ICIs.

Established risk stratification tools for cancer-​associated VTE such as Khorana were developed before the advent of immunotherapies. Data on their performance in patients taking ICIs have shown mixed results, noted Dr. Ay.

Thus, Dr. Ay, first author Florian Moik, MD, PhD, also of the Medical University of Vienna, and the rest of their team explored longitudinal levels of CRP during ICI therapy as a potential marker for VTE risk. The retrospective cohort study included a discovery cohort (n=405) and a validation cohort (n=417). All patients had at least a baseline CRP measurement and two follow-up CRP measurements taken within the first three months of starting ICI therapy, and patients were stratified based on their CRP trajectories during this time.

In patients with a CRP rise (at least a two-fold increase from baseline; 39.3%), the cumulative incidence of VTE was 19.9% (95% Cl 8.4%-34.8%) in the initial cohort. This contrasted with only 8.6% (95% CI 3.1%-17.6%) in those without such a CRP rise. After adjusting for various confounders, the hazard ratio (HR) for VTE in patients with a CRP rise was 2.64 (95% Cl 1.06-6.62). Findings were similar in the external validation cohort (HR=2.25; 95% Cl 1.03-4.94). These associations remained even after adjusting for disease progression in a time-dependent analysis.

Thus, early CRP changes during ICI therapy are associated with an increased risk of VTE, potentially implying an association between ICI-induced inflammation and hypercoagulability, although this is still unclear.

Due to its retrospective nature, the study is somewhat limited in terms of generalizability; for example, CRP levels could not be assessed at standardized testing intervals, and certain complex confounding factors might be better controlled in a prospective study.

In addition to potentially marking VTE risk, increases in CRP may also imply some benefits. Several studies have shown that transient elevations after starting ICIs may be a favorable prognostic biomarker for treatment response and survival, potentially reflecting anti-cancer immune response.1,3

ICIs are allowing increased patient survival at more advanced cancer stages. But somewhat paradoxically, ICI use itself and this increased lifespan may put patients at greater long-term risk of eventually suffering a VTE.4

Ultimately, these observations might prove a useful addition to established clinical risk prediction models for VTE in patients with cancer. “Our study provides a simple yet innovative approach to identify patients at increased risk of VTE,” Dr. Ay said. “Importantly, as CRP is an established and readily available biomarker routinely measured in clinical practice, implementation of a CRP-based risk assessment of VTE during ICI might be feasible.”

Any conflicts of interest declared by the authors can be found in the original article.

References

  1. Moik F, Reidl JM, Barth D, et al. Early change in c-reactive protein and venous thromboembolism in patients treated with immune checkpoint inhibitors [published online ahead of print, 2024 Nov. 12]. JACC: CardioOncology. doi: 10.1016/j.jaccao.2024.09.007.
  2. Dix C, Zeller J, Stevens H, et al. C-reactive protein, immunothrombosis and venous thromboembolismFront Immunol. 2022;13:1002652.
  3. Klümper N, Saal J, Berner F, et al. C reactive protein flare predicts response to checkpoint inhibitor treatment in non-small cell lung cancerJ Immunother Cancer. 2022;10(3):e004024.
  4. Moik F, Riedl JM, Englisch C, et al. Update on thrombosis risk in patients with cancer: focus on novel anticancer immunotherapiesHamostaseologie. 2024;44(1):40-48.

 

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