# The FLARE Score and Circulating Neutrophils in Patients with Cancer and COVID-19 Disease

## TL;DR

This study introduces the FLARE score, a tool to predict severe COVID-19 outcomes in cancer patients, and highlights the role of immature neutrophils in disease progression.

## Contribution

The FLARE score is a novel clinical tool combining tumor- and infection-induced inflammation to predict severe outcomes in cancer patients with COVID-19.

## Key findings

- The FLARE score effectively categorizes cancer patients with COVID-19 into four prognostic groups with significantly different 30-day mortality rates.
- Cancer patients with elevated dNLR before and during COVID-19 had worse outcomes, with immature neutrophils and higher IL-6 levels linked to severe disease.
- The FLARE score is an independent predictor of early mortality in cancer patients with COVID-19.

## Abstract

Understanding the inflammatory interplay between cancer and COVID-19 infection is essential for improving patient care. Our study bridges a vital knowledge gap by exploring how a pre-existing tumor-induced inflammatory state can exacerbate the inflammatory response to COVID-19, adversely impacting COVID-19 outcomes. We introduce the FLARE score, a robust predictor derived from circulating inflammatory markers, that provides clinicians a practical tool for early identification of patients with cancer at higher risk of severe COVID-19 complications who might benefit most from immediate and intensive treatment strategies. Additionally, our study also underscore the role of immature neutrophils in the progression of COVID-19 in patients with cancer, advocating for further investigation into how these cells contribute to both cancer and COVID-19 disease.

Purpose: Inflammation and neutrophils play a central role in both COVID-19 disease and cancer. We aimed to assess the impact of pre-existing tumor-related inflammation on COVID-19 outcomes in patients with cancer and to elucidate the role of circulating neutrophil subpopulations. Methods: We conducted a multicenter retrospective analysis of 524 patients with cancer and SARS-CoV-2 infection, assessing the relationship between clinical outcomes and circulating inflammatory biomarkers collected before and during COVID-19 infection. Additionally, a single-center prospective cohort study provided data for an exploratory analysis, assessing the immunophenotype of circulating neutrophils and inflammatory cytokines. The primary endpoints were 30-day mortality and the severity of COVID-19 disease. Results: Prior to COVID-19, 25% of patients with cancer exhibited elevated dNLR, which increased to 55% at the time of COVID-19 diagnosis. We developed the FLARE score, incorporating both tumor- and infection-induced inflammation, which categorized patients into four prognostic groups. The poor prognostic group had a 30-day mortality rate of 68%, significantly higher than the 23% in the favorable group (p < 0.0001). This score proved to be an independent predictor of early mortality. This prospective analysis revealed a shift towards immature forms of neutrophils and higher IL-6 levels in patients with cancer and severe COVID-19 infection. Conclusions: A pre-existing tumor-induced pro-inflammatory state significantly impacts COVID-19 outcomes in patients with cancer. The FLARE score, derived from circulating inflammatory markers, emerges as an easy-to-use, globally accessible, effective tool for clinicians to identify patients with cancer at heightened risk of severe COVID-19 complications and early mortality who might benefit most from immediate and intensive treatment strategies. Furthermore, our findings underscore the significance of immature neutrophils in the progression of COVID-19 in patients with cancer, advocating for further investigation into how these cells contribute to both cancer and COVID-19 disease.