The FLARE score, circulating neutrophils, and association with COVID-19 outcomes in patients with solid tumors

Background: Inflammation and neutrophils play a central role in severe Covid-19 disease. In previous data, we showed that the FLARE score, combining both tumor and Covid-19-induced proinflammatory status (proinflamstatus), predicts early mortality in cancer patients (pts) with Covid-19 infection. We aimed to assess the impact of this score in a larger cohort and characterize the immunophenotype (IF) of circulating neutrophils. Methods: Multicenter retrospective cohort (RC) of pts with cancer and Covid-19 infection across 14 international centers. Circulating inflammatory markers were collected at two timepoints: baseline (-15 to -45d before Covid-19 diagnosis) and Covid-19 diagnosis. Tumor-induced proinflam-status was defined by high dNLR (neutrophils/(leucocytes-neutrophils)> 3) at baseline. Covid-19-induced proinflam-status was defined by +100% increase of dNLR between both timepoints. We built the FLARE score combining both Tumor and Infection-induced inflammation: T+/I+ (poor), if both proinflam-status;T+/I- (T-only), if inflammation only due to tumor;T-/I+ (I-only), if inflammation only due to Covid;T-/I- (favorable), if no proinflam-status. The IF of circulating neutrophils by flow cytometry was determined in a unicenter prospective cohort (PC) of pts with cancer during Covid-19 infection and in healthy volunteers (HV). Primary endpoint was 30-day mortality. Results: 524 pts were enrolled in the RC with a median follow- up of 84d (95%CI 78-90). Median age was 69 (range 35-98), 52% were male and 78% had baseline PS <1.Thoracic cancers were the most common (26%). 70% had active disease, 51% advanced stage and 57% were under systemic therapy. dNLR was high in 25% at baseline vs 55% at Covid-19 diagnosis. The median dNLR increase between both timepoints was +70% (IQR: 0-349%);42% had +100% increase of dNLR. Pts distribution and mortality across FLARE groups is resumed in the Table. Overall mortality rate was 26%. In multivariate analysis, including gender, stage and PS, the FLARE poor group was independently associated with 30-day mortality [OR 5.27;1.37-20.3]. 44 pts were enrolled in the PC. Median circulating neutrophils were higher in pts with cancer (n=10, 56.7% [IQR: 39-78.4%]) vs HV (n=6, 35.8% [IQR: 25.6-21%]), and particularly higher in pts with cancer and severe Covid-19 infection (n=7, 88.6% [IQR: 80.9-94%] (p=0.003). A more comprehensive characterization of the IF of circulating neutrophils, including Lox1/CD62/CD64, will be presented at ASCO. Conclusions: The FLARE score, combining tumor and Covid-19-induced proinflam-status, can identify the population at higher risk for mortality. A better characterization of circulating neutrophils may help improve the prediction of Covid-19 outcomes in pts with cancer. (Table Presented).

COVID-19 disease in patients with LUNG cancer in Spain: GRAVID LunG canceR pAtients coVid19 Disease (GRAVID STUDY)

Background: Patients with cancer may be more susceptible to infection and at increased risk of more severe COVID-19 disease;however, prognostic factors are not yet clearly identified. The LunG canceR pAtients coVid19 Disease (GRAVID) study aimed to describe clinical characteristics, outcomes, and predictors of poor outcome in patients with lung cancer and COVID-19. Methods: In this large nationwide study, we reviewed medical records of patients with lung cancer and confirmed COVID-19 diagnosis from 65 Spanish hospitals. Clinical features, treatments and disease outcomes were collected. The primary endpoint was to determine all-cause mortality;secondary endpoints were hospitalization and admission to intensive care units (ICU). Risk factors for poor prognosis were identified by univariate and multivariate logistic regression models. Results: Overall, 447 patients were included for analysis. Mean age was 67 1 ± 9 8 years;332 (74 3%) were men, and 383 (85 7%) current/former smokers. NSCLC was the most frequent type of cancer (377, 84 5%), consisting mainly of adenocarcinoma (228, 51 0%), and stage III metastatic or unresectable disease (354, 79 2%). Two-hundred and sixty-six (59 5%) patients were receiving anticancer treatment, mostly first-line chemotherapy. In total, 350 (78 3%) patients were hospitalized for a mean of 13 4 ± 11 4 days, nine (2 0%) patients were admitted to the ICU, and 146 (32 7%) died. Advanced disease and the use of corticosteroids to treat COVID-19 during hospitalization were predictors of mortality. Hospitalized, non-endof-life stage patients with lymphocytopenia and high LDH had an increased risk of death. Severity of COVID-19 correlated to higher mortality, ICU admission, and mechanical ventilation rates. Conclusions: Due to their underlying comorbidities and immunocompromised status, patients with lung cancer and COVID-19 show high hospitalization and mortality rates. These outcomes, alongside the identification of prognostic factors, may inform physicians on the risks and benefits in this population, in order to provide individualized oncological care.

A multicenter analysis of the outcome of cancer patients with neutropenia and COVID-19 infection optionally treated with granulocyte colony-stimulating factor (G-CSF)

Background: Infection by SARS-CoV-2 can turn into an acute respiratory infection. Approximately 15% of patients will develop a distress syndrome responsible in most cases of mortality. A host hyperinflammatory response induced by a cytokine storm, is the main cause of this severe complication. Chemotherapy myelosuppression is associated with higher risk of infections and mortality in cancer patients. There have been no previous reports about the clinical management of patients with neutropenia and concomitant COVID- 19. Herein, we present a multicenter experience in several hospitals during COVID-19 outbreak in neutropenic cancer patients infected by SARSCov- 2. Methods: Retrospective clinical data were collected from clinical reports. Protocol was approved by a Clinical Research Ethics Committee (HULP: PI-4194). Inclusion criteria were cancer patients with neutropenia (<1500 cells/mm3) and concomitant COVID-19 infection. Comorbidities, tumor type and stage, treatment, neutropenia severity, filgrastim (G-CSF), COVID-19 parameters and mortality were analyzed. Exploratory analysis included a description of all data collected and bivariate analyses among different pairs of variables, including their impact in mortality in this cohort. In addition, multivariable logistic regression was used to predict respiratory failure and death as a function of multiple variables. Results: Among 943 patients with cancer screened in 14 hospitals in Spain, eighty-three patients (8%) had a febrile neutropenia and COVID-19 infection. Lung (26%), breast (22%), colorectal (13%) and digestive noncolorectal (17%) cancers were the main locations and most patients had advanced disease (67%). Fifty-three (63%) of patients included died because respiratory failure. Neumonia was presented in 76% of patients, bilateral in 47% and 12% of all patients had thrombotic events. The median of neutrophils was 650cls/mm3 and 49% received GCSF with a median of days on treatment around 4,5 days. Among all variables related with mortality in neutropenic cancer patients with COVID-19 infection, we found that the number of days with GCSF showed a significant trend toward worse outcome and higher mortality. In particular, a logistic regression model was developed to predict respiratory failure, as a function of the number of days of G-CSF treatment. As adjusting covariates, sex, age, treatment purpose (palliative vs curative, to adjust for patient status), tumor type, and the lowest level of neutrophils in the patient (to adjust for neutropenic status) were used. A significant effect was obtained for the days of G-CSF treatment (OR = 1.4, 95% CI [1.03, 1.92], p-value = 0.01). Conclusions: Our findings suggest that a prolonged G-CSF treatment could be disadvantageous for these cancer patients with COVID-19, with a higher probability of worse outcome.

First results of the COCO study: COVID-19 outcomes in patients with cancer

Background: COVID-19 pandemic has drastically changed the management of patients with cancer;however, limited data exists regarding which pre-conditions affect the course of COVID-19 infection. Here, we sought to assess the clinical features and outcomes of COVID-19 infection in a large cohort of patients with cancer. Methods: We conducted a multicenter retrospective cohort study of patients with cancer diagnosed with SARS-CoV-2 infection by RT-PCR/Ag detection (n=274) or CT-scan (N=13) between 7/March and 30/April across 12 international centers. Clinical, pathological and biological data were collected. Primary endpoints were 30-day mortality rate and the rate of severe acute respiratory failure (SARF), defined by oxygen requirements >15 L/min. Descriptive statistics were used. Results: 287 patients were enrolled with a median follow-up of 23 days [95%CI 22-26]. Median age was 69 (range 35-98), 52% were male, 49% had hypertension and 23% had cardiovascular disease. As per cancer characteristics, 68% had active disease, 52% advanced stage and 79% had a baseline ECOG PS ≤1. Most frequent cancer-types were: 26% thoracic, 21% gastrointestinal, 19% breast and 15% genitourinary. Most patients (61%) were under systemic therapy, including chemotherapy (51%), endocrine therapy (23%) and immunotherapy (19%). At COVID-19 diagnosis, 44% of patients had moderate/severe symptoms such as fever (70%), cough (54%) and dyspnea (48%). The majority of patients (90%) required in-patient management and the median hospital stay duration was 10 days (range 1-52);8% of patients required intermediate or intensive care unit admission. Patients received treatment with: hydroxychloroquine (81%), azithromycin (61%), antiviral therapy (38%) and immunomodulatory drugs (14%). Finally, the overall mortality rate was 27% and the rate of SARF was 26%. In patients admitted to intermediate/intensive care units, the mortality and SARF rates were 45% and 73%, respectively. Mortality rate according to ECOG PS before COVID-19 was 20% in PS≤1 and 51% in PS>2 (p<0.0001). Conclusions: Patients with cancer are a susceptible population with a high likelihood of severe complications and high mortality from COVID-19 infection. Final results and treatment outcomes will be presented at the ESMO Congress. Legal entity responsible for the study: Aleix Prat. Funding: Has not received any funding. Disclosure: E. Auclin: Travel/Accommodation/Expenses: Mundipharma;Speaker Bureau/Expert testimony: Sanofi Genzymes. S. Pilotto: Speaker Bureau/Expert testimony: Astra-Zeneca;Eli-Lilly;BMS;Boehringer Ingelheim;MSD;Roche. L. Mezquita: Speaker Bureau/Expert testimony, Research grant/Funding (self), Travel/Accommodation/Expenses: Bristol-Myers Squibb;Speaker Bureau/Expert testimony: Tecnofarma;Speaker Bureau/Expert testimony, Non-remunerated activity/ies: AstraZeneca;Advisory/Consultancy, Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: Roche;Research grant/Funding (self): Boehringer Ingelheim. A. Prat: Honoraria (institution), Speaker Bureau/Expert testimony: Roche;Daiichi Sankyo;Honoraria (institution), Advisory/Consultancy, Speaker Bureau/Expert testimony: Pfizer;Novartis;Amgen;Speaker Bureau/Expert testimony: BMS;Advisory/Consultancy: Puma;Oncolytics Biotech;MSD;Honoraria (institution), Advisory/Consultancy: Lilly;Honoraria (institution), Speaker Bureau/Expert testimony: Nanostring technologies;Officer/Board of Directors: Breast International Group;Officer/Board of Directors: Solti's Foundation;Leadership role: Actitud Frente al Cancer Foundation;Honoraria (institution): Boehringer;Honoraria (institution): Sysmex Europa GmbH;Honoraria (institution): Medica Scientia inno. Research;Honoraria (institution): Celgene;Honoraria (institution): Astellas Pharma. All other authors have declared no conflicts of interest.

Change of circulating pro-inflammatory markers between pre-COVID-19 condition and COVID-19 diagnosis predicts early death in cancer patients: The FLARE score

Background: Inflammation plays a central role in severe COVID-19 disease. Likewise, in cancer patients (pts), a circulating pro-inflammatory status (proinflam-status) is associated with poor outcomes. We aimed to assess if a proinflam-status induced by cancer can negatively impact on COVID-19 outcomes. Methods: Multicenter retrospective cohort of cancer pts with SARS-CoV-2 infection across 12 international centers. Circulating inflammatory markers were collected at two timepoints: pre-COVID condition (-15 to -45d before COVID-19 diagnosis) and COVID-19 diagnosis. Tumor-induced proinflam-status was defined by high derived neutrophil to lymphocyte ratio (dNLR>3) at pre-COVID condition. COVID-induced proinflam-status was defined by +100% increase of dNLR between both timepoints. We built the FLARE score, combining both Tumor and Infection-induced inflammation: T+/I+ (poor), if both proinflam-status;T+/I- (T-only), if inflammation only due to tumor;T-/I+ (I-only), if inflammation only due to COVID;and T-/I- (favorable), if no inflam-status. Primary endpoint was 30-day mortality. Results: 287 pts were enrolled with a median follow-up of 23d [95%CI 22-26]. Median age was 69 (range 35-98), 52% were male and 49% had hypertension. As per cancer characteristics: 68% had active disease, 52% advanced stage and 79% had a baseline PS≤1. Thoracic cancers were the most common (26%) and 61% of pts were under systemic therapy. The dNLR was high in 24% at pre-COVID condition vs. 55% at COVID-19 diagnosis. Median change between both timepoints was +67% (IQR: 0% to +153%);40% had +100% increase of dNLR. Pts distribution across FLARE groups were: 5% in poor (n=9), 20% in T-only (n=39), 35% in I-only (n=69) and 40% in favorable (n=80). Overall mortality rate was 27%. According to FLARE score: 67% mortality for poor vs. 35% for I-only vs. 33% for T-only vs. 19% in favorable group (p=0.008). The FLARE poor group was independently associated with 30-day mortality [OR 5.7;1.02-31.2]. Conclusions: Both tumor and infection-induced proinflam-status impact on COVID-19 outcomes in cancer pts. The FLARE score, based on simple dynamics between two timepoints, allows to identify the population at higher risk for early death. Legal entity responsible for the study: Aleix Prat. Funding: Has not received any funding. Disclosure: E. Auclin: Travel/Accommodation/Expenses: Mundipharma;Speaker Bureau/Expert testimony: Sanofi Genzymes. S. Pilotto: Speaker Bureau/Expert testimony: AstraZeneca;Eli-Lilly;BMS;Boehringer Ingelheim;MSD;Roche. A. Prat: Honoraria (institution), Speaker Bureau/Expert testimony: Roche;Honoraria (institution), Advisory/Consultancy, Speaker Bureau/Expert testimony: Pfizer;Novartis;Amgen;Speaker Bureau/Expert testimony: BMS;Honoraria (institution), Speaker Bureau/Expert testimony: Daiichi Sankyo;Nanostring technologies;Advisory/Consultancy: Puma;Oncolytics Biotech;MSD;Honoraria (institution), Advisory/Consultancy: Lilly;Honoraria (institution): Boehringer;Sysmex Europa GmbH;Medica Scientia inno. Research;Celgene;Astellas Pharma;Officer/Board of Directors: Breast International Group;Solti's Foundation;Leadership role: Actitud Frente al Cancer Foundation. L. Mezquita: Speaker Bureau/Expert testimony, Research grant/Funding (self), Travel/Accommodation/Expenses: Bristol-Myers Squibb;Speaker Bureau/Expert testimony: Tecnofarma;Speaker Bureau/Expert testimony, Non-remunerated activity/ies: AstraZeneca;Advisory/Consultancy, Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: Roche;Research grant/Funding (self): Boehringer Ingelheim. All other authors have declared no conflicts of interest.