The acute phase response identifies cancer patients with adverse outcomes from SARS-CoV-2 infection as quantified by the OnCovid Inflammatory Score

We sought to determine parameters of the acute phase response, a feature of innate immunity activated by infectious noxae and cancer, deranged by Covid-19 and establish oncological indices' prognostic potential for patients with concomitant cancer and Covid-19. Between 27/02 and 23/06/2020, OnCovid retrospectively accrued 1,318 consecutive referrals of patients with cancer and Covid-19 aged 18 from the U.K., Spain, Italy, Belgium, and Germany. Patients with myeloma, leukemia, or insufficient data were excluded. The neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR), prognostic nutritional index (PNI), modified Glasgow prognostic score (mGPS), and prognostic index (PI) were evaluated for their prognostic potential, with the NLR, PLR, and PNI risk stratifications dichotomized around median values and the pre-established risk categorizations from literature utilized for the mGPS and PI. 1,071 eligible patients were randomly assorted into a training set (TS, n=529) and validation set (VS, n=542) matched for age (67.9±13.3 TS, 68.5±13.5 VS), presence of 1 comorbidity (52.1% TS, 49.8% VS), development of 1 Covid-19 complication (27% TS, 25.9% VS), and active malignancy at Covid-19 diagnosis (66.7% TS, 61.6% VS). Among all 1,071 patients, deceased patients tended to categorize into poor risk groups for the NLR, PNI, mGPS, and PI (P<0.0001) with a return to pre-Covid-19 diagnosis NLR, PNI, and mGPS categorizations following recovery (P<0.01). In the TS, higher mortality rates were associated with NLR>6 (44.6% vs 28%, P<0.0001), PNI<40 (46.6% vs 20.9%, P<0.0001), mGPS (50.6% for mGPS2 vs 30.4% and 11.4% for mGPS1 and 0, P<0.0001), and PI (50% for PI2 vs 40% for PI1 and 9.1% for PI0, P<0.0001). Findings were confirmed in the VS (P<0.001 for all comparisons). Patients in poor risk categories had shorter median overall survival [OS], (NLR>6 30 days 95%CI 1-63, PNI<40 23 days 95%CI 10-35, mGPS2 20 days 95%CI 8-32, PI2 23 days 95%CI 1-56) compared to patients in good risk categories, for whom median OS was not reached (P<0.001 for all comparisons). The PLR was not associated with survival. Analyses of survival in the VS confirmed the NLR (P<0.0001), PNI (P<0.0001), PI (P<0.01), and mGPS (P<0.001) as predictors of survival. In a multivariable Cox regression model including all inflammatory indices and pre-established prognostic factors for severe Covid-19 including sex, age, comorbid burden, malignancy status, and receipt of anti-cancer therapy at Covid-19 diagnosis, the PNI was the only factor to emerge with a significant hazard ratio [HR] in both TS and VS analysis (TS HR 1.97, 95%CI 1.19-3.26, P=0.008;VS HR 2.48, 95%CI 1.47- 4.20, P=0.001). We conclude that systemic inflammation drives mortality from Covid-19 through hypoalbuminemia and lymphocytopenia as measured by the PNI and propose the PNI as the OnCovid Inflammatory Score (OIS) in this context.

Prevalence and impact of COVID-19 sequelae on treatment pathways and survival of cancer patients who recovered from SARS-CoV-2 infection

Background: The long-term impact of COVID-19 in cancer patients (pts) is undefined. Methods: Among 2795 consecutive pts with COVID-19 and cancer registered to OnCovid between 01/2020 and 02/2021, we examined clinical outcomes of pts reassessed post COVID-19 recovery. Results: Among 1557 COVID-19 survivors, 234 (15%) reported sequelae including respiratory symptoms (49.6%), fatigue (41%) and cognitive/psychological dysfunction (4.3%). Persisting COVID-19 sequelae were more likely found in males (p=0.0407) aged ≥65 years (p=0.0489) with ≥2 comorbidities (p=0.0006) and positive smoking history (p=0.0004). Sequelae were associated with history of prior hospitalisation (p<0.0001), complicated disease (p<0.0001) and COVID-19 therapy (p=0.0002). With a median post-COVID-19 follow up of 128 days (95%CI 113-148), multivariable analysis of survival revealed COVID-19 sequelae to be associated with an increased risk of death (HR 1.76, 95%CI 1.16-2.66) after adjusting for sex, age, comorbidities, tumour characteristics, anticancer therapy and COVID-19 severity. Out of 473 patients who were on systemic anticancer therapy (SACT) at COVID-19 diagnosis;62 (13.1%) permanently discontinued therapy and 75 (15.8%) received SACT adjustments, respectively. Discontinuations were due to worsening performance status (45.1%), disease progression (16.1%) and residual organ disfunction (6.3%). SACT adjustments were pursued to avoid hospital attendance (40%), prevent immunosuppression (57.3%) or adverse events (20.3%). Multivariable analyses showed permanent discontinuation to be associated with an increased risk of death (HR 4.2, 95%CI: 1.62-10.7), whereas SACT adjustments did not adversely affect survival. Conclusions: Sequelae post-COVID-19 affect up to 15% of patients with cancer and adversely influence survival and oncological outcomes after recovery. SACT adjustments can be safely pursued to preserve oncological outcomes in patients who remain eligible to treatment. Clinical trial identification: NCT04393974. Legal entity responsible for the study: Imperial College London. Funding: Has not received any funding. Disclosure: A. Cortellini: Financial Interests, Personal, Advisory Board: MSD;Financial Interests, Personal, Advisory Board: BMS;Financial Interests, Personal, Advisory Board: Roche;Financial Interests, Personal, Invited Speaker: Novartis;Financial Interests, Personal, Invited Speaker: AstraZeneca;Financial Interests, Personal, Invited Speaker: Astellas;Financial Interests, Personal, Advisory Board: Sun Pharma. D.J. Pinato: Financial Interests, Personal, Advisory Board: ViiV Healthcare;Financial Interests, Personal, Invited Speaker: Bayer;Financial Interests, Personal, Advisory Board: Eisai;Financial Interests, Personal, Invited Speaker: Roche;Financial Interests, Personal, Invited Speaker: AstraZeneca. All other authors have declared no conflicts of interest.

Clinical portrait of the SARS-CoV-2 epidemic in European cancer patients

Background: There is uncertainty as to the contribution of cancer patients' features on severity and mortality from Covid-19 and little guidance as to the role of anti-cancer and anti-Covid-19 therapy in this population. Method(s): OnCovid is a retrospective observational study conducted across 19 European centers that recruited cancer patients aged >18 and diagnosed with Covid-19 between 26/02 and 01/04/2020. Uni- and multivariable regression models were used to evaluate predictors of Covid-19 severity and mortality. Result(s): We identified 890 patients from UK (n=218, 24%), Italy (n=343, 37%), Spain (n=323, 36%) and Germany (n=6, 1%). Most patients were male (n=503, 56%) had a diagnosis of solid malignancy (n=753, 84%) and 556 (62%) had active disease. Mean (+/-SD) patient age was 68+/-13 years, and 670 (75%) had >1 co-morbidity, most commonly hypertension (n=386, 43%). Commonest presenting symptoms were fever (n=569, 63%) and cough (n=448, 50%), beginning 6.3 (+/-9.5 SD) days before diagnosis. Most patients (n=565, 63%) had >1 complication from Covid-19, including respiratory failure (n=527, 59%) and acute respiratory distress syndrome (n=127, 22%). In total, 110 patients (14%) were escalated to high-dependency or intensive care. At time of analysis, 299 patients had died (33%). Multi-variate logistic regression identified male gender, age>65 (p<0.0001) presence of >2 comorbidities (p=0.001) active malignancy (p=0.07) as predictors of complicated Covid-19. Mortality was associated with active malignancy (p<0.0001), age>65 and co-morbid burden (p=0.002). Provision of chemotherapy, targeted therapy or immunotherapy was not associated with higher mortality. Exposure to anti-malarials alone (chloroquine/hydroxychloroquine, n=182, p<0.001) or in combination with anti-virals (n=195, p<0.001) or tocilizumab (n=51, p=0.004) was associated with improved mortality compared to patients who did not receive any of these therapies (n=446) independent of patients' gender, age, tumour stage and severity of Covid-19. Conclusion(s): This study highlights the clinical utility of demographic factors for individualized risk-stratification of patients and supports further research into emerging anti Covid-19 therapeutics in SARS-Cov-2 infected cancer patients. Clinical trial identification: NCT04393974. Legal entity responsible for the study: Imperial College London. Funding(s): Has not received any funding. Disclosure: D.J. Pinato: Speaker Bureau/Expert testimony: ViiV Healthcare;Advisory/Consultancy, Travel/Accommodation/Expenses: Bayer;Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution), Travel/Accommodation/Expenses: BMS;Honoraria (self), Advisory/Consultancy: MiNa Therapeutics;Advisory/Consultancy: Eisai;Advisory/Consultancy, Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: Roche;Advisory/Consultancy: AstraZeneca;Research grant/Funding (institution): MSD. All other authors have declared no conflicts of interest.Copyright © 2020 European Society for Medical Oncology

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.

Active smoking and severity of COVID-19 infection in cancer patients

Background: Smoking is the leading cause of cancer worldwide. Active smoking alters the inflammatory environment of the respiratory epithelium, increasing the production of potent pro-inflammatory cytokines that promote the recruitment of macrophages and neutrophils, leading to lung damage. We hypothesize that smoking-induced inflammation can impact on COVID-19 infection severity and mortality related to the proinflammatory cascade. Methods: Multicenter retrospective cohort of cancer patients (pts) with COVID-19 infection diagnosed by PCR/Ag detection (n=274) and CT-scan (N=13) in Mar-Apr/20r in 12 centers. Clinical and biological data were collected. Smoker was defined as active tobacco consumption and heavy smoker as >30 pack-year (PY). Primary endpoints were 30-day mortality rate and the rate of severe acute respiratory failure (SARF), defined by oxygen requirements >15 L/min. Results: A total of 287 pts were enrolled: 25 (9%) were active smokers, 127 (47%) were former and 116 (43%) never smoker. Among active smokers: 73% were heavy smokers, median age was 62y, 60% were male and median body mass index was 22. Regarding their comorbidities: 25% had hypertension, 8% cardiovascular disease, 28% chronic obstructive pulmonary disease and 24% diabetes. Thoracic tumors were the most common (52%), 72% had advanced disease and 56% were under systemic therapy. 92% of active smokers required hospitalization, 68% developed pneumonia and 58% required oxygen. Only 4% were escalated to the intensive care unit. Active smokers received treatment with hydroxychloroquine (91%), azithromycin (61%), antiviral therapy (33%) and steroids (29%). Only 4% received immunomodulatory drugs. SARF was the most common complication (25%) and no thromboembolic events were observed. A pro-inflammatory status was observed at COVID-19 diagnosis in active smokers, e.g. median of absolute neutrophil count was 6.35 (vs. 5.4), mean ferritin was 1269 (vs. 991) and D-Dimer was 2422 (vs. 1816);but with no significant differences. Overall mortality rate was 27%. Mortality rate was higher in active smokers (40% vs. 24% in non-smokers;p=0.08). Conclusions: Active smoking might be associated with severe COVID-19 infection and early death in cancer patients. Smoking induced-inflammation should be further explored. Legal entity responsible for the study: Aleix Prat. Funding: Has not received any funding. Disclosure: E. Auclin: Travel/Accommodation/Expenses: Mundifarma;Speaker Bureau/Expert testimony: Sanofi Genzime. S. Pilotto: Speaker Bureau/Expert testimony: Astra-Zeneca;Speaker Bureau/Expert testimony: Boehringer Ingelheim;Speaker Bureau/Expert testimony: Eli-Lilly;Speaker Bureau/Expert testimony: BMS. A. Prat: Honoraria (institution), Speaker Bureau/Expert testimony: Roche;Advisory/Consultancy, Speaker Bureau/Expert testimony: Pfizer;Honoraria (institution), Advisory/Consultancy, Speaker Bureau/Expert testimony: Novartis;Amgen;Speaker Bureau/Expert testimony: BMS;Honoraria (institution), Speaker Bureau/Expert testimony: Daiichi Sankyo;Nanostring;Advisory/Consultancy: Puma;Oncolytics Biotech;MSD;Honoraria (institution), Advisory/Consultancy: Lilly;Boehringer;Sysmex Europa GmbH;Medican Scientia inno. Research;Celgene;Astellas;Officer/Board of Directors: Breast International Group;Solti's Foundation;Actitud frente al cancer foundation. L. Mezquita: Speaker Bureau/Expert testimony, Research grant/Funding (self), Travel/Accommodation/Expenses: Bristol-Meyers Squibb;Speaker Bureau/Expert testimony: Tecnofarma;Honoraria (institution), Speaker Bureau/Expert testimony: Astrazeneca;Advisory/Consultancy, Speaker Bureau/Expert testimony: Roche;Research grant/Funding (self): Boehringer Intelligence. All other authors have declared no conflicts of interest.

Influence of recent administration and type of oncological treatment (T) in survival of oncological patients (p) with COVID-19: Experience of Vall d'Hebron University Hospital

Background: SARS-CoV-2 outbreak has impacted on the management of oncological p, leading to treatment delays in a considerable number of cases. The aim of this study was to evaluate if oncological T affected negatively COVID-19 outcome. Methods: We retrospectively analyzed clinical data from p with solid tumors under active systemic T (received in the last 6 months) that were diagnosed with SARS-CoV-2 infection (defined as positive PCR) between March and 11th May 2020 in our center. Study endpoint was death due to COVID-19. We divided the patients in two groups;those who had received treatment in the last 4 weeks and those who had not. Descriptive and univariate analysis were performed to detect the effect of T type and other variables on COVID-19 related mortality. Results: A total of 70 p were included with a median follow-up of 28 days (10-47) and active oncological T had been administered in the past 4 weeks to 44 p. Median age was 66 (IQR 56-74), 23 p (52.27%) were female and 41 (93.2%) had a baseline ECOG≤1. The most frequent primary site was lung tumor (12 p [27.3%]), followed by breast (11 p [25%]) and gastrointestinal (5 p [11.4%]). Thirty-one p (70.5%) had metastatic disease and 13 (29.5%) were included in clinical trials. Twenty-four p (54.5%) received chemotherapy (CT), 14 (31.8%) targeted therapies, 9 (20.4%) immunotherapy (IT), 5 (11.4%) radiotherapy and 6 (13.6%) hormonotherapy. A total of 13 p (29.5%) received different combinations of oncological T. Death due to COVID-19 occurred in 5/22 (22.7%) p receiving CT and 6/21 (28.5%) p in the non-CT (p>0.05). Only 1/9 (11.1%) p treated with IT died compared to 11/35 (31.4%) p in the rest of the cohort (p>0.05). Age>71, comorbidities such as chronic obstructive pulmonary disease and ECOG status>2 were associated to a higher mortality. The distribution of these variables between the anticancer T groups was not different. Conclusions: Our results suggest that CT and other anticancer T might not worsen COVID-19 related mortality;nevertheless, the number of patients was small. and decision making has to be individualized. Our findings may warrant further investigation in larger studies. Legal entity responsible for the study: The authors. Funding: Has not received any funding. Disclosure: E. Felip: Advisory/Consultancy, Speaker Bureau/Expert testimony: AbbVie;AstraZeneca;Blueprint medicines;Boehringer Ingelheim;Bristol-Myers Squibb;Celgene;Eli Lilly;Guardant Health;Janssen;Medscape;Merck KGaA;Novartis;Pfizer;Roche;Takeda;Touchtime;Research grant/Funding (self), Research grant/Funding (institution): Fundación Merck Salud;Oncology Innovation EMD Serono. J. Carles: Advisory/Consultancy, Speaker Bureau/Expert testimony: Johnson & Johnson;Bayer;Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (self): Astellas Pharma;Advisory/Consultancy: Pfizer;Sanofi;MSD Oncology;Advisory/Consultancy, Research grant/Funding (self): Roche;Advisory/Consultancy, Research grant/Funding (self), Travel/Accommodation/Expenses: AstraZéneca;Speaker Bureau/Expert testimony: Asofarma;Research grant/Funding (self), Travel/Accommodation/Expenses: BMS;ravel/Accommodation/Expenses: Ipsen;Roche;Research grant/Funding (self): AB Science;Aragon Pharmaceuticals;Pharmaceuticals;INC;Blueprint Medicines Corporation;N Immunotherapeutics INC;Boehringer Ingelheim España, S.A.;Clovis Oncology;Cougar Biotechnology INC;Deciphera Pharmaceuticals LLC;Exelixis INC;F. Hoffmann-La Roche LTD;Genentech INC;Glaxosmithkline;Incyte Corporation;Janssen-Cilag International NV;Karyopharm Therapeutics INC;Laboratoires Leurquin Mediolanum SAS. J. Tabernero: Honoraria (self): Array Biopharma;AstraZeneca;Bayer;BeiGene;Boehringer Ingelheim;Chugai;Genentech;Genmab A/S;Halozyme;Imugene Limited;Inflection Biosciences Limited;Ipsen;Kura Oncology;Lilly;MSD;Merck Serono;Menarini;Merrimack;Merus;Molecular Partners;Novartis;Peptomyc;Pfizer;Pharmacyclics;ProteoDesign SL;Rafael Pharmaceuticals;F. Hoffmann-La Roche Ltd;): Sanofi;eaGen;Seattle Genetics, Servier, Symphogen, Taiho, VCN Biosciences, Biocartis, Foundation Medicine, HalioDX SAS and Roche Diagnostics. All other authors have declared no conflicts of interest.