The Effect of Neutropenia and Filgrastim (G-CSF) on Cancer Patients With Coronavirus Disease 2019 (COVID-19) Infection.

BACKGROUND: Neutropenia is commonly encountered in cancer patients. Recombinant human granulocyte colony-stimulating factor (G-CSF, filgrastim), a cytokine that initiates proliferation and differentiation of mature granulocytes, is widely given to oncology patients to counteract neutropenia, reducing susceptibility to infection. However, the clinical impact of neutropenia and G-CSF use in cancer patients with coronavirus disease 2019 (COVID-19) remains unknown. METHODS: An observational cohort of 379 actively treated cancer patients with COVID-19 was assembled to investigate links between concurrent neutropenia and G-CSF administration on COVID-19-associated respiratory failure and death. These factors were encoded as time-dependent predictors in an extended Cox model, controlling for age and underlying cancer diagnosis. To determine whether the degree of granulocyte response to G-CSF affected outcomes, the degree of response to G-CSF, based on rise in absolute neutrophil count (ANC) 24 hours after growth factor administration, was also incorporated into a similar Cox model. RESULTS: In the setting of active COVID-19 infection, outpatient receipt of G-CSF led to an increased number of hospitalizations (hazard ratio [HR]: 3.54, 95% confidence interval [CI]: 1.25-10.0, P value: .017). Furthermore, among inpatients, G-CSF administration was associated with increased need for high levels of oxygen supplementation and death (HR: 3.56, 95% CI: 1.19-10.2, P value: .024). This effect was predominantly seen in patients that exhibited a high response to G-CSF based on their ANC increase post-G-CSF administration (HR: 7.78, 95% CI: 2.05-27.9, P value: .004). CONCLUSIONS: The potential risks versus benefits of G-CSF administration should be considered in neutropenic cancer patients with COVID-19, because G-CSF administration may lead to worsening clinical and respiratory status.

Outcomes of Patients with COVID-19 from a Specialized Cancer Care Emergency Room.

PURPOSE: Our goal was to identify discrete clinical characteristics associated with safe discharge from an emergency department/urgent care for patients with a history of cancer and concurrent COVID-19 infection during the SARS-CoV-2 pandemic and prior to widespread vaccination. PATIENTS AND METHODS: We retrospectively analyzed 255 adult patients with a history of cancer who presented to Memorial Sloan Kettering Cancer Center (MSKCC) urgent care center (UCC) from March 1, 2020 to May 31, 2020 with concurrent COVID-19 infection. We evaluated associations between patient characteristics and 30-day mortality from initial emergency department (ED) or urgent care center (UCC) visit and the absence of a severe event within 30 days. External validation was performed on a retrospective data from 29 patients followed at Fred Hutchinson Cancer Research Center that presented to the local emergency department. A late cohort of 108 additional patients at MSKCC from June 1, 2020 to January 31, 2021 was utilized for further validation. RESULTS: In the MSKCC cohort, 30-day mortality and severe event rate was 15% and 32% respectively. Using stepwise regression analysis, elevated BUN and glucose, anemia, and tachypnea were selected as the main predictors of 30-day mortality. Conversely, normal albumin, BUN, calcium, and glucose, neutrophil-lymphocyte ratio <3, lack of (severe) hypoxia, lack of bradycardia or tachypnea, and negative imaging were selected as the main predictors of an uneventful course as defined as a Lack Of a Severe Event within Thirty Days (LOSETD). Utilizing this information, we devised a tool to predict 30-day mortality and LOSETD which achieved an area under the operating curve (AUC) of 79% and 74% respectively. Similar estimates of AUC were obtained in an external validation cohort. A late cohort at MSKCC was consistent with the prior, albeit with a lower AUC. CONCLUSION: We identified easily obtainable variables that predict 30-day mortality and the absence of a severe event for patients with a history of cancer and concurrent COVID-19. This has been translated into a bedside tool that the clinician may utilize to assist disposition of this group of patients from the emergency department or urgent care setting.

Rates and mechanisms of bacterial mutagenesis from maximum-depth sequencing.

In 1943, Luria and Delbrück used a phage-resistance assay to establish spontaneous mutation as a driving force of microbial diversity. Mutation rates are still studied using such assays, but these can only be used to examine the small minority of mutations conferring survival in a particular condition. Newer approaches, such as long-term evolution followed by whole-genome sequencing, may be skewed by mutational 'hot' or 'cold' spots. Both approaches are affected by numerous caveats. Here we devise a method, maximum-depth sequencing (MDS), to detect extremely rare variants in a population of cells through error-corrected, high-throughput sequencing. We directly measure locus-specific mutation rates in Escherichia coli and show that they vary across the genome by at least an order of magnitude. Our data suggest that certain types of nucleotide misincorporation occur 10(4)-fold more frequently than the basal rate of mutations, but are repaired in vivo. Our data also suggest specific mechanisms of antibiotic-induced mutagenesis, including downregulation of mismatch repair via oxidative stress, transcription­replication conflicts, and, in the case of fluoroquinolones, direct damage to DNA.

Racial disparities in patients with coronavirus disease 2019 infection and gynecologic malignancy.

BACKGROUND: Mounting evidence suggests disproportionate coronavirus disease 2019 (COVID-19) hospitalizations and deaths because of racial disparities. The association of race in a cohort of gynecologic oncology patients with severe acute respiratory syndrome-coronavirus 2 infection is unknown. METHODS: Data were abstracted from gynecologic oncology patients with COVID-19 infection among 8 New York City area hospital systems. A multivariable mixed-effects logistic regression model accounting for county clustering was used to analyze COVID-19-related hospitalization and mortality. RESULTS: Of 193 patients who had gynecologic cancer and COVID-19, 67 (34.7%) were Black, and 126 (65.3%) were non-Black. Black patients were more likely to require hospitalization compared with non-Black patients (71.6% [48 of 67] vs 46.0% [58 of 126]; P = .001). Of 34 (17.6%) patients who died from COVID-19, 14 (41.2%) were Black. Among those who were hospitalized, compared with non-Black patients, Black patients were more likely to: have ≥3 comorbidities (81.1% [30 of 37] vs 59.2% [29 of 49]; P = .05), to reside in Brooklyn (81.0% [17 of 21] vs 44.4% [12 of 27]; P = .02), to live with family (69.4% [25 of 36] vs 41.6% [37 of 89]; P = .009), and to have public insurance (79.6% [39 of 49] vs 53.4% [39 of 73]; P = .006). In multivariable analysis, among patients aged <65 years, Black patients were more likely to require hospitalization compared with non-Black patients (odds ratio, 4.87; 95% CI, 1.82-12.99; P = .002). CONCLUSIONS: Although Black patients represented only one-third of patients with gynecologic cancer, they accounted for disproportionate rates of hospitalization (>45%) and death (>40%) because of COVID-19 infection; younger Black patients had a nearly 5-fold greater risk of hospitalization. Efforts to understand and improve these disparities in COVID-19 outcomes among Black patients are critical.

COVID-19 outcomes of patients with gynecologic cancer in New York City.

BACKGROUND: New York City (NYC) is the epicenter of severe acute respiratory syndrome coronavirus 2 (coronavirus disease 2019 [COVID-19]) in the United States. Clinical characteristics and outcomes of vulnerable populations, such as those with gynecologic cancer who develop COVID-19 infections, is limited. METHODS: Patients from 6 NYC-area hospital systems with known gynecologic cancer and a COVID-19 diagnosis were identified. Demographic and clinical outcome data were abstracted through a review of electronic medical records. RESULTS: Records for 121 patients with gynecologic cancer and COVID-19 were abstracted; the median age at the COVID-19 diagnosis was 64.0 years (interquartile range, 51.0-73.0 years). Sixty-six of the 121 patients (54.5%) required hospitalization; among the hospitalized patients, 45 (68.2%) required respiratory intervention, 20 (30.3%) were admitted to the intensive care unit, and 9 (13.6%) underwent invasive mechanical ventilation. Seventeen patients (14.0%) died of COVID-19 complications. No patient requiring mechanical ventilation survived. On multivariable analysis, hospitalization was associated with an age ≥64 years (risk ratio [RR], 1.73; 95% confidence interval [CI], 1.18-2.51), African American race (RR, 1.56; 95% CI, 1.13-2.15), and 3 or more comorbidities (RR, 1.43; 95% CI, 1.03-1.98). Only recent immunotherapy use (RR, 3.49; 95% CI, 1.08-11.27) was associated with death due to COVID-19 on multivariable analysis; chemotherapy treatment and recent major surgery were not predictive of COVID-19 severity or mortality. CONCLUSIONS: The case fatality rate among gynecologic oncology patients with a COVID-19 infection is 14.0%. Recent immunotherapy use is associated with an increased risk of mortality related to COVID-19 infection. LAY SUMMARY: The case fatality rate among gynecologic oncology patients with a coronavirus disease 2019 (COVID-19) infection is 14.0%; there is no association between cytotoxic chemotherapy and cancer-directed surgery and COVID-19 severity or death. As such, patients can be counseled regarding the safety of continued anticancer treatments during the pandemic. This is important because the ability to continue cancer therapies for cancer control and cure is critical.

Inflammatory markers in gynecologic oncology patients hospitalized with COVID-19 infection.

OBJECTIVE: Elevated inflammatory markers are predictive of COVID-19 infection severity and mortality. It is unclear if these markers are associated with severe infection in patients with cancer due to underlying tumor related inflammation. We sought to further understand the inflammatory response related to COVID-19 infection in patients with gynecologic cancer. METHODS: Patients with a history of gynecologic cancer hospitalized for COVID-19 infection with available laboratory data were identified. Admission laboratory values and clinical outcomes were abstracted from electronic medical records. Severe infection was defined as infection requiring ICU admission, mechanical ventilation, or resulting in death. RESULTS: 86 patients with gynecologic cancer were hospitalized with COVID-19 infection with a median age of 68.5 years (interquartile range (IQR), 59.0-74.8). Of the 86 patients, 29 (33.7%) patients required ICU admission and 25 (29.1%) patients died of COVID-19 complications. Fifty (58.1%) patients had active cancer and 36 (41.9%) were in remission. Patients with severe infection had significantly higher ferritin (median 1163.0 vs 624.0 ng/mL, p < 0.01), procalcitonin (median 0.8 vs 0.2 ng/mL, p < 0.01), and C-reactive protein (median 142.0 vs 62.3 mg/L, p = 0.02) levels compared to those with moderate infection. White blood cell count, lactate, and creatinine were also associated with severe infection. D-dimer levels were not significantly associated with severe infection (p = 0.20). CONCLUSIONS: The inflammatory markers ferritin, procalcitonin, and CRP were associated with COVID-19 severity in gynecologic cancer patients and may be used as prognostic markers at the time of admission.

Obesity shapes selection for driver mutations in cancer.

Obesity is a leading risk factor for cancer, but whether obesity is linked to specific genomic subtypes of cancer is unknown. Here, we examined the relationship between obesity and tumor genotype in two large clinicogenomic corpora. Obesity was associated with specific driver mutations in lung adenocarcinoma, endometrial carcinoma, and cancers of unknown primary, independent of clinical covariates and genetic ancestry. Obesity is therefore a putative driver of etiologic heterogeneity across cancers.

High-risk and silent clonal hematopoietic genotypes in patients with nonhematologic cancer.

ABSTRACT: Clonal hematopoiesis (CH) identified by somatic gene variants with variant allele fraction (VAF) ≥ 2% is associated with an increased risk of hematologic malignancy. However, CH defined by a broader set of genotypes and lower VAFs is ubiquitous in older individuals. To improve our understanding of the relationship between CH genotype and risk of hematologic malignancy, we analyzed data from 42 714 patients who underwent blood sequencing as a normal comparator for nonhematologic tumor testing using a large cancer-related gene panel. We cataloged hematologic malignancies in this cohort using natural language processing and manual curation of medical records. We found that some CH genotypes including JAK2, RUNX1, and XPO1 variants were associated with high hematologic malignancy risk. Chronic disease was predicted better than acute disease suggesting the influence of length bias. To better understand the implications of hematopoietic clonality independent of mutational function, we evaluated a set of silent synonymous and noncoding mutations. We found that silent CH, particularly when multiple variants were present or VAF was high, was associated with increased risk of hematologic malignancy. We tracked expansion of CH mutations in 26 hematologic malignancies sequenced with the same platform. JAK2 and TP53 VAF consistently expanded at disease onset, whereas DNMT3A and silent CH VAFs mostly decreased. These data inform the clinical and biological interpretation of CH in the context of nonhematologic cancer.

DNA liquid biopsy-based prediction of cancer-associated venous thromboembolism.

Cancer-associated venous thromboembolism (VTE) is a major source of oncologic cost, morbidity and mortality. Identifying high-risk patients for prophylactic anticoagulation is challenging and adds to clinician burden. Circulating tumor DNA (ctDNA) sequencing assays ('liquid biopsies') are widely implemented, but their utility for VTE prognostication is unknown. Here we analyzed three plasma sequencing cohorts: a pan-cancer discovery cohort of 4,141 patients with non-small cell lung cancer (NSCLC) or breast, pancreatic and other cancers; a prospective validation cohort consisting of 1,426 patients with the same cancer types; and an international generalizability cohort of 463 patients with advanced NSCLC. ctDNA detection was associated with VTE independent of clinical and radiographic features. A machine learning model trained on liquid biopsy data outperformed previous risk scores (discovery, validation and generalizability c-indices 0.74, 0.73 and 0.67, respectively, versus 0.57, 0.61 and 0.54 for the Khorana score). In real-world data, anticoagulation was associated with lower VTE rates if ctDNA was detected (n = 2,522, adjusted hazard ratio (HR) = 0.50, 95% confidence interval (CI): 0.30-0.81); ctDNA- patients (n = 1,619) did not benefit from anticoagulation (adjusted HR = 0.89, 95% CI: 0.40-2.0). These results provide preliminary evidence that liquid biopsies may improve VTE risk stratification in addition to clinical parameters. Interventional, randomized prospective studies are needed to confirm the clinical utility of liquid biopsies for guiding anticoagulation in patients with cancer.

Optimal systemic treatment and real-world clinical application of ctDNA in patients with metastatic HER2-mutant lung cancer.

INTRODUCTION: No definitive answers currently exist regarding optimal first-line therapy for HER2-mutant NSCLC. Access to rapid tissue sequencing is a major barrier to precision drug development in the first-line setting. ctDNA analysis has the potential to overcome these obstacles and guide treatment. METHODS: We retrospectively analyzed patients with metastatic HER2-mutant NSCLC who underwent prospective clinical ctDNA sequencing and received systemic therapy at Memorial Sloan Kettering Cancer Center (MSK) from January 2016 to September 2022. HER2 mutations were identified by next-generation sequencing through MSK-IMPACT, MSK-ACCESS or Resolution ctDx LungTM assay. Primary endpoints were time to the next treatment (TTNT) and overall survival (OS). RESULTS: Sixty-three patients were included in the primary analysis. Chemoimmunotherapy (33/63, 52.4 %) was the predominant first-line treatment with a median TTNT of 5.1 months (95 %CI 4.1 - 6.1) whereas 55.0 % (22/40) of patients who received second-line T-DXd obtained a median TTNT of 9.2 m (95 % CI, 0-22.2). Plasma ctDNA was tested before first-line therapy in 40 patients with a median OS of 28.0 months (95 % CI 21-34), in whom 31 patients (78.0 %) had detectable ctDNA. HER2 mutations were detected on ctDNA with a median turnaround time of 13 days, occasionally co-occurred with EGFR and MET alterations and were tracked longitudinally correlating with treatment response. Patients with detectable baseline ctDNA had significantly shorter OS (hazard ratio (HR), 5.25; 95 % CI, 1.2-23.9; p = 0.019). CONCLUSION: Chemoimmunotherapy remains a major treatment option for metastatic HER2-mutant NSCLC. ctDNA can rapidly detect HER2 and co-mutations, and it has the potential to guide and monitor optimal first-line therapy. As a negative prognostic biomarker, detectable ctDNA at baseline would need to be taken into account for patient selection in future studies.

Tumor sequencing of African ancestry reveals differences in clinically relevant alterations across common cancers.

Cancer genomes from patients with African (AFR) ancestry have been poorly studied in clinical research. We leverage two large genomic cohorts to investigate the relationship between genomic alterations and AFR ancestry in six common cancers. Cross-cancer type associations, such as an enrichment of MYC amplification with AFR ancestry in lung, breast, and prostate cancers, and depletion of BRAF alterations are observed in colorectal and pancreatic cancers. There are differences in actionable alterations, such as depletion of KRAS G12C and EGFR L858R, and enrichment of ROS1 fusion with AFR ancestry in lung cancers. Interestingly, in lung cancer, KRAS mutations are less common in both smokers and non-smokers with AFR ancestry, whereas the association of TP53 mutations with AFR ancestry is only seen in smokers, suggesting an ancestry-environment interaction that modifies driver rates. Our study highlights the need to increase representation of patients with AFR ancestry in drug development and biomarker discovery.

ctDNA-based detection of molecular residual disease in stage I-III non-small cell lung cancer patients treated with definitive radiotherapy.

Background: Sensitive and reliable biomarkers for early detection of recurrence are needed to improve post-definitive radiation risk stratification, disease management, and outcomes for patients with unresectable early-stage or locally advanced non-small cell lung cancer (NSCLC) who are treated with definitive radiation therapy (RT). This prospective, multistate single-center, cohort study investigated the association of circulating tumor DNA (ctDNA) status with recurrence in patients with unresectable stage I-III NSCLC who underwent definitive RT. Methods: A total of 70 serial plasma samples from 17 NSCLC patients were collected before, during, and after treatment. A personalized, tumor-informed ctDNA assay was used to track a set of up to 16 somatic, single nucleotide variants in the associated patient's plasma samples. Results: Pre-treatment ctDNA detection rate was 82% (14/17) and varied based on histology and stage. ctDNA was detected in 35% (6/17) of patients at the first post-RT timepoint (median of 1.66 months following the completion of RT), all of whom subsequently developed clinical progression. At this first post-RT time point, patients with ctDNA-positivity had significantly worse progression-free survival (PFS) [hazard ratio (HR): 24.2, p=0.004], and ctDNA-positivity was the only significant prognostic factor associated with PFS (HR: 13.4, p=0.02) in a multivariate analysis. All patients who developed clinical recurrence had detectable ctDNA with an average lead time over radiographic progression of 5.4 months, and post-RT ctDNA positivity was significantly associated with poor PFS (p<0.0001). Conclusion: Personalized, longitudinal ctDNA monitoring can detect recurrence early in patients with unresectable NSCLC patients undergoing curative radiation and potentially risk-stratify patients who might benefit most from treatment intensification.

The GENIE BPC NSCLC Cohort: A Real-World Repository Integrating Standardized Clinical and Genomic Data for 1,846 Patients with Non-Small Cell Lung Cancer.

PURPOSE: We describe the clinical and genomic landscape of the non-small cell lung cancer (NSCLC) cohort of the American Association for Cancer Research (AACR) Project Genomics Evidence Neoplasia Information Exchange (GENIE) Biopharma Collaborative (BPC). EXPERIMENTAL DESIGN: A total of 1,846 patients with NSCLC whose tumors were sequenced from 2014 to 2018 at four institutions participating in AACR GENIE were randomly chosen for curation using the PRISSMM data model. Progression-free survival (PFS) and overall survival (OS) were estimated for patients treated with standard therapies. RESULTS: In this cohort, 44% of tumors harbored a targetable oncogenic alteration, with EGFR (20%), KRAS G12C (13%), and oncogenic fusions (ALK, RET, and ROS1; 5%) as the most frequent. Median OS (mOS) on first-line platinum-based therapy without immunotherapy was 17.4 months [95% confidence interval (CI), 14.9-19.5 months]. For second-line therapies, mOS was 9.2 months (95% CI, 7.5-11.3 months) for immune checkpoint inhibitors (ICI) and 6.4 months (95% CI, 5.1-8.1 months) for docetaxel ± ramucirumab. In a subset of patients treated with ICI in the second-line or later setting, median RECIST PFS (2.5 months; 95% CI, 2.2-2.8) and median real-world PFS based on imaging reports (2.2 months; 95% CI, 1.7-2.6) were similar. In exploratory analysis of the impact of tumor mutational burden (TMB) on survival on ICI treatment in the second-line or higher setting, TMB z-score harmonized across gene panels was associated with improved OS (univariable HR, 0.85; P = 0.03; n = 247 patients). CONCLUSIONS: The GENIE BPC cohort provides comprehensive clinicogenomic data for patients with NSCLC, which can improve understanding of real-world patient outcomes.

ACT: aggregation and correlation toolbox for analyses of genome tracks.

UNLABELLED: We have implemented aggregation and correlation toolbox (ACT), an efficient, multifaceted toolbox for analyzing continuous signal and discrete region tracks from high-throughput genomic experiments, such as RNA-seq or ChIP-chip signal profiles from the ENCODE and modENCODE projects, or lists of single nucleotide polymorphisms from the 1000 genomes project. It is able to generate aggregate profiles of a given track around a set of specified anchor points, such as transcription start sites. It is also able to correlate related tracks and analyze them for saturation--i.e. how much of a certain feature is covered with each new succeeding experiment. The ACT site contains downloadable code in a variety of formats, interactive web servers (for use on small quantities of data), example datasets, documentation and a gallery of outputs. Here, we explain the components of the toolbox in more detail and apply them in various contexts. AVAILABILITY: ACT is available at http://act.gersteinlab.org CONTACT: pi@gersteinlab.org.

Overall survival with circulating tumor DNA-guided therapy in advanced non-small-cell lung cancer.

Circulating tumor DNA (ctDNA) sequencing guides therapy decisions but has been studied mostly in small cohorts without sufficient follow-up to determine its influence on overall survival. We prospectively followed an international cohort of 1,127 patients with non-small-cell lung cancer and ctDNA-guided therapy. ctDNA detection was associated with shorter survival (hazard ratio (HR), 2.05; 95% confidence interval (CI), 1.74-2.42; P < 0.001) independently of clinicopathologic features and metabolic tumor volume. Among the 722 (64%) patients with detectable ctDNA, 255 (23%) matched to targeted therapy by ctDNA sequencing had longer survival than those not treated with targeted therapy (HR, 0.63; 95% CI, 0.52-0.76; P < 0.001). Genomic alterations in ctDNA not detected by time-matched tissue sequencing were found in 25% of the patients. These ctDNA-only alterations disproportionately featured subclonal drivers of resistance, including RICTOR and PIK3CA alterations, and were associated with short survival. Minimally invasive ctDNA profiling can identify heterogeneous drivers not captured in tissue sequencing and expand community access to life-prolonging therapy.

Biodegradation of polyester polyurethane by endophytic fungi.

Bioremediation is an important approach to waste reduction that relies on biological processes to break down a variety of pollutants. This is made possible by the vast metabolic diversity of the microbial world. To explore this diversity for the breakdown of plastic, we screened several dozen endophytic fungi for their ability to degrade the synthetic polymer polyester polyurethane (PUR). Several organisms demonstrated the ability to efficiently degrade PUR in both solid and liquid suspensions. Particularly robust activity was observed among several isolates in the genus Pestalotiopsis, although it was not a universal feature of this genus. Two Pestalotiopsis microspora isolates were uniquely able to grow on PUR as the sole carbon source under both aerobic and anaerobic conditions. Molecular characterization of this activity suggests that a serine hydrolase is responsible for degradation of PUR. The broad distribution of activity observed and the unprecedented case of anaerobic growth using PUR as the sole carbon source suggest that endophytes are a promising source of biodiversity from which to screen for metabolic properties useful for bioremediation.

Association of Antineoplastic Therapy With Decreased SARS-CoV-2 Infection Rates in Patients With Cancer.

Importance: Novel therapies for SARS-CoV-2 infection are urgently needed. Antineoplastic compounds that target cellular machinery used by SARS-CoV-2 for entry and replication, including angiotensin-converting enzyme 2 (ACE2), may disrupt SARS-CoV-2 activity. Objectives: To determine whether patients with cancer treated with potential ACE2-lowering antineoplastic compounds exhibit lower SARS-CoV-2 infection rates. Design, Setting, and Participants: We used the Library of Integrated Network-Based Cellular Signatures database to identify antineoplastic compounds associated with decreased ACE2 gene expression across cell lines. We then evaluated a retrospective cohort of 1701 patients who were undergoing antineoplastic therapy at Memorial Sloan Kettering Cancer Center in New York, New York, during the COVID-19 pandemic to determine if treatment with an ACE2-lowering antineoplastic was associated with a decreased odds ratio (OR) of SARS-CoV-2 infection. Patients included in the analysis underwent active treatment for cancer and received a SARS-CoV-2 test between March 10 and May 28, 2020. Main Outcome and Measure: The association between potential ACE2-lowering antineoplastic treatment and a positive SARS-CoV-2 test. Results: In the cohort of 1701 patients, SARS-CoV-2 infection rates were determined for 949 (55.8%) female and 752 (44.2%) male patients (mean [SD] age, 63.1 [13.1] years) with diverse cancers receiving antineoplastic therapy. In silico analysis of gene expression signatures after drug treatment identified 91 compounds associated with downregulation of ACE2 across cell lines. Of the total cohort, 215 (12.6%) patients were treated with 8 of these compounds, including 3 mTOR/PI3K inhibitors and 2 antimetabolites. In a multivariable analysis of patients who received an ACE2-lowering antineoplastic adjusting for confounders, 15 of 215 (7.0%) patients had a positive SARS-CoV-2 test compared with 191 of 1486 (12.9%) patients who received other antineoplastic therapies (OR, 0.53; 95% CI, 0.29-0.88). Findings were confirmed in additional sensitivity analyses including cancer type, steroid use, and a propensity-matched subcohort. Gemcitabine treatment was associated with reduced SARS-CoV-2 infection (OR, 0.42; 95% CI, 0.17-0.87). Conclusions and Relevance: In this cohort study, in silico analysis of drug-associated gene expression signatures identified potential ACE2-lowering antineoplastic compounds, including mTOR/PI3K inhibitors and antimetabolites. Patients who received these compounds exhibited statistically significantly lower rates of SARS-CoV-2 infection compared with patients given other antineoplastics. Further evaluation of the biological and clinical anti-SARS-CoV-2 properties of identified antineoplastic compounds is warranted.

Neutropenia in adult acute myeloid leukemia patients represents a powerful risk factor for COVID-19 related mortality.

Patients with hematological malignancies are at risk for poor outcomes when diagnosed with coronavirus disease 2019 (COVID-19). It remains unclear whether cytopenias and specific leukemia subtypes play a role in the clinical course of COVID-19 infection. Here, we report outcomes and their clinical/laboratory predictors for 65 patients with acute and chronic leukemias diagnosed with COVID-19 between 8 March 2020 and 19 May 2020 at Memorial Sloan Kettering Cancer Center in New York City. Most patients had CLL (38%) or AML (26%). A total of 14 (22%) patients required high flow nasal cannula or were intubated for mechanical ventilation and 11 patients (17%) died. A diagnosis of AML (OR 4.7, p=.028), active treatment within the last 3 months (OR 5.22, p=.047), neutropenia within seven days prior and up to 28 days after SARS-CoV-2 diagnosis (11.75, p=.001) and ≥3 comorbidities (OR 6.55, p=.019) were associated with increased odds of death.