Clonal hematopoiesis is associated with risk of severe Covid-19 (preprint)

Acquired somatic mutations in hematopoietic stem and progenitor cells (clonal hematopoiesis or CH) are associated with advanced age, increased risk of cardiovascular and malignant diseases, and decreased overall survival. These adverse sequelae may be mediated by altered inflammatory profiles observed in patients with CH. A pro-inflammatory immunologic profile is also associated with worse outcomes of certain infections, including SARS-CoV-2 and its associated disease Covid-19. Whether CH predisposes to severe Covid-19 or other infections is unknown. Among 515 individuals with Covid-19 from Memorial Sloan Kettering (MSK) and the Korean Clonal Hematopoiesis (KoCH) consortia, we found that CH was associated with severe Covid-19 outcomes (OR=1.9, 95%=1.2-2.9, p=0.01). We further explored the relationship between CH and risk of other infections in 14,211 solid tumor patients at MSK. CH was significantly associated with risk of Clostridium Difficile (HR=2.0, 95% CI: 1.2-3.3, p=6x10-3) and Streptococcus/Enterococcus infections (HR=1.5, 95% CI=1.1-2.1, p=5x10-3). These findings suggest a relationship between CH and risk of severe infections that warrants further investigation.

PI3K/mTOR and topoisomerase inhibitors with potential activity against SARS-CoV-2 infection (preprint)

There is an urgent need to identify therapies to prevent and treat SARS-CoV-2 infection. We performed a statistical evaluation of in vitro gene expression profiles reflecting exposure to 1,835 drugs, and found topoisomerase inhibitors and PI3K/mTOR pathway inhibitors among the strongest candidates for reduced expression of ACE2, a host gene associated with SARS-CoV-2 infection. Retrospective clinical data suggest that patients on these agents may be less likely to test positive for SARS-CoV-2.

The Effect of Neutropenia and Filgrastim (G-CSF) in Cancer Patients With COVID-19 Infection (preprint)

BackgroundNeutropenia is commonly encountered in cancer patients, and recombinant human granulocyte colony-stimulating factor (G-CSF, filgrastim) is widely given to oncology patients to counteract neutropenia and prevent infection. G-CSF is both a growth factor and cytokine that initiates proliferation and differentiation of mature granulocytes. However, the clinical impact of neutropenia and G-CSF use in cancer patients, who are also afflicted with coronavirus disease 2019 (COVID-19), remains unknown. MethodsAn observational cohort of 304 hospitalized patients with COVID-19 at Memorial Sloan Kettering Cancer Center was assembled to investigate links between concurrent neutropenia (N=55) and G-CSF administration (N=16) on COVID-19-associated respiratory failure and death. These factors were assessed as time-dependent predictors using an extended Cox model, controlling for age and underlying cancer diagnosis. To determine whether the degree of granulocyte response to G-CSF affected outcomes, a similar model was constructed with patients that received G-CSF, categorized into "high"- and "low"- response, based on the level of absolute neutrophil count (ANC) rise 24 hours after growth factor administration. ResultsNeutropenia (ANC < 1 K/mcL) during COVID-19 course was not independently associated with severe respiratory failure or death (HR: 0.71, 95% Cl: 0.34-1.50, P value: 0.367) in hospitalized COVID-19 patients. When controlling for neutropenia, G-CSF administration was associated with increased need for high oxygen supplementation and death (HR: 2.97, 95% CI: 1.06-8.28, P value: 0.038). 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: 5.18, 95% CI: 1.61-16.64, P value: 0.006). ConclusionPossible risks versus benefits of G-CSF administration should be weighed in neutropenic cancer patients with COVID-19 infection, as G-CSF may lead to worsening clinical and respiratory status in this setting.

Oncologic Immunomodulatory Agents in Patients with Cancer and COVID-19 (preprint)

Background Corticosteroids, anti-CD20 agents, immunotherapies, and cytotoxic chemotherapy are commonly used in the treatment of patients with cancer. How these agents impact patients with cancer who are infected with SARS-CoV-2 remains unclear. Methods We retrospectively investigated associations between SARS-CoV-2-associated respiratory failure or death with receipt of the aforementioned medications and with pre-COVID-19 neutropenia. The study included all cancer patients diagnosed with SARS-CoV-2 at Memorial Sloan Kettering Cancer Center until June 2, 2020 (N=820). We controlled for cancer-related characteristics known to predispose to worse COVID-19. To address that more acutely ill patients receive therapeutic corticosteroids, we examined patient subsets based on different levels of respiratory support: <=2 L/min supplemental oxygen, >2L/min supplemental oxygen, and advanced respiratory support prior to death. Results Corticosteroid administration was associated with worse outcomes in the pre-2L supplemental oxygen cohort; no statistically significant difference was observed in the >2L/min supplemental oxygen and post-critical cohorts. Interleukin-6 (IL-6) and C-reactive protein (CRP) levels were lower, and ferritin levels were higher, after corticosteroid administration. In patients with metastatic thoracic cancer, 9 of 25 (36%) and 10 of 31 (32%) had respiratory failure or death among those who did and did not receive immunotherapy, respectively. Seven of 23 (30%) and 52 of 187 (28%) patients with hematologic cancer had respiratory failure or death among those who did and did not receive anti-CD20 therapy, respectively. Chemotherapy itself was not associated with worse outcomes, but pre-COVID-19 neutropenia was associated with worse COVID-19 course. Relative prevalence of chemotherapy-associated neutropenia in previous studies may account for different conclusions regarding the risks of chemotherapy in patients with COVID-19. In the absence of prospective studies and evidence-based guidelines, our data may aid providers looking to assess the risks and benefits of these agents in caring for cancer patients in the COVID-19 era.