The Dysregulation of the Monocyte-Dendritic Cell Interplay Is Associated with In-Hospital Mortality in COVID-19 Pneumonia (preprint)

Background: The monocyte-phagocyte system (MPS), including monocytes/macrophages and dendritic cells (DCs), plays a key role in anti-viral immunity. We aimed to analyze the prognostic value of the MPS components on in-hospital mortality in a cohort of 58 patients (M/F ; mean ageSD years) with COVID-19 pneumonia and 22 age- and sex-matched healthy controls. Methods: We measured frequencies and absolute numbers of peripheral blood CD169+ monocytes, conventional CD1c+ and CD141+ (namely cDC2 and cDC1), and plasmacytoid CD303+ DCs by means of multi-parametric flow cytometry. A gene profile analysis of 770 immune-inflammatory related human genes and 20 SARS-CoV-2 genes was also performed. Results: Median frequencies and absolute counts of CD169-expressing monocytes were significantly higher in COVID-19 patients than in controls (p 0.04 and p 0.01, respectively). Conversely, percentages and absolute numbers of all DC subsets were markedly depleted in patients (p

Evaluation of the patients with hematologic malignancies and coronavirus disease 2019 (COVID-19): A single center retrospective study (preprint)

Introduction: One of the most important risk factor for COVID-19 infection is malignancy especially hematologic ones. Focusing on the clinical, radiological and laboratory characteristics of COVID-19 infected cancer patients remain largely important. Materials and Methods: In this retrospective study, we analyzed the data of 194 patients with hematologic malignancy and COVID-19 pneumonia. We categorized patients based on the type of the hematologic malignancy and phase of the treatment. All associated and important laboratory data including complete blood count, pro-inflammatory markers, and computerized tomography scan findings were reported to assess the risk factors associated mortality. Results: From January 2020 to March 2021, a total of 194 COVID-19 infected patients with hematologic malignancies were included in different phase of treatments. Median age was 44 (15-81) years. 135 of the cases were male and 59 of the cases were female. Acute myeloid leukemia was the most frequent cancer type (43.8%). A total of 119 patients had severe COVID-19 and 61 patients were admitted to intensive care unit. A total of 92 deaths occurred among all cases for an overall case fatality rate of 47%. Male gender (P=0.03), pre-induction and induction phase of the treatment (P<0.001), Intensive care unit admission (P<0.001), low level of oxygen saturation at the onset of COVID-19 disease (P<0.001) and high level of fibrinogen (P=0.002) were associated with COVID-19 mortality among patients with hematologic malignancies. Conclusion: The results of this study showed male gender, pre-induction and induction phase of the treatment, Intensive care admission, low levels of oxygen saturation at the onset of COVID-19 disease, RH positivity and higher fibrinogen level were associated with the risk of death. Identification of factors potentially associated with mortality for cancer patients are important in assessment strategy in these high risk group.

Incidence of symptomatic Covid-19 infections in patients with mastocytosis and chronic myeloid leukemia: A comparison with the general Austrian population.

BACKGROUND: The SARS-COV-2 (Covid-19) pandemic has impacted the management of patients with hematologic disorders. In some entities, an increased risk for Covid-19 infections was reported, whereas others including chronic myeloid leukemia (CML) had a lower mortality. We have analyzed the prevalence of Covid-19 infections in patients with mastocytosis during the Covid-19 pandemic in comparison to data from CML patients and the general Austrian population. MATERIALS AND METHODS: The prevalence of infections and PCR-proven Covid-19 infections was analyzed in 92 patients with mastocytosis. As controls, we used 113 patients with CML and the expected prevalence of Covid-19 in the general Austrian population. RESULTS: In 25% of the patients with mastocytosis (23/92) signs and symptoms of infection, including fever (n = 11), dry cough (n = 10), sore throat (n = 12), pneumonia (n = 1), and dyspnea (n = 3) were recorded. Two (8.7%) of these symptomatic patients had a PCR-proven Covid-19 infection. Thus, the prevalence of Covid-19 infections in mastocytosis was 2.2%. The number of comorbidities, subtype of mastocytosis, regular exercise, smoking habits, age, or duration of disease at the time of interview did not differ significantly between patients with and without Covid-19 infections. In the CML cohort, 23.9% (27/113) of patients reported signs and symptoms of infection (fever, n = 8; dry cough, n = 17; sore throat, n = 11; dyspnea, n = 5). Six (22.2%) of the symptomatic patients had a PCR-proven Covid-19 infection. The prevalence of Covid-19 in all CML patients was 5.3%. The observed number of Covid-19 infections neither in mastocytosis nor in CML patients differed significantly from the expected number of Covid-19 infections in the Austrian population. CONCLUSIONS: Our data show no significant difference in the prevalence of Covid-19 infections among patients with mastocytosis, CML, and the general Austrian population and thus, in mastocytosis, the risk of a Covid-19 infection was not increased compared to the general population.

A First in man study to Evaluate the Safety, Pharmacokinetics, and Pharmacodynamics of RP7214, a Dihydroorotate Dehydrogenase (DHODH) inhibitor in Healthy Subjects (preprint)

RP7214 is a potent and selective inhibitor of human mitochondrial enzyme dihydroorotate dehydrogenase (DHODH). This paper describes the results from a Phase 1 study that evaluated safety and pharmacokinetics of single and multiple ascending doses (SAD and MAD) and the food effect of RP7214 in healthy subjects. Target engagement of DHODH was also evaluated. A randomized, double-blind, placebo-controlled trial of single-dose (100, 200, and 400 mg QD) and multiple doses (200 and 400 mg BID for 7 days) followed by food effect at a single dose of 200 mg was conducted. A total of 18 healthy volunteers (HVs) (6 subjects in each of three cohorts) in the SAD part, 12 (6 subjects each in two cohorts) in the MAD part, and 12 in the food effect study were enrolled. RP7214 was well tolerated at all dose levels. None of the subjects reported any RP7214-related adverse events. RP7214 showed dose-proportional pharmacokinetics after single and multiple dosing. Steady-state concentrations were reached within about 3–6 days. The mean plasma half-life of RP724 at steady-state was approximately 13h. RP7214 showed accumulation on multiple dosing.. Food did not impact the absorption of RP7214. RP7214 showed dose-dependent inhibition of DHODH as measured by analyzing accumulating DHO levels, confirming target engagement. The rapid absorption and high systemic exposure of RP724 with a favorable safety profile shows the potential for the development of RP7214 in SARS-CoV-2 infection and acute myeloid leukemia. (NCT04680429). Keywords: RP7214, dihydroorotate dehydrogenase, SAD, MAD, HV

COVID-19-Associated Multisystem Inflammatory Syndrome with skin lesions after induction in AML pediatric patient: A case report (preprint)

Severe SARS-CoV-2 infections in pediatrics are rare and usually presented as multisystem inflammatory syndrome in children. There are few descriptions about pediatric oncology patients. We describe a case of 5-year-old male with acute myeloid leukemia. He presented febrile neutropenia with skin lesions and progressive clinical worsening. He had positive RT-PCR test for SARS-CoV-2 and criteria for MIS-C. He received methylprednisolone, immunoglobulin and granulocyte-colony-stimulating factor. Anti-interleukin 6 was administrated due to severe lung disease and refractory to treatment, presenting response and slow clinical recovery. Chemotherapy was restarted, he didn’t present relapse during treatment and has no sequelae of COVID-19.

COVID-19 Management and Outcome of 76 Pediatric Cancer Patients, a Single Centre Experience from Developing Country (preprint)

Background: Coronavirus disease 2019 (COVID-19) is a global pandemic with no enough data regarding its impact on pediatric cancer patients. Our main aim is to describe the clinical management and outcome of COVID-19 in this vulnerable group. Methods: This prospective study included 76 pediatric oncology patients with confirmed infection in the period between 1st of May and end of November, 2020 with at least two-month follow-up from recruitment. Remdesivir (RDV) was the antiviral therapy used. Findings: The median age of patients was 9 years. Sixty patients were on first line treatment. Haematological malignancies constituted 86.8% of patients. Severe to critical form of infection represent 35.4% of cases. The commonest presentation was fever (93.4%). Chemotherapy was delayed in 59.2% of cases and doses were modified in 30.2%. Most acute lymphoblastic leukemia/lymphoblastic lymphoma (88%) were in maintenance treatment phase while 55% of acute myeloid leukemia were in induction phase. Sixty days overall survival (OS) was 86.6% and mortalities occurred only in critically ill cases. Of the sixteen acute leukemia who were in first induction phase, 13 survived and 10 achieved induction remission. The commonest CT chest finding was ground glass opacities (74.2%). A negative PCR within 2 weeks and improvement of radiological findings were statistically related to disease severity (p=0.008and, 0.002 respectively).Better OS was associated with regression of radiological finding after 30 days from infection (p=0.002). Of the forty-five cases who received RDV, 70% were severe to critically ill cases, yet morality was comparable to NoRDV with no serious adverse events observed. Interpretation: COVID-19 in pediatric cancer patients has good clinical outcome except for critical form of infection at presentation. New oncologic cases tolerate induction therapy with good disease outcome. RDS was well tolerated with no OS difference compared to patients who did not receive the drug.Funding: The present work was funded by the Children’s Cancer Hospital Foundation and Association of Friends of the National Cancer-free Initiative (AFNCI)Declaration of Interest: All authors declare no competing financial interests.Ethical Approval: The approval of hospital ethical committee and family consents were obtained.

Treating Acute Leukemia During the COVID-19 Pandemic in an Environment With Limited Resources: A Multicenter Experience in Four Latin American Countries.

PURPOSE: The COVID-19 pandemic is a colossal challenge for global health; nonetheless, specific subgroups face considerably higher risks for infection and mortality. Among patients with malignant diseases, those with hematologic neoplasms are at a higher risk for poor outcomes. The objective of this study was to register treatment modifications associated with the COVID-19 pandemic and their short-term consequences in Latin America. METHODS: Multicenter, prospective, observational, cohort study including patients older than 14 years from 14 centers in four countries (Mexico, Peru, Guatemala, and Panama) who had a confirmed diagnosis of acute leukemia, and who were undergoing active treatment since the first COVID-19 case in each country until the cutoff on July 15, 2020. RESULTS: We recruited 635 patients. Treatment modifications because of the COVID-19 pandemic were reported in 40.8% of cases. The main reason for such modifications was logistic issues (55.0%) and the most frequent modification was chemotherapy delay (42.0%). A total of 13.1% patients developed COVID-19 disease, with a mortality of 37.7%. Several factors were identified as independently associated with mortality, including a diagnosis of acute myeloid leukemia (odds ratio 2.38 [95% CI, 1.47 to 3.84]; P < .001), while the use of telemedicine was identified as a protective factor (odds ratio 0.36 [95% CI, 0.18 to 0.82]; P = .014). CONCLUSION: These results highlight the collateral damage of COVID-19 in oncology patients.

Treatment of Acute Leukemia During COVID-19: Focused Review of Evidence.

The Coronavirus disease-2019 (COVID-19) pandemic is an unprecedented health care crisis and has led to over 1.5 million deaths worldwide. The risk of severe COVID-19 and mortality is markedly raised in patients with cancer, prompting several collaborative groups to issue guidelines to mitigate the risk of infection by delaying or de-escalating immunosuppressive therapy. However, delayed therapy is often not feasible for patients requiring treatment for acute leukemia or stem cell transplantation. We provide a focused review of the recommendations and evidence for managing this high-risk group of patients while minimizing the risk of COVID-19 infection, and provide a small snapshot of treatment data from our center.

Characteristics and mechanisms to control a COVID-19 outbreak on a leukemia and stem cell transplantation unit.

Immunosuppressed patients like patients with leukemia or lymphoma, but also patients after autologous or allogeneic stem cell transplantation are at particular risk for an infection with COVID-19. We describe a COVID-19 outbreak on our leukemia and stem cell transplantation unit (LSCT-Unit) originating from a patient with newly diagnosed acute myeloid leukemia. The patient was treated with intensive induction chemotherapy and we characterize the subsequent outbreak of COVID-19 on a LSCT-Unit. We describe the characteristics of the 36 contacts among the medical team, the results of their PCR and antibody tests and clinical aspects and features of infected employees. Of these 36 close contacts, 9 employees of the LSCT-Unit were infected and were tested positive by PCR and/or antibody-testing. 8/9 of them were symptomatic, 3/9 with severe, 5/9 with mild symptoms, and one person without symptoms. Due to stringent hygiene measures, the outbreak did not lead to infections of other patients despite ongoing clinical work. Moreover, we demonstrate that incubation period and clinical course of a COVID-19 infection in an immunosuppressed patient could be unusual compared to that of immunocompetent patients. Consistent PCR and antibody testing are helpful to understand, control, and prevent outbreaks. For the safety of health-care workers and patients alike, all employees wore FFP2 masks and were trained to adhere to several further safety guidelines. The implementation of rigorous hygiene measures is the key to controlling an outbreak and preventing infections of other patients.

Consensus transcriptional states describe human mononuclear phagocyte diversity in the lung across health and disease (preprint)

SUMMARY Monocytes, dendritic cells, and macrophages, commonly referred to as mononuclear phagocytes (MNPs), are innate immune cells capable of adopting diverse homeostatic and pathogenic phenotypes. Recent single-cell RNA-sequencing studies across many diseases in the lung have profiled this diversity transcriptionally, defining new cellular states and their association with disease. Despite these massive cellular profiling efforts, many studies have focused on defining myeloid dysfunction in specific diseases without identifying common pan-disease trends in the mononuclear phagocyte compartment within the lung. To address these gaps in our knowledge, we collate, process, and analyze 561,390 cellular transcriptomes from 12 studies of the human lung across multiple human diseases. We develop a computational framework to identify and compare dominant gene markers and gene expression programs and characterize MNP diversity in the lung, proposing a conserved dictionary of gene sets. Utilizing this reference, we efficiently identify disease-associated and rare MNP populations across multiple diseases and cohorts. Furthermore, we demonstrate the utility of this dictionary in characterizing a recently published dataset of bronchoalveolar lavage cells from COVID-19 patients and healthy controls which further reveal novel transcriptional shifts directly relatable to other diseases in the lung. These results underline conserved MNP transcriptional programs in lung disease, provide an immediate reference for characterizing the landscape of lung MNPs and establish a roadmap to dissecting MNP transcriptional complexity across tissues.

Effect of hydroxychloroquine on COVID-19 prevention in cancer patients undergoing treatment: A structured summary of a study protocol for a randomised controlled trial. (preprint)

This is a multi-center, two-arm, parallel-group, triple-blind, phase 2-3 randomised controlled trial. All patients over the age of 15 from 5 types of cancer, acute lymphoid and myeloid leukemias, non-Hodgkin's lymphoma, breast and colon cancer will enter the study. Patients are randomly assigned to two groups. During two months of treatment, the two groups are treated with either hydroxychloroquine or placebo. Patients will be monitored for COVID-19 symptoms. The primary end point of the study is to investigate the incidence of COVID-19 in patients.Randomisation will be performed using randomly permuted blocks. The allocation ratio in two groups is 1:1. Participants, caregivers, outcome assessor and the data analyst are blinded to group assignment.The calculated total sample size is 60 patients, with 30 patients in each group. The trial began on April 14, 2020 and recruitment is ongoing. Recruitment is anticipated to be completed by June 14, 2020. This trial has been registered on the Iranian Registry of Clinical Trials (IRCT) with the registration number of IRCT20200405046958N1.

Identification of Human Immune Cell Subtypes Most Vulnerable to IL-1β-induced Inflammatory Signaling Using Mass Cytometry (preprint)

ABSTRACT IL-1β has emerged as a key mediator of the cytokine storm linked to high morbidity and mortality from COVID-19 and blockade of the IL-1 receptor (IL-1R) with Anakinra has entered clinical trials in COVID-19 subjects. Yet, knowledge of the specific immune cell subsets targeted by IL-1β and IL-1β-induced signaling pathways in humans is limited. Utilizing mass cytometry (CyTOF) of human peripheral blood mononuclear cells, we identified effector memory CD4 T cells and CD4 − CD8 low/- CD161 + T cells as the circulating immune subtypes with the greatest expression of p-NF-κB in response to IL-1β stimulation. Notably, CCR6 distinctly identified T cells most responsive to IL-1β. Other subsets including CD11c myeloid dendritic cells (mDCs), classical monocytes (CM), two subsets of natural killer cells (CD16 − CD56 bright CD161 − and CD16 − CD56 dim CD161 + ) and a population of lineage − (Lin-) cells expressing CD161 and CD25 also showed IL-1β-induced expression of p-NF-kB. The IL-1R antagonist, Anakinra significantly inhibited IL-1β-induced p-NF-kB in the CCR6 + T cells and CD11c mDCs with a trending inhibition in CD14 monocytes and Lin − CD161 + CD25 + cells. IL-1β also induced a rapid but much less robust increase in p-p38 expression as compared to p-NF-kB in the majority of these same immune cell subsets. Prolonged IL-1β stimulation greatly increased p-STAT3 and to a much lesser extent p-STAT1 and p-STAT5 in T cell subsets, monocytes, DCs and the Lin − CD161 + CD25 + cells suggesting IL-1β-induced production of downstream STAT-activating cytokines, consistent with its role in cytokine storm. Interindividual heterogeneity and inhibition of this activation by Anakinra raises the intriguing possibility that assays to measure IL-1β-induced p-NF-kB in CCR6 + T cell subtypes could identify those at higher risk of cytokine storm and those most likely to benefit from Anakinra therapy.