Pooled analysis of first-line treatment with targeted agents in patients with chronic lymphocytic leukemia aged 80 years and older.

Patients aged 80 years and older make up a fifth of patients with CLL but are underrepresented in clinical trials. We analyzed the outcomes of these patients treated with targeted agents in the front-line setting in six trials of the German CLL Study Group. Targeted agents included venetoclax, ibrutinib, and idelalisib, mainly used in combination with anti-CD20 antibodies. Among 716 patients, 33 matched the selection criteria (5%). Of those, the majority had relevant comorbidity, organ dysfunctions, and/or high-/very high-risk disease. The overall response rate was 73%. The median progression-free survival was 49.2 months compared with those not reached in younger patients. There were 11 documented deaths of which two were deemed related to therapy. Additional results including 40 patients treated with BTK-inhibitors from the GCLLSG registry suggest that treatment with targeted agents is feasible and effective. Dedicated studies are warranted for this particular subgroup of patients.

Analysis of immune responses in CLL patients after heterologous COVID-19 vaccination

Patients with chronic lymphocytic leukemia (CLL) treated with B-cell pathway inhibitors and anti-CD20 antibodies exhibit low humoral response rates following SARS-CoV-2 vaccination. To investigate this observation, a prospective single-institution study was conducted comparing peripheral blood mononuclear cell transcriptional response with antibody and T cell response rates following heterologous BNT162b2/ChAdOx1 vaccination of 15 CLL/SLL patients. Two-dose antibody response rate was 40%, increasing to 53% after booster. Patients on Bruton tyrosine kinase inhibitor (BTKi), venetoclax ± anti-CD20 antibody within 12 months of vaccination, responded inferiorly to those under BTKi alone. The two-dose T cell response rate was 80%, increasing to 93% after booster. Key transcriptional findings were that interferon-mediated signaling activation including activation of the JAK-STAT pathway generally occurred within days of vaccination but was independent from the magnitude of the antibody response. Increasing counts of IGHV genes were associated with B-cell reconstitution and improved humoral response rate in the vaccinated patients. T cell responses in CLL patients appeared independent of treatment status while higher humoral response rate was associated with BTKi treatment and B-cell reconstitution. Boosting was particularly effective when intrinsic immune status was improved by CLL-treatment. Limitations included study of a relatively small cohort receiving different treatments and vaccination schedules.

Analysis of immune responses in patients with CLL after heterologous COVID-19 vaccination.

Patients with chronic lymphocytic leukemia (CLL) treated with B-cell pathway inhibitors and anti-CD20 antibodies exhibit low humoral response rates following SARS-CoV-2 vaccination. To investigate this observation, a prospective single-institution study was conducted comparing peripheral blood mononuclear cell transcriptional response with antibody and T-cell response rates following heterologous BNT162b2/ChAdOx1 vaccination of 15 patients with CLL/small lymphocytic lymphoma (SLL). Two-dose antibody response rate was 40%, increasing to 53% after booster. Patients on Bruton tyrosine kinase inhibitor (BTKi) and venetoclax ± anti-CD20 antibody within 12 months of vaccination responded inferiorly compared with those under BTKi alone. The 2-dose-T-cell response rate was 80%, which increased to 93% after the booster dose. Key transcriptional findings were that interferon-mediated signaling activation including activation of the JAK-STAT pathway generally occurred within days of vaccination, but was independent from the magnitude of the antibody response. Increasing counts of IGHV genes were associated with B-cell reconstitution and improved humoral response rate in the vaccinated patients. T-cell responses in patients with CLL appeared independent of treatment status, whereas higher humoral response rate was associated with BTKi treatment and B-cell reconstitution. Boosting was particularly effective when intrinsic immune status was improved by CLL treatment. Limitations included studying a relatively small cohort, with different treatments and vaccination schedules.

EASIX for Prediction of Outcome in Hospitalized SARS-CoV-2 Infected Patients.

BACKGROUND: The coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) and has evoked a pandemic that challenges public health-care systems worldwide. Endothelial cell dysfunction plays a key role in pathophysiology, and simple prognosticators may help to optimize allocation of limited resources. Endothelial activation and stress index (EASIX) is a validated predictor of endothelial complications and outcome after allogeneic stem cell transplantation. Aim of this study was to test if EASIX could predict life-threatening complications in patients with COVID-19. METHODS: SARS-CoV-2-positive, hospitalized patients were enrolled onto a prospective non-interventional register study (n=100). Biomarkers were assessed at hospital admission. Primary endpoint was severe course of disease (mechanical ventilation and/or death, V/D). Results were validated in 126 patients treated in two independent institutions. RESULTS: EASIX at admission was a strong predictor of severe course of the disease (odds ratio for a two-fold change 3.4, 95%CI 1.8-6.3, p<0.001), time to V/D (hazard ratio (HR) for a two-fold change 2.0, 95%CI 1.5-2.6, p<0.001) as well as survival (HR for a two-fold change 1.7, 95%CI 1.2-2.5, p=0.006). The effect was retained in multivariable analysis adjusting for age, gender, and comorbidities and could be validated in the independent cohort. At hospital admission EASIX correlated with increased suppressor of tumorigenicity-2, soluble thrombomodulin, angiopoietin-2, CXCL8, CXCL9 and interleukin-18, but not interferon-alpha. CONCLUSION: EASIX is a validated predictor of COVID19 outcome and an easy-to-access tool to segregate patients in need for intensive surveillance.

Immunogenicity and efficacy of the COVID-19 candidate vector vaccine MVA-SARS-2-S in preclinical vaccination.

Severe acute respiratory syndrome (SARS) coronavirus 2 (SARS-CoV-2) has emerged as the infectious agent causing the pandemic coronavirus disease 2019 (COVID-19) with dramatic consequences for global human health and economics. Previously, we reached clinical evaluation with our vector vaccine based on modified vaccinia virus Ankara (MVA) against the Middle East respiratory syndrome coronavirus (MERS-CoV), which causes an infection in humans similar to SARS and COVID-19. Here, we describe the construction and preclinical characterization of a recombinant MVA expressing full-length SARS-CoV-2 spike (S) protein (MVA-SARS-2-S). Genetic stability and growth characteristics of MVA-SARS-2-S, plus its robust expression of S protein as antigen, make it a suitable candidate vaccine for industrial-scale production. Vaccinated mice produced S-specific CD8+ T cells and serum antibodies binding to S protein that neutralized SARS-CoV-2. Prime-boost vaccination with MVA-SARS-2-S protected mice sensitized with a human ACE2-expressing adenovirus from SARS-CoV-2 infection. MVA-SARS-2-S is currently being investigated in a phase I clinical trial as aspirant for developing a safe and efficacious vaccine against COVID-19.

SARS-CoV-2 Proteome-Wide Analysis Revealed Significant Epitope Signatures in COVID-19 Patients.

The WHO declared the COVID-19 outbreak a public health emergency of international concern. The causative agent of this acute respiratory disease is a newly emerged coronavirus, named SARS-CoV-2, which originated in China in late 2019. Exposure to SARS-CoV-2 leads to multifaceted disease outcomes from asymptomatic infection to severe pneumonia, acute respiratory distress and potentially death. Understanding the host immune response is crucial for the development of interventional strategies. Humoral responses play an important role in defending viral infections and are therefore of particular interest. With the aim to resolve SARS-CoV-2-specific humoral immune responses at the epitope level, we screened clinically well-characterized sera from COVID-19 patients with mild and severe disease outcome using high-density peptide microarrays covering the entire proteome of SARS-CoV-2. Moreover, we determined the longevity of epitope-specific antibody responses in a longitudinal approach. Here we present IgG and IgA-specific epitope signatures from COVID-19 patients, which may serve as discriminating prognostic or predictive markers for disease outcome and/or could be relevant for intervention strategies.