ABSTRACT
Coronavirus disease 2019 (COVID-19) infection results in high rates of both acute and long-term mortality patients with hematologic malignancies, but the immunologic mechanisms underlying poor outcomes in this population remain poorly understood. In this presentation, we discuss how immune dysregulation, resulting from either underlying hematologic malignancy or immune-directed therapies, affects COVID-19 morbidity and mortality. First, we evaluated both clinical and immunological parameters of hospitalized cancer patients with COVID-19 infection. To our surprise, neither receipt of anti-CD20 therapy nor diminished B-cell counts were predictive of mortality in this population;however total CD8+ T-cell counts and lack of functional T-cell responses to COVID-19- derived antigens were strongly predictive of mortality. These results indicate that T-cell immunity is the dominant predictor of COVID-19-infected hematologic malignancy patients, and that loss of Bcell immunity is not associated with increased mortality so long as T-cell immunity is sufficient. In addition to short-term mortality, persistent and/or recurrent COVID-19 infection has been exclusively described in hematologic malignancy patients, but the primary drivers of persistent infection are not well understood. We identified patients with B-cell lymphomas as having a particularly high risk for persistent SARS-CoV-2 positivity. Subsequent analysis of patients with lymphoid malignancies and COVID-19 identified discrete risk factors for severity of primary infection as compared to disease chronicity. Active therapy and diminished T-cell counts were key drivers of acute mortality in lymphoma patients with COVID-19 infection. Conversely, B-cell depleting therapy was the primary driver of re-hospitalization for COVID-19. In patients with persistent SARS-CoV-2 positivity, we observed high levels of viral entropy consistent with intrahost viral evolution, particularly in patients with impaired CD8+ T-cell immunity. These results suggest that persistent COVID-19 infection is likely to remain a risk in patients with impaired adaptive immunity and that additional therapeutic strategies are needed to enable viral clearance in this high-risk population. Finally, we discuss disease and therapy-specific predictors of humoral responses to COVID-19 vaccination in the hematologic cancer population. As expected, patients with hematologic cancers had a blunted humoral response to vaccination when compared to healthy donors, and this defect was even more profound when considering the neutralizing capacity of these antibodies, suggesting both a qualitative and quantitative defect to the humoral immune response in patients with hematologic cancers. Second, we identified novel populations of patients with poor humoral responses to vaccination, such as patients receiving anti-CD38 antibodies and BH3 mimetics. Our current ongoing work is exploring the development of functional T-cell memory in these unique patient populations.