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Background: Patients with hematological malignancies are at greater risk of severe COVID-19 and have been prioritized for COVID-19 vaccination. A significant proportion of them have an impaired vaccine response, both due to the underlying disease and to the treatments. Methods: We conducted a prospective observational study to identify the specific risks of the outpatient population with hematological diseases. Result: Between 22 December 2021 to 12 February 2022, we followed 338 patients of which 16.9% (<i>n</i> = 57) developed SARS-CoV-2 infection despite previous vaccination (94.7%). COVID-19 patients were more likely to have received immunotherapy (85.5% vs. 41%, <i>p</i> < 10⁻⁴), and particularly anti-CD20 monoclonal antibodies (40% vs. 14.9%, <i>p</i> < 10⁻⁴) and Bruton’s tyrosine kinase inhibitors (BTKi) (7.3% vs. 0.7%, <i>p</i> < 10⁻²). There was no significant difference in demographic characteristics or hematological malignancies between COVID-19-positive and non-positive patients. Patients hospitalized for COVID-19 had more frequently received immunotherapy than patients with asymptomatic or benign forms (100% vs. 77.3%, <i>p</i> < 0.05). Hospitalized COVID-19 patients had a higher proportion of negative or weakly positive serologies than non-hospitalized patients (92.3% vs. 61%, <i>p</i> < 0.05). Patients who received tixagevimab/cilgavimab prophylaxis (<i>n</i> = 102) were less likely to be COVID-19-positive (4.9 vs. 22%, <i>p</i> < 0.05) without significant difference in hospitalization rates. Conclusion: In the immunocompromised population of patients with hematological malignancies, the underlying treatment of blood cancer by immunotherapy appears to be a risk factor for SARS-CoV-2 infection and for developing a severe form.