Patients with chronic lymphocytic leukemia (CLL) have an increased risk for severe COVID-19 disease and mortality. The goal of this study (NCT04746092) was to determine the efficacy of COVID-19 vaccine in patients with CLL. We evaluated humoral immune responses to BNT162b2 mRNA COVID-19 vaccine in patients with CLL and compared responses with those obtained in age-matched healthy controls. Patients received two vaccine doses, 21 days apart, and antibody titers were measured using Elecsys® Anti-SARS-CoV-2S assay after administration of the second dose. In a total of 167 patients with CLL the antibody response rate was 39.5%. A comparison between 52 patients with CLL and 52 sex- and aged-matched healthy controls, revealed a significantly reduced response rate among patients (52% vs 100%, respectively; adjusted odds ratio=0.010, 95% CI 0.001-0.162; p<0.001). Response rate was highest in patients who obtained clinical remission after treatment (79.2%), followed by 55.2% in treatment-naïve and 16% only in patients under treatment at the time of vaccination. In patients treated with either BTK inhibitors or venetoclax ± anti-CD20 antibody, response rates were considerably low (16.0% and 13.6%, respectively). None of the patients exposed to anti-CD20 antibodies <12 months prior to vaccination responded. In a multivariate analysis, the independent predictors of response were younger age, females, lack of currently active treatment, IgG levels ≥550 mg/dL and IgM levels ≥40mg/dL. In conclusion, antibody-mediated response to BNT162b2 mRNA COVID-19 vaccine in patients with CLL is markedly impaired and affected by disease activity and treatment.

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