COVID-19 Vaccine Failure in Chronic Lymphocytic Leukemia and Monoclonal B-Lymphocytosis; Humoral and Cellular Immunity

Chronic lymphocytic leukemia (CLL) is associated with immunocompromise and high risk of severe COVID-19 disease and mortality. Monoclonal B-Lymphocytosis (MBL) patients also have immune impairment. We evaluated humoral and cellular immune responses in 181 patients with CLL (160) and MBL (21) to correlate failed seroconversion (<50AU/mL SARS-CoV-2 II IgG assay, antibody to spike protein, Abbott Diagnostics) following each of 2 vaccine doses with clinical and laboratory parameters. Following first and second doses, 79.2% then 45% of CLL, and 50% then 9.5% of MBL respectively remained seronegative, indicating 2 vaccine doses are crucial. There was significant association between post-dose 2 antibody level with pre-vaccination reduced IgM ( p <0.0001), IgG2 ( p <0.035), IgG3 ( p <0.046), and CLL therapy within 12 months ( p <0.001) in univariate analysis. By multivariate analysis, reduced IgM ( p <0.0002) and active therapy ( p <0.0002) retained significance. There was no significant correlation with age, gender, CLL duration, IgG, IgA or lymphocyte subsets. Anti-spike protein levels varied widely and were lower in CLL, than MBL, and both lower than normal donors. Neutralization activity showed anti-spike levels 1000AU/mL. In a representative subset of 32 CLL patients, 80% had normal T-cell responses by IFNγ and IL-2 FluoroSpot assay. Failed seroconversion occurred in 36.6%% of treatment-naive patients, 52.9% treatment-naive with reduced IgM, 78.1% on therapy, and 85.7% on ibrutinib. Vaccination failure is very common in CLL, including early-stage disease. 6 Key Novel Findings Comparison CLL vs MBL vs normal - 45% of CLL and 9.5% of MBL fail to seroconvert with 2 doses of COVID-19 vaccine Neutralization assay - SARS CoV-2 IgG levels <1000 AU/mL rarely associated with neutralization activity. COVID-19-specific T-cell function by FluoroSpot IFN-g and IL-2 production IgG, A, M class and IgG subclass: correlations by univariate and multivariate analysis - IgM (OR 7.29 p<0.0001), IgG2 and IgG3 subclass univariate significance Correlation with therapy – ICT, targeted therapies, and those on Ig replacement High risk of vaccination failure for all CLL, including early-stage disease, and MBL Key Points CLL and MBL show significantly impaired anti-spike antibody, viral neutralization, with cellular immune response to COVID-19 vaccination Failure to seroconvert is associated with low IgM, IgG2, IgG3, and recent therapy; many CLL and MBL patients remain COVID-19 vulnerable