Antigen-specific B cell responses in treatment-naive and chlorambucil-treated patients with chronic lymphocytic leukemia

Chronic lymphocytic leukemia (CLL) is characterized by secondary immunodeficiency, yet the extent to which global disease-associated immune dysregulation impairs the ability to generate antigen-specific B cell immunity—independent of targeted therapy—remains unclear. To address this, we assessed the non-malignant B cell compartment and responses to SARS-CoV-2 vaccination in treatment-naive (CLL-TN) and chlorambucil-treated (CLL-CTx) patients. Despite marked alterations in peripheral B cell subsets, both CLL-TN and CLL-CTx patients exhibited higher absolute numbers of SARS-CoV-2 spike-specific B cells than healthy controls (HCs). The phenotypes of spike-specific B cells were also similar between groups, with most class-switched to IgG and only a small fraction displaying the IgD⁻CD27⁻ phenotype. Most patients also mounted robust anti-spike IgG responses with live virus neutralization comparable to HCs. Nevertheless, neutralization of certain Omicron subvariants was reduced in CLL patients compared with HCs, suggesting a selective constraint in response breadth. Together, these findings indicate that, in the context of SARS-CoV-2 vaccination, disease-associated immune dysregulation in CLL does not preclude effective B cell or antibody responses to SARS-CoV-2, although the breadth of these responses may be limited.