Low-normal immunoglobulin suggests monoclonal B-cell lymphocytosis and constitutional CLL susceptibility: a dual-mechanism analysis.

Low-normal serum immunoglobulin (Ig) levels may reflect early immune dysregulation preceding chronic lymphocytic leukemia (CLL), but their prognostic significance years before diagnosis is unclear. We conducted a large retrospective cohort study, including 294,712 adults aged 40-80 years with routine Ig testing and up to 10 years of follow-up. Immunoglobulin G (IgG), A (IgA), and M (IgM) levels were assessed a decade before diagnosis and dichotomized at the median values observed in individuals who later developed CLL. Multivariable Cox regression was performed, with sensitivity analyses stratified by baseline lymphocyte counts to distinguish constitutional effects from occult monoclonal B-cell lymphocytosis (MBL). Low-normal IgA ( < 187 mg/dL) demonstrated the strongest association with future CLL (adjusted hazard ratio [aHR] 2.62), followed by IgM (aHR 1.77) and IgG (aHR 1.43). In individuals with low-normal lymphocyte counts, IgM and IgG lost predictive value, whereas IgA remained independently associated with CLL risk. Dose-response analyses revealed steep monotonic gradients across the normal range. Temporal analyses demonstrated that IgA-associated risk extended beyond a decade prior to diagnosis, while IgM and IgG associations attenuated earlier. These findings support a dual-mechanism model in which low IgM and IgG reflect tumor burden from undiagnosed MBL, whereas low IgA identifies a constitutional susceptibility phenotype.