Effects of the Bruton’s tyrosine kinase inhibitor ibrutinib on humoral immunity in patients with chronic lymphocytic leukemia (HUM1P.258)

Abstract

Abstract Chronic lymphocytic leukemia (CLL) is characterized by immune dysregulation, often including hypogammaglobulinemia. Ibrutinib, a covalent inhibitor of Bruton’s tyrosine kinase (BTK), is highly active in B cell malignancies, including CLL. Inactivating mutations in BTK cause X-linked agammaglobulinemia. We evaluated the impact of ibrutinib on immunoglobulin (Ig) levels in CLL patients (pts) treated at NIH. Consistent with previous reports, IgG remained stable during the first 6 months, but decreased from a median of 707 mg/dL at baseline to 611 mg/dL at 24 months (17% reduction, n=25, p<0.0001). In contrast, there was a sustained increase in IgA and a transient increase in IgM. Next, we assessed serum free light chains (FLCs) to distinguish the effects on clonal from non-clonal B cells. In κ-clonal CLL cases, the clonal (κ) FLC decreased from a median of 6.71 to 1.42 mg/dL after 6 months (n=39, p<0.0001). Interestingly, the non-clonal (λ) FLC increased, suggesting the recovery of normal B cell function. Consistently, we found an increase in normal B cells in blood and bone marrow, including early B cell precursors. In comparison, CLL pts (n=16) treated with anti-CD20-based chemoimmunotherapy also showed a decrease in IgG at 24 months (12% reduction, p=0.0052), and surprisingly, an improvement in IgA levels, suggesting that the latter effect is not drug-specific but due to tumor reduction. The consequences of long-term BTK inhibition on immune function require further study.