Association of Blood IgG with Tumor Necrosis Factor-alpha and Clinical Course of Chronic Lymphocytic Leukemia

The intrinsic humoral immunodeficiency of chronic lymphocytic leukemia (CLL) is often managed with immunoglobulin replacement therapy (IgRT) to maintain IgG levels in the low-normal range (6-8 g/L) but optimal targets for IgG and timing to commence IgRT are unclear. IgG levels fell near 6 g/L at rates of -0.85±0.14 g/L/year in 51 patients who required treatment for CLL within 4.5±0.4 years from initial diagnosis and - 0.27±0.04 g/L/year in 40 patients with progressive disease who remained untreated after 8.5±0.5 years. In contrast, endogenous IgG levels remained above 8 g/L in patients with highly indolent disease (n = 25) and TNFα and beta-2-microglobulin (β2M) in blood decreased when IgRT was used to increase IgG levels over 9 g/L. At 15 g/L but not 5 g/L, the IgRT product Hizentra® inhibited B cell receptor (BCR)-activation, TNFα production, and survival in vitro, particularly of CLL cells that spontaneously made little TNFα. These findings suggest deterioration of the humoral immune system is associated with progressive CLL and altering the dosing of IgRT to achieve higher than conventional IgG target levels may have therapeutic activity.