**8.1 CLL and hypogammaglobulinemia**

Hypogammaglobulinemia is the most predominant inherent immune defect in CLL patients, with subtypes IgG3 and IgG4 particularly affected. Hypogammaglobulinemia becomes more pronounced with longer disease duration and advanced-stage disease. There is generally no reversal in this defect, even with response to therapy. However, in one report, ibrutinib therapy resulted in partial reconstitution of humoral immunity, with an increase in IgA levels [73]. The most common site of infection in CLL patients is the respiratory tract, which may be related to serum IgA and IgG4 deficiencies and possibly to mucosal immune defects. The majority of patients with CLL will develop hypogammaglobulinemia at some point in the course of their disease. The use of prophylactic intravenous immunoglobulin (IVIG) to restore IgG levels is controversial. For most patients with CLL, prophylactic IVIG is **not** recommended. For patients with CLL who have had recurrent infections requiring intravenous (IV) antibiotics or hospitalization and who also have a serum IgG <500 mg/dL, it is reasonable to administer IVIG. The usual dose is 200–400 mg/kg by IV infusion, given at three- to four-week intervals. The goal is to maintain the trough serum IgG in treated patients above 500–700 mg/dL as a general guideline. If there is a substantial decrease in the incidence of infections, treatment at gradually extended intervals may be considered. There is no good endpoint for when such therapy can be discontinued. The randomized trials of prophylactic IVIG found that patients who receive IVIG have a decreased incidence of minor and moderate, but not major, bacterial infections. However, IVIG does not appear to increase quality of life or survival [74]. Potential toxicities related to IVIG include anaphylaxis, fever, chills, "flu-like" symptoms, and headache. Another important aspect of IVIG therapy is that it replaces neither IgM nor IgA.
