CLL is a disease of inherent immune dysfunction—not only B-cell dysfunction, but also T-cell dysfunction—and there have been studies examining the type of infections that occur. In patients with CLL, there are difficulties related to hypogammaglobulinemia, and there are difficulties with immunologic synapse formation between T cells and CLL cells or other antigen-presenting cells. Consequently, there is an inherent state of immune dysfunction, and this is true not only from the perspective of infection, but also from the perspective of immune surveillance of malignancy. With certain fludarabine-based therapies, T cells and CD4⁺ T cells are depleted, and we use prophylaxis in that situation.

Strategies to decrease the risk of infection include vaccination and IVIG, and prophylaxis when appropriate. However, there is no single, clear strategy that improves infection risk in the long term. Clinically, IVIG is not used for all patients who have low levels of immunoglobulin G (IgG) in the absence of infection. Studies have suggested that if IgG levels are below 400 mg/dL or 500 mg/dL, you can reduce the incidence of infection and hospitalization if you replete the patient with IVIG. This does not affect survival, and it does not mean that everyone with a low IgG level should be repleted. There are many patients who have very low IgG levels who do not get infections. And that underscores some of the complexity. The only patients who benefit from IVIG are patients who have recurrent bacterial infection with their low IgG levels or who have trouble clearing bacterial infections (eg, sinus infections can sometimes be a big problem).

With that being said, trying to understand and exploit the differences between the cell biology of the CLL clone vs the normal immune system and normal B cells has led to the development of therapies such as ibrutinib. We have also seen strategies to either genetically augment T cells or augment T-cell function to help overcome some of these deficiencies. I think that a large body of scientific work in CLL demonstrates that there are inherent immune deficiencies to address, such as B-cell dysfunction and the use of IVIG as well as T-cell dysfunction (most likely related to prior therapies) and the use of appropriate antimicrobial prophylaxis.