CLL by itself has its intrinsic immunosuppression, which affects the different components of immunity, including low immunoglobulin levels but also cellular immune dysfunction. This can be a problem for both treated and untreated patients.

The immune dysfunction of CLL is not only B-cell dysfunction, but also T-cell dysfunction. There have been studies examining the type of infections that occur in patients with CLL and the types of infections associated with the immune deficits created by specific therapies. In patients with CLL, there are difficulties related to hypogammaglobulinemia and with immunologic synapse formation (ie, between T cells and CLL cells or other antigen-presenting cells), and, so, there is an inherent state of immune dysfunction that we recognize. This is true from the perspective of infection and from the perspective of immune surveillance of malignancy.

With respect to the impact of therapies, we can differentiate between chemoimmunotherapy and the novel agents in their different effects on immune function. Chemoimmunotherapy causes acute immunosuppression, contributing to infectious complications during treatment in a significant percentage of patients. As a later immune dysfunction, we have recognized that nucleoside analogs such as fludarabine cause lymphocyte depletion, especially T-cell depletion, which lasts for an extended period of time even after the treatment has finished. And prophylactic antibiotics such as trimethoprim/sulfamethoxazole are sometimes used in the setting of chemoimmunotherapy.

Yes, fludarabine, cyclophosphamide, and rituximab (FCR) is associated with a risk of infection, and that is an important factor in the suggested age cutoff for its use. Studies from the German CLL Study Group suggest a cutoff of age 65 because patients over that age had significantly more infectious complications than those who were under that age. Some individuals on ibrutinib and venetoclax develop neutropenia and require growth factors, although, generally, this is fairly manageable. I have seen some decline in immunoglobulins in patients on ibrutinib over the long-term; currently reported data are for 12 to 24 months only. And there have been some data from work published in JAMA Oncology suggesting that patients on ibrutinib may have reduced responses to seasonal influenza vaccines.

I think what needs to be said critically about those data related to mounting an immune response is that investigators focused on influenza vaccine responses, and the vaccines used are prepared against seasonal or more conserved epitopes of the influenza virus in circulation each season. A vaccine response is directed toward either de novo antigens or to recall antigens that a patient’s immune system has already seen as part of a prior vaccination or virus exposure. Thus, what is not clear is whether patients on B-cell receptor signaling inhibitors can mount immune responses toward de novo antigens. However, I think that there is a general sense that de novo immune responses are weakened by the continued suppression of B-cell receptor signaling.