Discussion
BTK belongs to a sub-family of non-receptor protein tyrosine kinases (TEC kinases) and plays an essential role in the proliferation, differentiation, and survival of B cells. BTK also plays a role in the function of innate cells and T cells and mediates Toll-like receptor signaling and NLRP3 inflammasome activation1. BTKis have revolutionized landscape therapy of B cell malignancies such as chronic lymphocytic leukemia, diffuse large B-cell lymphoma, mantle cell lymphoma, and Waldenstrom macroglobulinemia.
Ibrutinib was the first BTKi to be approved for the treatment of B cell malignancies. It binds irreversibly to BTK. Although it was generally well tolerated with rapid and durable response in clinical studies, the rate of discontinuation of this drug in community practice due to side effects is reportedly as high as 49%. The side effects of ibrutinib, including diarrhea, skin rash, infections, bleeding, atrial fibrillation, are thought to be associated to off binding of other protein tyrosine kinases. The next generation of BTKi, like zanubrutinib, have improved BTK binding profiles and selectivity, and were developed to decrease the rate of side effects observed with ibrutinib2,3. Serious side effects, such as disseminated fungal infections, are now being described with the next generation BTKis.
Disseminated fungal infections have been frequently described in patients treated with ibrutinib, with aspergillus being the most common pathogen. The underlying mechanism of BTKis causing impairment of the immune response to fungal infection is not well understood, but it appears to be related to not only B cell dysfunction but also macrophage and neutrophil dysfunction.
Mutations in the human BTK gene results in the development of X-linked agammaglobulinemia. This disorder is characterized by a primary humoral immunodeficiency where B cell development is arrested with subsequent almost total lack of immunoglobulin production. While patients with X-linked agammaglobulinemia have increased risk of opportunistic infections, disseminated fungal infections are rarely seen in this population. Laboratory studies suggest that the dysfunction of neutrophils, macrophages, T cells and platelets as well as abnormal toll-like receptor immune response is mediated by BTKis and appears to play a role in the impairment of fungal immune response4,5.
In the case of the reported patient, he had several factors that predisposed him to a higher risk of disseminated aspergillus infection. The first factor was that he was treated with ibrutinib for two years prior to transition to zanubrutinib, exposing him to potential immune dysfunction. Secondly, he was diagnosed with presumptive cryptogenic organizing pneumonia on initial presentation and was started on a prolonged steroid course. He may have already been infected with aspergillosis pneumonia at this time. The steroids likely caused further suppression of neutrophil function in the setting of zanubrutinib use. In a small trial of primary central nervous system lymphoma treated with a combination of ibrutinib and steroids, up to 39% of patients developed aspergillosis6.
Zanubrutinib is a newer BTKi that is advertised as having greater specificity for the BTK receptor compared to the prior formulations7. Compared to ibrutinib, there is reduced affinity to off-target receptors such as epidermal growth factor receptor (EGFR), interleukin 2-inducible T-cell kinase (ITK), and Janus kinase 3 (JAK3)2. These receptors ensure appropriate neutrophil and macrophage function, thus improving the innate immune response against fungal infections in those treated with novel BTKi. However, there are currently limited studies comparing the affinity of BTK receptors on innate immune cells, as BTK is also involved in neutrophil recruitment and activation along with macrophage phagocytosis7. Given the high mortality rate of these disseminated fungal infections, a better understanding of the underlying mechanisms of BTK impairing the immune system response to fungal infections would likely impact clinical decisions regarding its use.
In review of published cases of infections in the setting of ibrutinib use, multiple factors seem to impact the patient’s innate immune response. A majority of the patients were treated for CLL, a condition that causes immunosuppression in itself. Most patients had other pre-disposing risk factors such as prior immunotherapy and chemotherapy, steroid use, and neutropenia. A few patients had no other factors other than initiation of ibrutinib. Thus far, there has been one reported case of fungal infection with cryptococcus with use of zanubrutinib complicated by neutropenia and prior rituximab use with persistent cytopenia.