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.