Ibrutinib induces multiple functional defects in the neutrophil response against Aspergillus fumigatus

The Bruton tyrosine kinase inhibitor ibrutinib has become a leading therapy against chronic lymphoid leukemia. Recently, ibrutinib has been associated with the occurrence of invasive fungal infections, in particular invasive aspergillosis. The mechanisms underlying the increased susceptibility to fungal infections associated with exposure to ibrutinib are currently unknown. Innate immunity, in particular polymorphonuclear neutrophils, represents the cornerstone of anti-Aspergillus immunity; however, the potential impact of ibrutinib on neutrophils has been little studied. Our study investigated the response to Aspergillus fumigatus and neutrophil function in patients with chronic lymphoid leukemia or lymphoma, who were undergoing ibrutinib therapy. We studied the consequences of ibrutinib exposure on the functions and anti-Aspergillus responses of neutrophils obtained from healthy donors and 63 blood samples collected at different time points from 32 patients receiving ibrutinib for lymphoid malignancies. We used both flow cytometry and video-microscopy approaches to analyze neutrophils' cell surface molecule expression, cytokine production, oxidative burst, chemotaxis and killing activity against Aspergillus. Ibrutinib is associated, both in vitro and in patients under treatment, with multiple functional defects in neutrophils, including decreased production of reactive oxygen species, impairment of their capacity to engulf Aspergillus and inability to efficiently kill germinating conidia. Our results demonstrate that ibrutinib-exposed neutrophils develop significant functional defects that impair their response against Aspergillus fumigatus, providing a plausible explanation for the emergence of invasive aspergillosis in ibrutinib-treated patients.