Ibrutinib blocks Btk-dependent NF-ĸB and NFAT responses in human macrophages during Aspergillus fumigatus phagocytosis

Ibrutinib is a small molecule Bruton tyrosine kinase (Btk) inhibitor approved by the Food and Drug Administration for clinical use in the treatment of chronic lymphocytic leukemia, Waldenström macroglobulinemia, and as a second-line treatment of lymphoma and chronic graft-versus-host disease.1 An association with pulmonary aspergillosis was observed shortly after Ibrutinib was licensed for use.2 A recent phase Ib study of Ibrutinib treatment of primary central nervous system lymphoma reported a 39% incidence of invasive aspergillosis, in patients concurrently treated with corticosteroids, in the absence of neutropenia.3 Studies of Aspergillus fumigatus infection in Btk−/− mice revealed focal pneumonia and large airway mucous plugs, mirroring findings in macrophage-depleted models of pulmonary aspergillosis.