Ibrutinib and Aspergillus: a Btk-targeted risk

In this issue of Blood, Bercusson and colleagues report a mechanism underlying susceptibility to Aspergillus fumigatus infections in patients treated with the Bruton tyrosine kinase (Btk) inhibitor ibrutinib. 1 This drug has been paradigm-shifting in a number of B-cell malignancies, which has led to widespread use in the diseases for which Food and Drug Administration approval currently exists, and clinical trials of the drug alone and in combination in these and many other malignancies. However, although well tolerated in the majority of patients, a few troublesome toxicities have become apparent as use of the drug has expanded. One such toxicity is a relatively high rate of A fumigatus infections. Although patients with hematologic malignancies are certainly at risk for opportunistic infections, A fumigatus infections at a higher rate than expected have been noted in multiple prospective studies, most notably a rate of 39% in patients on a trial of ibrutinib in primary central nervous system (CNS) lymphoma who were concurrently treated with corticosteroids. 2 Although the incidence in other hematologic malignancies is likely quite a bit lower (2.5% in a large institutional cohort of 566 patients treated over 1225 person-years), 3 this finding has been worrisome. A previous study by this group, exploring the risk of A fumigatus in patients treated with calcineurin inhibitors, demonstrated that Btk is required for the macrophage inflammatory response that clears A fumigatus from the airways, 4 and a separate study showed that Btk null mice infected with A fumigatus developed pneumonia, similar to what is seen in macrophage-deplete models. 2 However, the implications for these findings in patients where Btk is present but pharmacologically inactivated were previously unknown.