Bruton tyrosine kinase inhibitors and invasive aspergillosis and mucormycosis: a case report and multi-center exploratory retrospective study

Background Bruton tyrosine kinase inhibitors (BTKIs) are increasingly utilized for patients with certain malignant hematologic conditions. While cases of invasive fungal infections have been reported in patients on BTKIs, no multi-center epidemiological studies have been performed. The Epic Cosmos platform, a nationwide electronic health record data set, provides an opportunity to assess real-world epidemiologic data. Case Summary A 69-year-old female with recently diagnosed Waldenström macroglobulinemia with associated autoimmune hemolytic anemia undergoing treatment with zanubrutinib and prednisone presented with fatigue and acute kidney injury. Imaging demonstrated a bladder mass with bilateral hydronephrosis leading to transurethral resection of the bladder mass with histopathology revealing both broad ribbon-like hyphae resembling Mucorales spp. and acute-angle branching resembling Aspergillus spp. with angioinvasion. Additional imaging revealed bilateral pulmonary cavitary lesions and renal and brain involvement. Bronchoalveolar lavage returned a positive galactomannan and culture growth of Aspergillus fumigatus . The patient was treated with liposomal amphotericin B with eventual transition to oral isavuconazole. Zanubrutinib and steroids were discontinued. To assess real-world occurrence of IFIs in patients on BTKIs, we performed an exploratory analysis using Epic Cosmos. Conclusion IFIs continue to be described in patients undergoing treatment with BTKIs. Through exploratory analysis using Epic Cosmos, aspergillosis occurred not infrequently (0.5%–1.9%) in patients on various BTKIs. Of patients on ibrutinib with a diagnosis of chronic graft-versus-host disease, aspergillosis was identified in 32 (8.3%) patients. Patients on BTKIs who developed aspergillosis were frequently on corticosteroids. Mucormycosis in patients on BTKIs was rare (<0.1%).