Invasive Aspergillosis with Impaired Neutrophil Responses against Aspergillus fumigatus in Patients Treated with Acalabrutinib – findings from three cases

Objectives Ibrutinib, a first-generation covalent BTK inhibitor was found to be a risk factor for the occurrence of invasive fungal complications. Acalabrutinib is a second-generation covalent BTKi using to treat B-cell malignancies. Healthy donor neutrophils incubated ex-vivo with acalabrutinib lose ability to control Aspergillus conidia germination. In patients receiving acalabrutinib, the potential effect on neutrophil antifungal activity is unknown. Furthermore, only two cases of invasive aspergillosis have been reported during treatment with acalabrutinib, outside of a few cases in a clinical trial. Methods We describe three new cases of invasive aspergillosis occurring within the first months of acalabrutinib therapy in patients with chronic lymphocytic leukemia. We used videomicroscopy and flow cytometry approaches to investigate the basic functional responses against Aspergillus of neutrophils from acalabrutinib-treated patients. Results We showed an alteration in the anti-Aspergillus response after one month of acalabrutinb therapy: neutrophils lost their capacities of killing Aspergillus fumigatus germinating conidia and decreased their Reactive Oxygen Species production when stimulated by Aspergillus. Conclusions It is important to follow-up patients treated with acalabrutinib for the risk of aspergillosis as well as those treated with ibrutinib.