Second generation BTK inhibitors impair the anti-fungal response of macrophages and neutrophils

Abstract

BTK inhibitors (BTKi) play a major role in the treatment of Chronic Lymphocytic Leukemia (CLL). Ibrutinib, the first in class BTKi, impairs macrophage and neutrophil functions and also cell-mediated effector mechanisms of action of anti-CD20 mAb. Acalabrutinib, recently approved for CLL treatment, and spebrutinib, are second generation BTKi with greater selectivity for BTK. Because ibrutinib was linked with fungal invasive infections, we aimed to evaluate the effect of second generation BTKi on macrophage and neutrophil response to fungi. We found that acalabrutinib impaired macrophage M1-polarization and their response to C. albicans and A. fumigatus as reported for ibrutinib, while spebrutinib showed a milder inhibition. On the other hand, neutrophil activation in response to C. albicans and A. fumigatus were strongly and comparably inhibited by the three BTKi. These results show that second generation BTKi also have detrimental effects on macrophages and neutrophils that may impair the anti-microbial innate-immune response. We found that the anti-CD20 mAb mechanism of action mediated by macrophages was not inhibited by second generation BTKi, while that mediated by NK cells was impaired by spebrutinib. The lower interference of second generation BTKi with anti-CD20 mAb suggests they represent a better option for combination therapy.