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

COLADO, ANA; MARÍN FRANCO, JOSÉ L.; ELÍAS, ESTEBAN E.; AMONDARAIN, MIKELE; VERGARA RUBIO, MARICEF; SARAPURA MARTÍNEZ, VALERIA; CORDINI, GREGORIO; FUENTES, FEDERICO; BALBOA, LUCIANA; FERNANDEZ GRECCO, HORACIO; PAVLOVSKY, MIGUEL; BEZARES, FERNANDO; MORANDE, PABLO; GIORDANO, MIRTA; GAMBERALE, ROMINA; BORGE, MERCEDES

AMERICAN JOURNAL OF HEMATOLOGY

WILEY-LISS, DIV JOHN WILEY & SONS INC

Año: 2020

0361-8609

Bruton's tyrosine kinase inhibitors (BTKi) have changed the treatmentparadigm for chronic lymphocytic leukemia (CLL) and other B-cell malignancies.Ibrutinib is a first in-class BTKi approved for CLL treatment,and although it shows impressive clinical efficacy in different riskgroups, most patients do not achieve complete responses and requirecontinuous administration. Infection rates during ibrutinib treatment aresimilar or lower compared to other treatments, but they are still one ofthe most frequent adverse events leading to drug-discontinuation,especially in relapsed/refractory patients. The emergence of invasivefungal infections in some treated patients, including cases of invasiveaspergillosis with central nervous system involvement, suggests thatibrutinib may disturb immunological mechanisms implicated in fungaldefense. In line with these clinical observations, substantial evidenceshowed that ibrutinib affects functions on macrophages andneutrophils, both critical players for antimicrobial immune response.our results show that BTKi have inhibitory effectson innate immune cells. Second-generation BTKi, particularlyacalabrutinib, showed detrimental effects on macrophages and neutrophils,comparable to those of ibrutinib, which may impair the antimicrobialinnate-immune response in vivo and should be taken intoaccount especially in the presence of other factors that weaken theimmune system. On the other hand, second generation BTKi showfewer effects on anti-CD20 mAbs-activity and should be consideredas better partners for combinatory treatment.