TY - JOUR
T1 - Inhibition of Bruton tyrosine kinase in patients with severe COVID-19
AU - Roschewski, Mark
AU - Lionakis, Michail S.
AU - Sharman, Jeff P.
AU - Roswarski, Joseph
AU - Goy, Andre
AU - Monticelli, M. Andrew
AU - Roshon, Michael
AU - Wrzesinski, Stephen H.
AU - Desai, Jigar V.
AU - Zarakas, Marissa A.
AU - Collen, Jacob
AU - Rose, Keith M.
AU - Hamdy, Ahmed
AU - Izumi, Raquel
AU - Wright, George W.
AU - Chung, Kevin K.
AU - Baselga, Jose
AU - Staudt, Louis M.
AU - Wilson, Wyndham H.
N1 - Publisher Copyright:
Copyright © 2020 The Authors, some rights reserved.
PY - 2020/6
Y1 - 2020/6
N2 - Patients with severe COVID-19 have a hyperinflammatory immune response suggestive of macrophage activation. Bruton tyrosine kinase (BTK) regulates macrophage signaling and activation. Acalabrutinib, a selective BTK inhibitor, was administered off label to 19 patients hospitalized with severe COVID-19 (11 on supplemental oxygen and 8 on mechanical ventilation), 18 of whom had increasing oxygen requirements at baseline. Over a 10- to 14-day treatment course, initiation of acalabrutinib treatment was associated with improved oxygenation in a majority of patients, often within 1 to 3 days, and had no discernable toxicity. Measures of inflammation - C-reactive protein and interleukin-6 (IL-6) - normalized quickly in most patients, as did lymphopenia, in correlation with improved oxygenation. At the end of acalabrutinib treatment, 8 of 11 (72.7%) patients in the supplemental oxygen cohort had been discharged on room air, and 4 of 8 (50%) patients in the mechanical ventilation cohort had been successfully extubated, with 2 of 8 (25%) discharged on room air. Ex vivo analysis revealed significantly elevated BTK activity, as evidenced by autophosphorylation, and increased IL-6 production in blood monocytes from patients with severe COVID-19 compared with blood monocytes from healthy volunteers. These results suggest that targeting excessive host inflammation with a BTK inhibitor is a therapeutic strategy in severe COVID-19 and has led to a confirmatory international prospective randomized controlled clinical trial.
AB - Patients with severe COVID-19 have a hyperinflammatory immune response suggestive of macrophage activation. Bruton tyrosine kinase (BTK) regulates macrophage signaling and activation. Acalabrutinib, a selective BTK inhibitor, was administered off label to 19 patients hospitalized with severe COVID-19 (11 on supplemental oxygen and 8 on mechanical ventilation), 18 of whom had increasing oxygen requirements at baseline. Over a 10- to 14-day treatment course, initiation of acalabrutinib treatment was associated with improved oxygenation in a majority of patients, often within 1 to 3 days, and had no discernable toxicity. Measures of inflammation - C-reactive protein and interleukin-6 (IL-6) - normalized quickly in most patients, as did lymphopenia, in correlation with improved oxygenation. At the end of acalabrutinib treatment, 8 of 11 (72.7%) patients in the supplemental oxygen cohort had been discharged on room air, and 4 of 8 (50%) patients in the mechanical ventilation cohort had been successfully extubated, with 2 of 8 (25%) discharged on room air. Ex vivo analysis revealed significantly elevated BTK activity, as evidenced by autophosphorylation, and increased IL-6 production in blood monocytes from patients with severe COVID-19 compared with blood monocytes from healthy volunteers. These results suggest that targeting excessive host inflammation with a BTK inhibitor is a therapeutic strategy in severe COVID-19 and has led to a confirmatory international prospective randomized controlled clinical trial.
UR - http://www.scopus.com/inward/record.url?scp=85086007909&partnerID=8YFLogxK
U2 - 10.1126/SCIIMMUNOL.ABD0110
DO - 10.1126/SCIIMMUNOL.ABD0110
M3 - Article
C2 - 32503877
AN - SCOPUS:85086007909
SN - 2470-9468
VL - 5
JO - Science Immunology
JF - Science Immunology
IS - 48
M1 - eabd0110
ER -