Inhibition of Bruton tyrosine kinase in patients with severe COVID-19

Abstract

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; 8 on mechanical ventilation), 18 of whom had increasing oxygen requirements at baseline. Over a 10-14 day treatment course, acalabrutinib improved oxygenation in a majority of patients, often within 1-3 days, and had no discernable toxicity. Measures of inflammation – C-reactive protein and IL-6 – normalized quickly in most patients, as did lymphopenia, in correlation with improved oxygenation. At the end of acalabrutinib treatment, 8/11 (72.7%) patients in the supplemental oxygen cohort had been discharged on room air, and 4/8 (50%) patients in the mechanical ventilation cohort had been successfully extubated, with 2/8 (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.

Perspective: Cancer Patient Management Challenges During the COVID-19 Pandemic

“…In a recently published letter, Treon et al ( 18 ) reported a beneficial effect of treatment with the Bruton’s tyrosine kinase (BTK) inhibitor ibrutinib on lung inflammation and hypoxia in five patients with Waldenström macroglobulinemia. This lead has been followed by other groups that have reported the potential protective effect of acalabrutinib in patients with lymphoproliferative disorders affected by severe forms of COVID-19 ( 19 ) and by the initiation of clinical trials with BTK inhibitors in patients with severe COVID-19. The mechanisms underlying the activity of BTK inhibitors in improving hypoxia in patients with severe COVID-19 seem to be mediated by an inhibition of exaggerated monocyte autophosphorylation and reduction in interleukin (IL)-6 production.…”

NF-kappaB pathway as a potential target for treatment of critical stage COVID-19 patients

“…The concept of a central role of NF-kB pathway in critical stage SARS-CoC-2 infected patients is supported by two recently published studies showing pronounced clinical effect in critical COVID-19 patients by Bruton tyrosine kinase (BTK) inhibitors, correlating with signi cantly decrease in in ammatory parameters (C-reactive protein and IL-6), normalized lymphopenia, and improved oxygenation 40,41 . Bruton tyrosine kinase is known to be involved in TLR7/8-induced TNFa transcription via NF-κB recruitment at the stage of phosphorylation of p65 42 .…”

Perspectives on Platelet Heterogeneity and Host Immune Response in Coronavirus Disease 2019 (COVID-19)

“…44 Many other agents that may specifically interfere with thromboinflammatory platelet responses are also of interest, including tyrosine kinase inhibitors that block platelet GPVI signaling (i.e., ibrutinib, acalabrutinib). 39,45,46 Intrinsic and extrinsic coagulation pathways that regulate thrombin formation and promote procoagulant platelet phenotypes are also targets of interest in COVID-19. 41,47 Platelet Phenotype and Function in COVID- 19…”