acp-196 and Inflammation

As the SARS-CoV-2 (COVID-19) pandemic spreads and the number of Bruton's tyrosine kinase inhibitor (BTKi)-treated COVID-19-affected patients grows, we must consider the pros and cons of BTKi discontinuation for our patients. In favor of BTKi continuation, BTK plays an active role in macrophage polarization. By modulating key transcription factors, BTK may regulate macrophage polarization downstream of classic M1 and M2 polarizing stimuli and mitigate the hyperinflammatory state associated with COVID-19. In favor of BTKi discontinuation, we note a potentially increased risk of secondary infections and impaired humoral immunity. We hypothesize that the potential benefit of blunting a hyperinflammatory response to SARS-CoV-2 through attenuation of M1 polarization outweighs the potential risk of impaired humoral immunity, not to mention the risk of rapid progression of B-cell malignancy following BTKi interruption. On the basis of this, we suggest continuing BTKi in patients with COVID-19.

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Anti-Inflammatory Agents; Antineoplastic Agents; Benzamides; Betacoronavirus; Coronavirus Infections; COVID-19; Humans; Inflammation; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma, B-Cell; Macrophages; Pandemics; Piperidines; Pneumonia, Viral; Protein Kinase Inhibitors; Pyrazines; Pyrazoles; Pyrimidines; SARS-CoV-2

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.

Topics: Agammaglobulinaemia Tyrosine Kinase; Aged; Aged, 80 and over; Benzamides; Betacoronavirus; Coronavirus Infections; COVID-19; COVID-19 Drug Treatment; Critical Illness; Female; Follow-Up Studies; Humans; Inflammation; Interleukin-6; Male; Middle Aged; Monocytes; Pandemics; Pneumonia, Viral; Prospective Studies; Pyrazines; Respiration, Artificial; SARS-CoV-2; Treatment Outcome