Early data from a clinical study published in Science Immunology1 suggest that blocking the Bruton’s tyrosine kinase (BTK) protein provided clinical benefit to a small group of patients with severe COVID-19 infection.1 Roschewski et al observed that the off-label use of the BTK inhibitor acalabrutinib, which is approved to treat several blood cancers, was associated with reduced respiratory distress and a reduction in the overactive immune response in most of the treated patients.
BTK inhibitors are approved to treat certain cancers, but they are not approved as a treatment for COVID-19. This strategy must be tested in a randomized, controlled clinical trial to understand the best and safest treatment options for patients with severe COVID-19 infection.
Prospective Clinical Study Findings
This study was developed to test whether blocking the BTK protein with acalabrutinib would reduce inflammation and improve the clinical outcome for hospitalized patients with severe COVID-19. This prospective off-label clinical study included 19 patients with a confirmed COVID-19 diagnosis who required hospitalization; they also had with low blood-oxygen levels and evidence of inflammation. Of these patients, 11 had been receiving supplemental oxygen for a median of 2 days, and 8 others had been on a ventilator for a median of 1.5 days (range 1–22 days).
Within 1 to 3 days after receiving acalabrutinib, the majority of patients who received supplemental oxygen experienced a substantial decrease in inflammation, and their breathing improved. Of these 11 patients, 8 were able to come off supplemental oxygen and were discharged from the hospital. Among patients on a ventilator, four of the eight patients were able to come off the ventilator, and two were eventually discharged. The authors noted the group on a ventilator was clinically diverse and included patients who had been on a ventilator for prolonged periods and had major organ dysfunction. Two of the patients in this group died.
Blood samples from patients in the study showed that levels of interleukin-6 (IL-6), a major cytokine associated with hyperinflammation in severe COVID-19, decreased after treatment with acalabrutinib. Counts of lymphocytes also rapidly improved in most patients. In addition, the researchers tested blood cells from patients with severe COVID-19 infection who were not in the study. In comparison with samples from healthy volunteers, they found these patients with severe COVID-19 infection had higher activity of the BTK protein and greater production of IL-6.
These findings suggest acalabrutinib may have been effective because its target, BTK, is hyperactive in severe COVID-19 immune cells. The results of this study were used to inform the trial design of the CALAVI (acalabrutinib) randomized, controlled clinical trial, which will examine the safety and efficacy of acalabrutinib in patients with severe COVID-19 infection.
DISCLOSURE: The study was led by researchers in the Center for Cancer Research at the National Cancer Institute, in collaboration with researchers from the National Institute of Allergy and Infectious Diseases, as well as the U.S. Department of Defense’s Walter Reed National Military Medical Center, and four other hospitals nationally. For full disclosures of the study authors, visit immunology.sciencemag.org.
1. Roschewski M, Lionakis MS, Sharman JP, et al: Inhibition of Bruton tyrosine kinase in patients with severe COVID-19. Sci Immunol 5:eabd0110, 2020.