Early data from a clinical study suggest that blocking Bruton tyrosine kinase (BTK) provides clinical benefits for a small group of patients with severe COVID-19. The researchers responsible for the study observed that untagged use of the anticancer drug acalabrutinib was associated with reduced dyspnea and hyperactive immune response in most patients receiving treatment. The results of the study were recently published in the journal Science Immunology, and the paper is entitled “Inhibition of Bruton tyrosine kinase in patients with severe COVID-19”.
These findings should not be seen as clinical recommendations, but they are shared to help public health respond to COVID-19. Although BTK inhibitors are approved for the treatment of some cancers, they are not approved as treatments for COVID-19. This strategy must be tested in randomized controlled clinical trials to understand the best and safest treatment for critically ill COVID-19 patients.
BTK proteins play an important role in the normal immune system, including macrophages, which are innate immune cells that can cause inflammation by producing proteins called cytokines. Cytokines, as chemical messengers, help to stimulate and guide the immune response. In some patients with severe COVID-19, a large number of cytokines will be released from the body at one time, resulting in the immune system not only attacking infection, but also destroying the function of lungs and other organs. This dangerously high inflammatory state is called a “cytokine storm”. At present, there is no mature treatment strategy for this stage of disease. Acartini is a BTK inhibitor that has been approved for the treatment of a variety of blood cancers. This new clinical study aims to test whether blocking BTK protein with acatinib can reduce inflammation and improve the clinical effect of hospitalized patients with severe COVID-19.
This prospective untagged clinical study included 19 patients diagnosed with COVID-19 requiring hospitalization with low blood oxygen levels and evidence of inflammation in the body. Of these patients, 11 patients had received a median of 2 days of oxygen supplementation, and 8 patients had used a median ventilator of 1.5 days (range 1 to 22).
Within 1 to 3 days after the start of acartini treatment, most patients in the oxygen supplement group had significant reductions in inflammation and improved breathing. Of the 11 patients, 8 were discharged without the need for oxygen. Although the benefit of acalabrutinib was not significant among ventilator patients, four of the eight patients were able to stop needing a ventilator, and two of them were eventually discharged. The authors point out that ventilator patients are clinically diverse, including patients with long-term ventilator use and major organ dysfunction. Two patients in the group died.
Blood samples from patients participating in the study showed that levels of interleukin-6 (IL-6) decreased after treatment with acalabrutinib, where IL-6 is a major cytokine associated with high inflammation in patients with severe COVID-19. The count of lymphocytes (a type of white blood cell) in most patients also improved rapidly. Low lymphocyte count is associated with worse clinical outcomes in patients with severe COVID-19. The researchers also examined blood cells from patients with severe COVID-19 who were not involved in the study. Compared with healthy volunteers, they found that these patients with severe COVID-19 had higher BTK protein activity and higher IL-6 production. These results suggest that acalabrutinib may be effective because its target BTK has high activity in immune cells of critically ill COVID-19 patients.
References
1.Roschewski, M., Lionakis, M. S., Sharman, J. P., Roswarski, J., Goy, A., Monticelli, M. A., … & Collen, J. (2020). Inhibition of Bruton tyrosine kinase in patients with severe COVID-19. Science Immunology, 5(48).
2.Treon, S. P., Castillo, J., Skarbnik, A. P., Soumerai, J. D., Ghobrial, I. M., Guerrera, M. L., … & Yang, G. (2020). The BTK-inhibitor ibrutinib may protect against pulmonary injury in COVID-19 infected patients. Blood.