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Medical Director of Hematology Research
Willamette Valley Cancer Institute
Jeff P. Sharman, MD, has disclosed that he has received funds for research support from AbbVie, AstraZeneca, Genentech, Gilead Sciences, Pharmacyclics, and TG Therapeutics and consulting fees from AbbVie, AstraZeneca, Genentech, Pharmacyclics, and TG Therapeutics.
The Role of BTK in Hyperinflammatory Immune Response
Those of us who take care of patients with CLL are familiar with the use of the BTK inhibitors, ibrutinib and acalabrutinib, in treating this disease. In a recent CCO activity, Nicole Lamanna, MD, Danielle M. Brander, MD, and I discussed the BCR pathway and BTK in tumor development, as well as the use of BTK inhibitors in the treatment-naive and relapsed/refractory settings in CLL, in addition to future directions for this class of agents. One topic that came up in our discussion was BTK inhibitors as antiinflammatory agents and some new data emerging regarding their potential for the management of patients with COVID-19. BTK regulates signaling and activation of macrophages and patients with severe COVID-19 have demonstrated hyperinflammatory immune responses indicative of macrophage activation. On ex vivo analysis, substantially elevated BTK activity was noted with autophosphorylation and increased IL-6 production from patients with severe COVID-19 vs healthy volunteers. In fact, ibrutinib actually has demonstrated efficacy as an effective therapy in dampening hyperinflammatory immune response and has an indication for the management of chronic (steroid-refractory) graft-vs-host disease (GVHD), a life-threatening inflammatory complication of allogeneic stem cell transplantation. In addition, there is a preclinical model in which mice were deliberately infected with a lethal dose of influenza (another RNA virus) resulting in pulmonary pathology very similar to what is seen in COVID. Those mice could be protected by use of BTK inhibitors.
New Data for BTK Inhibitors in Patients with COVID-19
My colleagues and I published a paper recently in Science Immunology, in which acalabrutinib was used as a therapy for patients with COVID-19 infection and severe acute respiratory distress syndrome (ARDS). This was an exploratory dataset. When a monocyte swallows the virus, this signals through the BTK pathway, leading to the exaggerated inflammatory response or “cytokine storm” through modulation of pulmonary macrophages, dendritic cells, and/or neutrophils. That cytokine storm becomes the mechanism by which patients get into trouble with respect to inflammation and severe respiratory complications. Patients with COVID-19 demonstrate elevated levels of inflammatory cytokines and chemokines, which are even higher in those requiring intensive care. As this inflammatory response biologically mirrors macrophage activation syndrome, this suggests that targeting the immune system may be effective at reducing the severity of severe respiratory complications in patients with COVID-19.
In this pilot study, acalabrutinib was administered during a 10- to 14-day period off label to 19 patients who were hospitalized with severe COVID-19—11 were receiving supplemental oxygen and 8 were on mechanical ventilation. Eighteen of the 19 patients had increasing oxygen demand at the time of treatment initiation. A proportion of patients also received concomitant treatments for COVID-19, including steroids and/or hydroxychloroquine but none had received an anti–IL-6 receptor antibody (eg, tocilizumab) or antiviral therapy with remdesivir.
Pulmonary Function and Inflammation After Acalabrutinib in Patients With COVID‑19
As described in the paper, among patients receiving oxygen and those who were mechanically ventilated, gas exchange improved over time with acalabrutinib, inflammatory markers (C-reactive protein and IL-6) decreased rapidly, and we also saw improvement in the absolute lymphocyte count. And, plotting the gas exchange relative to inflammation, there was a clear indirect relationship that was statistically significant and—for those patients not on mechanical ventilation—the same was true of the lymphocyte count.
Following acalabrutinib therapy, oxygenation improved in 9 of 11 (82%) of patients in the supplemental oxygen group and 8 of 11 (73%) patients in this cohort were discharged on room air. Four of 8 patients in the mechanical ventilation group were successfully extubated (2 were discharged on room air).
These are pilot data, but it gives us greater comfort utilizing BTK inhibitors for patients with CLL who require therapy. It also extends a preclinical hypothesis that these agents may effectively treat COVID. Further study is required.
On the Horizon
These exciting preliminary data suggest that BTK inhibition is a promising therapeutic strategy in treating patients with severe COVID-19 and 2 confirmatory, prospective, randomized controlled phase II trials (the CALAVI trial at locations in Europe and the CALAVI US trial in the United States) have been initiated as well as a phase II trial of ibrutinib in patients with severe COVID-19 and pulmonary injury (iNSPIRE). We look forward to those results.
Would you recommend a clinical trial of acalabrutinib in your patients with COVID-19? Would you be more likely to use BTK inhibitors to treat patients with CLL who are at higher risk for contracting SARS-CoV-2? Please join the discussion by sharing your experiences in the comment box!