BOSTON – Observations from the Dana Farber Cancer Institute suggested that Bruton tyrosine kinase (BTK) inhibitors used to treat blood cancers might also be effective in controlling “cytokine storms,” the exaggerated immune response associated with COVID-19 in severely ill patients.

A letter in the journal Blood discussed the potential for ibrutinib, which is used to treat indolent B-cell malignancies and chronic graft-versus-host disease, to moderate pulmonary inflammatory cytokines, lung injury, and death. Those effects also were  demonstrated in a highly relevant lethal flu animal model, according to Dana Farber researchers.1

Meanwhile, a randomized, global clinical trial has been launched to assess the potential of the BTK inhibitor acalabrutinib, marketed as Calquence, in the treatment of the exaggerated immune response (cytokine storm) associated with COVID-19 infection in severely ill patients.

The Phase II CALAVI trial is based on earlier clinical data; researchers reported that acalabrutinib showed that a decrease in inflammation caused by BTK inhibition appeared to reduce the severity of COVID-19-induced respiratory distress in a small number of patients at Walter Reed National Military Medical Center.

In terms of ibrutinib, marketed as  Imbruvica, the study team sought to clarify its effect in COVID-19 patients. The Dana Farber researchers pointed out that they care for 600 to 800 Waldenstrom macroglobulinemia (WM) patients each year, and about 300 of them are on a BTK inhibitor.

When six WM patients receiving ibrutinib were diagnosed with COVID-19, they gave consent for the use of their data. The patients had median age of 66 years, and five were on the recommended treatment dose of 420 mg/d, while the sixth patient was on a reduced dose of 140 mg/d because of arthralgias. For all patients, the median time on ibrutinib was 52 months.

The letter authors advised that the median time with COVID-19–related symptoms prior to diagnostic testing was five days, and the median time since diagnosis of COVID-19 was 22 days. All six patients experienced cough and fever as prodromal symptoms.

Yet, the authors point out, the five patients on ibrutinib, 420 mg/d, did not experience dyspnea and did not require hospitalization. “Their course was marked by steady improvement, and resolution or near resolution of COVID-19–related symptoms during the follow-up period,” according to the report.

The patient on reduced dose ibrutinib experienced progressive dyspnea and hypoxia prompting hospitalization, however. “Chest computed tomography showed bilateral ground glass opacities and a pleural effusion on admission prompting a hold on ibrutinib, during which his hypoxia acutely worsened, necessitating supplemental oxygen use,” according to the letter. “Hydroxychloroquine (HCQ) and azithromycin were administered. Azithromycin was stopped after 3 days because of wide QRS complex tachyarrhythmia; HCQ was given for a total of 5 days. Hypoxia worsened and fever persisted during HCQ course. Ibrutinib was restarted at 140 mg/d, and tocilizumab, 400 mg, was coadministered on hospital day 5 with improved oxygenation, as well as decreased C-reactive protein (CRP) levels (83 mg/L to 9 mg/L). IV immunoglobulin was also given on hospital days 6 through 10. On day 10 of hospitalization, the patient experienced worsening hypoxia that was accompanied by increased CRP (28 mg/L) and required mechanical ventilation.”

Noting the lack of hypoxia in the other COVID-19–infected WM patients on full-dose ibrutinib, clinicians increased ibrutinib for the severely ill patient to 420 mg/d on days 11 and 12. They reported that a rapid improvement in oxygenation followed, and that, by day 14, oxygen saturation was 95% on room air, and he was discharged home off of supplemental oxygen and prescribed 420 mg/d of ibrutinib.

The authors noted that ibrutinib monotherapy appears to reduce proinflammatory and chemoattractant cytokines that greatly overlapped with those reported to be elevated in the plasma of SARS-CoV-1 and SARS-CoV-2 patients.

“Therefore, ibrutinib, and possibly other BTK inhibitors, may provide protection against lung injury and even improve pulmonary function in hypoxic patients with COVID-19, as we observed in this series of WM patients on ibrutinib,” the researchers wrote. “These findings should be considered hypothesis generating and preliminary in nature. Patients on ibrutinib, and possibly other BTK inhibitors, may well benefit with continuation of their therapy, despite the diagnosis of COVID-19.”

The authors called for validating their findings in other patient populations who are taking BTK inhibitors, including chronic lymphocytic leukemia patients.

The large, multicenter, global, randomized trial of acalabrutinib, meanwhile, uses a two-part patient-centric design to accelerate data capture and analysis. Part one evaluates the addition of the BTK inhibitor to best support care vs. best supportive care alone in patients hospitalized with COVID-19 who are not in the intensive care unit (ICU). The second part assesses the addition of acalabrutinib to best supportive care in a cohort of patients in the ICU.

  1. Treon SP, Castillo JJ, Skarbnik AP, et al. The BTK inhibitor ibrutinib may protect against pulmonary injury in COVID-19-infected patients. Blood. 2020;135(21):1912‐ doi:10.1182/blood.2020006288