In a letter published in the journal Blood, Steven P. Treon, MD, PhD, and colleagues reported a potential protective effect against pulmonary injury with the Bruton’s tyrosine kinase (BTK) inhibitor ibrutinib in patients diagnosed with COVID-19 who were receiving the agent for Waldenström’s macroglobulinemia.

Steven P. Treon, MD, PhD

Patient Courses

The authors identified six patients receiving ibrutinib for Waldenström’s macroglobulinemia who were diagnosed with COVID-19. Patients had a median age of 66 years. Five were receiving the recommended ibrutinib dose of 420 mg/d, with the sixth receiving a reduced dose of 140 mg/d due to the occurrence of arthralgias. The median time on ibrutinib was 52 months. All six patients had cough and fever as prodromal symptoms. The median time with COVID-19–related symptoms was 5 days prior to diagnostic testing and 22 days after COVID-19 diagnosis.

The five patients receiving ibrutinib at 420 mg/d experienced no dyspnea and did not require hospitalization. Their course was characterized by steady improvement and resolution or near-resolution of COVID-19–related symptoms during follow-up. The patient receiving ibrutinib at 140 mg/d developed progressive dyspnea and hypoxia and was hospitalized. Chest computed tomography scan showed bilateral ground glass opacities and a pleural effusion, which prompted withholding of ibrutinib; the hypoxia worsened, resulting in supplemental oxygen use.

The patent received treatment with hydroxychloroquine for 5 days and azithromycin, with hypoxia worsening. On day 5, the patient restarted ibrutinib at 140 mg/d and received tocilizumab at 400 mg, with improved oxygenation and decreased C-reactive protein (CRP) levels. Intravenous immunoglobulin was given on days 6 to 10. On day 10, hypoxia worsened and CRP level increased. Ibrutinib was increased to 420 mg/d on days 11 and 12, with a subsequent rapid improvement in oxygenation. After extubation late on day 12, improved oxygenation was maintained on supplemental oxygen.

By day 14, oxygen saturation was 95% on room air and CRP level had decreased to 6 mg/L. The patient was discharged home off supplemental oxygen on 420 mg/d of ibrutinib. At last follow-up at 7 days after discharge, the patient was continuing to do well, exhibiting no fever, cough, or dyspnea at rest. The patient remains on and is tolerating ibrutinib at 420 mg/d.

Potential Protective Effect of Ibrutinib

The authors discussed multiple lines of evidence that indicate that elevated levels of numerous inflammatory cytokines and chemoattractants found in patients with severe COVID-19 underlie the pulmonary injury observed in such cases. They described the potential role of BTK and its upstream activator HCK, which is also inhibited by ibrutinib, in driving inflammatory cytokine production initiated by alveolar type II cells in the lung (to which SARS-Cov-2 binds) and by resident macrophages. They observed that ibrutinib monotherapy has been found to reduce levels of  such inflammatory and chemoattractant cytokines in several disease states.

The authors concluded: “Ibrutinib and possibly other BTK inhibitors may therefore provide protection against lung injury, and even improve pulmonary function in hypoxic patients with COVID-19 as we observed in this series of [patients with Waldenström’s macroglobulinemia] on ibrutinib. These findings should be considered as 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. It will be important to further validate these findings in other patient populations on BTK inhibitors, including [patients with chronic lymphocytic leukemia]. Clinical trials examining the benefit of BTK inhibitors are being initiated by us and others in [patients with] COVID-19 in pulmonary distress, and the outcome of these prospective, randomized studies will be needed to confirm these preliminary observations.”

Dr. Treon, of Dana-Farber Cancer Institute, is the corresponding author for the Blood article.  

Disclosure: For full disclosures of the study authors, visit ashpublications.org/blood.