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The role of ibrutinib in COVID-19 hyperinflammation: A case report

Immune modulation in COVID-19 is emerging as an important therapeutic strategy as increasing evidence suggests that inflammatory pathways are implicated in lung damage. Bruton tyrosine kinase inhibitors (BTKi), such as ibrutinib, are commonly used to treat indolent B-cell neoplasms and chronic graft-versus-host disease (GvHD). Given their potential to suppress pulmonary inflammatory cytokines and lessen acute lung injury, this could be applicable in the context of hospitalised COVID-19 patients. We describe an 81 year-old male receiving ibrutinib for Waldenstrom macroglobulinaemia (WM) who was hospitalised with COVID-19. On stopping the BTKi due to concerns of additional immunosuppression, he required non-invasive ventilation (NIV) in the intensive care unit (ICU) and demonstrated prompt clinical recovery when ibrutinib was reinstated. Continuing ibrutinib in patients with COVID-19 may be advantageous given its immunomodulatory properties and withdrawal of ibrutinib therapy may be detrimental. Further evidence is required to explore the potential therapeutic impact of BTKis and other immunomodulatory agents on the clinical course of COVID-19 as is currently being carried out in a number of clinical trials.

Immune modulation in COVID-19 is emerging as an important therapeutic strategy as increasing evidence suggests that inflammatory pathways are implicated in lung damage. Bruton tyrosine kinase inhibitors (BTKi), such as ibrutinib, are commonly used to treat indolent B-cell neoplasms and chronic graft-versus-host disease (GvHD). Given their potential to suppress pulmonary inflammatory cytokines and lessen acute lung injury, this could be applicable in the context of hospitalised COVID-19 patients. We describe an 81 year-old male receiving ibrutinib for Waldenstrom macroglobulinaemia (WM) who was hospitalised with COVID-19. On stopping the BTKi due to concerns of additional immunosuppression, he required non-invasive ventilation (NIV) in the intensive care unit (ICU) and demonstrated prompt clinical recovery when ibrutinib was reinstated. Continuing ibrutinib in patients with COVID-19 may be advantageous given its immunomodulatory properties and withdrawal of ibrutinib therapy may be detrimental. Further evidence is required to explore the potential therapeutic impact of BTKis and other immunomodulatory agents on the clinical course of COVID-19 as is currently being carried out in a number of clinical trials.
Crown Copyright © 2021 Published by Elsevier Ltd on behalf of International Society for Infectious Diseases. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/ licenses/by-nc-nd/4.0/).

Background
Immune modulation in COVID-19 is emerging as an important therapeutic strategy as increasing evidence suggests that inflammatory pathways are implicated in lung damage (Mehta et al., 2020;Ye et al., 2020). Bruton tyrosine kinase inhibitors (BTKi), such as ibrutinib, are commonly used to treat indolent B-cell neoplasms and chronic graft-versus-host disease. Given their potential to suppress pulmonary inflammatory cytokines and lessen acute lung injury (Florence et al., 2019) this could be applicable in the context of hospitalised COVID-19 patients (Thibaud et al., 2020;Treon et al., 2020;Woyach, 2020). Patients already on treatment with BTKi may be at high risk of infection with poor outcomes given advanced age, comorbidities and immune dysfunction. However, a recent multicentre analysis did not show any negative impact of continuing BTKi treatment on the survival of patients with chronic lymphocytic leukaemia hospitalised due to COVID-19 infection (Mato et al., 2020). We report the outcome of an ibrutinib treated patient with COVID-19 who suffered respiratory deterioration after ibrutinib cessation and promptly improved after ibrutinib reintroduction.

Case
We describe an 81-year-old male receiving ibrutinib for Waldenstrom macroglobulinaemia who was hospitalised with COVID-19. Waldenstrom macroglobulinaemia is a relatively indolent lymphoproliferative disorder characterised by immunoglobulin(Ig)M monoclonal gammopathy and lymphoplasmacytic infiltrate in the bone marrow. On stopping the BTKi due to concerns of additional immunosuppression, he required noninvasive ventilation (NIV) in the intensive care unit (ICU) and demonstrated prompt clinical recovery when ibrutinib was reinstated.
On admission, the patient described a 1-week history of nausea, fever and dry cough with C-reactive protein (CRP) 73.4 mg/L and was commenced on intravenous piperacillin-tazobactam. COVID swab reverse transcription-polymerase chain reaction at admission was positive. His observations were stable, he did not require additional oxygen, and blood tests and chest x-ray were unremarkable. Five days later, 11 days since symptoms onset, he became pyrexial at 38 C, CRP had increased to 136 mg/L, and he was commenced on oral azithromycin and once-daily dexamethasone 8 mg. Repeat chest x-ray showed new pulmonary opacities, but he remained clinically stable with no oxygen requirement. Ibrutinib was withheld from day 6 of admission. CRP improved to 76 mg/L in accordance with the introduction of steroids (Markanday, 2015). Forty-four hours following the last dose of BTKi he developed a new, rapidly increasing, oxygen requirement and within 8 h he was admitted to ICU for NIV to achieve adequate oxygenation (day 7 of admission, 13 days since symptoms onset) (see Figure 1). Within 24 h of ITU admission, his BTKi was reinstated at full dose of 420 mg and remdesivir was commenced. A brief rise and subsequent fall in CRP followed (see Figure 1). After only 14 h of NIV (initial requirements of PEEP 8 and FiO2 55) his oxygen requirements decreased; the following day, he was stepped down to the ward on 4 L O 2 via nasal cannula. He continued to improve, and at 19 days after admission (day 25 of symptoms onset), he was medically fit for discharge with no supplementary oxygen requirement.

Discussion
With a half-life of only 4-6 h, the rapid deterioration of the patient occurred at a time point when the pharmacokinetics of ibrutinib suggest it would have been eliminated from the body; thus, any potential beneficial immune modulatory effects would no longer be active (Advani et al., 2020).
Consideration should be given to the potential contribution of 'ibrutinib withdrawal' symptoms, a known phenomenon typically occurring within 5 days following treatment cessation. However, documented symptoms of 'ibrutinib withdrawal'fever, generalised aches, headache and arthralgiawere absent. Furthermore, increased oxygen requirement has not been described as a withdrawal symptom (Castillo et al., 2018).
We acknowledge that commencing remdesivir as compassionate use, at the same time as reinstating ibrutinib, makes it difficult to attribute clinical and biochemical improvement to a specific agent. The timeliness of remdesivir's antiviral activity manifest as clinical improvement remains subject to ongoing research and as yet remains unclear (Rochwerg et al., 2020) and its efficacy remains debatable (Dyer, 2020).
The clinical events and timing of ibrutinib were not clearly mirrored in trends of ferritin or D-dimer.

Summary
Continuing ibrutinib in patients with COVID-19 may be advantageous given its immunomodulatory properties, and withdrawal of ibrutinib therapy may be detrimental. Further evidence is required to explore the potential therapeutic impact of BTKi and other immunomodulatory agents on the clinical course of COVID-19, as is currently being carried out in a number of clinical trials