TO THE EDITOR:
The Bruton tyrosine kinase (BTK) inhibitor ibrutinib is used to treat indolent B-cell
malignancies and chronic graft-versus-host disease (cGVHD). The potential for ibrutinib
to abrogate pulmonary inflammatory cytokines, lung injury, and death was demonstrated
in a highly relevant lethal flu animal model.
1
Therefore, we sought to clarify the impact of ibrutinib in COVID-19 patients. We care
for 600 to 800 Waldenstrom macroglobulinemia (WM) patients each year, ∼300 of whom
are on a BTK inhibitor. We identified 6 patients receiving ibrutinib for WM who were
diagnosed with COVID-19; these patients consented to the use of their data. Their
clinical characteristics appear in Table 1. Their median age was 66 years, and 5 were
on the recommended treatment dose of 420 mg/d; 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. Their median time with COVID-19–related symptoms prior to diagnostic
testing was 5 days, and the median time since diagnosis of COVID-19 was 22 days. All
6 patients experienced cough and fever as prodromal symptoms. The 5 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.
Table 1.
Clinical characteristics of 6 patients with WM on ibrutinib with COVID-19 infection
Demographics
Patient 1
Patient 2
Patient 3
Patient 4
Patient 5
Patient 6
Age, y
65
61
72
67
71
58
Sex
M
M
F
F
M
M
Time since B-cell diagnosis, mo
39
54
95
202
52
107
Received treatment prior to ibrutinib for WM
No
No
Yes
Yes
No
Yes
Time on ibrutinib, mo
39
54
83
50
47
85
Dose of ibrutinib, mg/d
420
420
420
420
420
140-HELD-420
COVID-19 symptoms
Time with symptoms prior to COVID-19 diagnostic testing, d
5
2
6
7
10
5
Time since COVID-19 diagnostic testing, d
24
20
17
28
13
29
Cough
Yes
Yes
Yes
Yes
Yes
Yes
Fever
Yes
Yes
Yes
Yes
Yes
Yes
Dyspnea
No
No
No
No
No
Yes
Sore throat
Yes
No
No
No
No
Yes
Taste loss
No
No
Yes
No
Yes
No
Smell loss
No
No
Yes
No
Yes
No
Hospitalization
No
No
No
No
No
Yes
Required ICU admission
Yes
No
No
No
No
Yes
Required supplemental O2
No
No
No
No
No
Yes
Required mechanical ventilation
No
No
No
No
No
Yes
Other COVID-19 symptoms
No
Anorexia
Diarrhea
Headache
No
No
Other medication for COVID-19
HCQ, AZ
NA
No
NA
No
HCQ, AZ, TOCI
Disposition
COVID-19 symptoms resolved
No
Yes
Yes
Yes
Yes
No
COVID-19 symptoms persist
Yes
No
Yes
Yes
No
Yes
COVID-19 symptoms improved
Yes
Yes
Yes
Yes
Yes
Yes
140-HELD-420 denotes that this patient was on 140 mg/d of ibrutinib prior to hospitalization
that was held upon admission; he experienced worsening hypoxia after ibrutinib was
held and required mechanical ventilation, following which he was restarted on 420
mg/d of ibrutinib and showed rapid improvement in oxygenation.
AZ, azithromycin; F, female; HCQ, hydroxychloroquine; ICU, Intensive Care Unit; M,
male; TOCI, tocilizumab.
The patient on reduced-dose ibrutinib (Patient 6; Table 1) experienced progressive
dyspnea and hypoxia prompting hospitalization. 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.
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. Given the lack of hypoxia in the other
COVID-19–infected WM patients on full-dose ibrutinib, ibrutinib was increased to 420
mg/d on days 11 and 12. A rapid improvement in oxygenation followed, and the patient
was successfully extubated late on day 12 and maintained oxygen saturations of 94%
to 96% on 3 L/min supplemental oxygen by nasal cannula. The next day, supplemental
oxygen was decreased to 2 L/min, with oxygen saturations of 96% to 98% and a CRP level
of 10 mg/L. On day 14, oxygen saturation was 95% on room air, repeat CRP level was
6 mg/L, and he was discharged home off supplemental oxygen and on 420 mg/d of ibrutinib.
Seven days later, he continues to do well, without fever, cough, or dyspnea at rest.
He remains on ibrutinib, 420 mg/d, and is tolerating therapy well.
Pulmonary failure is the main cause of mortality related to COVID-19 infection.
2,3
Up to 80% of patients hospitalized for COVID-19 infection require supplemental oxygenation,
of whom 30% to 40% may require mechanical ventilation.
2,4,5
SARS-CoV-2 binds via the ACE2 receptor that is highly expressed on alveolar type II
(ATII) cells in the lung.
6
ATII cells constitute 5% to 15% of the lung epithelium. Although ATI cells are highly
adapted for gas exchange, ATII cells have a specialized role in innate immune response.
7
-9
ATII cells express Toll-like receptors (TLRs) and can trigger inflammatory cytokines
and chemoattractants in response to pathogens that recruit and activate other immune
cells, including macrophages and neutrophils.
7
-9
Highly relevant to coronavirus infection, expression of proinflammatory and chemoattractant
cytokines interleukin-1β (IL-1β), IL-6, IP-10/CXCL10, monocyte chemoattractant protein-1
(MCP-1), and tumor necrosis factor-α (TNF-α) was identified in ACE2+ cells from autopsy
tissue of SARS-CoV-1–infected patients, which appeared to be causally related to the
acute lung injury and pathogenesis observed with SARS-CoV-1.
10
A similar profile of elevated cytokine levels was reported in the plasma of SARS-CoV-1
patients during the progressive and end stage of infection,
11
which was consistent with an M1-polarized macrophage response.
12
SARS-CoV-1 shares 86% homology with SARS-CoV-2. SARS-Cov-2 patients requiring intensive
care also showed elevated plasma levels of inflammatory cytokines and chemoattractants,
such as IL-2, IL-6, IL-7, IL-10, granulocyte colony-stimulating factor, IP-10/CXCL-10,
MCP-1/CCL2, MIP-1a/CCL3, and TNF-α.
13
The importance of inflammatory cytokines to lung injury in SARS-CoV-2–infected patients
has been suggested by reports of benefit with IL-6 and IL-6 receptor–blocking antibodies,
and clinical trials to examine their use have been initiated (NCT04317092, NCT04306705,
NCT04315298).
We and other investigators previously showed that BTK and its upstream activator HCK
were involved in TLR-mediated signaling.
14
-16
BTK and HCK are triggered by MYD88, a TLR adaptor protein that signals for all TLRs,
with the exception of TLR3, in response to viral and bacterial pathogens, including
coronaviruses.
17
ATII cells express TLRs, as do alveolar macrophages that coordinate inflammatory responses
with ATII cells.
7
-9
As components of TLR/MYD88 signaling, BTK and HCK can drive inflammatory cytokine
production through ERK1/2.
18
In a transgenic mouse model, activated HCK overexpression promoted extensive pulmonary
inflammation and an enhanced innate immune response, particularly in older mice.
19
Elevated levels of TNF-α were identified in the bronchoalveolar lavage fluids of these
mice following lipopolysaccharide challenge. The pulmonary pathology findings from
these mice show great overlap with those from patients with COVID-19 infection, which
included serous and fibrin exudation with alveolar infiltration consisting mostly
of macrophages and monocytes.
20
Ibrutinib is a highly potent covalent inhibitor of BTK (biochemical 50% inhibitory
concentration [IC50], 0.5 nM). Ibrutinib is also a potent reversible inhibitor of
HCK (IC50, 49 nM). The IC50 levels for BTK and HCK are within the pharmacologically
attainable dosimetry of orally administered ibrutinib.
16
Serially collected blood samples from patients with chronic lymphocytic leukemia (CLL),
WM, and cGVHD on ibrutinib monotherapy showed marked reductions in 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, as well as in ACE2+ cells from
lung tissue of SARS-CoV-1 patients (Table 2).
10,11,13,21
-23
In the ILLUMINATE randomized study, CLL subjects treated with ibrutinib immediately
prior to infusion with obinutuzumab also showed significantly decreased levels of
inflammatory cytokines associated with infusion-related reactions (a cytokine release
syndrome).
24
These findings are consistent with a shift from an M1- to an M2-polarized macrophage
response following ibrutinib and are supported by preclinical and clinical studies
showing dependence of macrophage lineage commitment on BTK function.
25
Table 2.
Summary of proinflammatory and chemoattractant cytokine patterns in patients infected
with SARS-CoV-1 and SARS-CoV-2 and following ibrutinib treatment in patients with
CLL, WM, or and cGVHD
He et al
10
Jiang et al
11
Huang et al
13
Niemann et al
21
Greil et al
24
Vos et al
22
Miklos et al
23
Patient population
CoV-1*
CoV-1*
CoV-2*
CLL on ibrutinib†
CLL on ibrutinib†
WM on ibrutinib†
cGVHD on ibrutinib†
Tissue
ACE2+ cells
Plasma
Plasma
Plasma
Plasma
Plasma
Plasma
GM-CSF
↑
↓
IL-1β
↑
IL-2
↑
↓ (IL2RA)
IL-6
↑
↑
↓
↓
↓
IL-7
↑
IL-8
↑
↓
↓
↓
↓
IL-10
↑
↓
↓
Variable
IP-10/CXCL10
↑
↑
↓
↓
↓
MCP-1/CCL2
↑
↑
↑
↓
↓
↓
MIP-1A/CCL3
↑
↓
↓
MIP-1B/CCL4
↑
↓
↓
↓
TNF-α
↑
↓
↓
↓
↓
↑, denotes elevated in patients with SARS-CoV-1 or SARS-CoV-2; ↓, denotes levels decreased
or inhibited in patients with the indicated condition with ibrutinib treatment; GM-CSF,
granulocyte-macrophage colony-stimulating factor.
*
Patients infected with SARS-CoV-1 or SARS-CoV-2.
†
Patients with CLL, WM, or cGVHD.
The potential for ibrutinib to abrogate lung injury and death was also demonstrated
in an experimental model wherein mice challenged with a lethal intranasal inoculum
of a mouse-adapted strain of H1N1 influenza virus were protected against lung injury.
Control mice developed respiratory failure, along with histological and computed tomography
findings consistent with lung injury, in sharp contrast to the mice that received
ibrutinib.
1
Control mice also lost weight and died, whereas those treated with ibrutinib recovered
their weight after a brief loss, and all survived.
1
Notably, mice treated with ibrutinib also showed decreased inflammatory cell infiltration,
as well as proinflammatory cytokines in lung tissues, that included proinflammatory
and chemoattractant cytokines, such as IL-1β, IL-6, KC/CXCL1, TNF-α, and MCP-1, in
SARS-Cov-1 and SARS-CoV-2 patients.
1
The findings provide rationale that an exaggerated cytokine release syndrome triggered
in ATII cells and resident macrophages by SARS-CoV-2 may underlie pulmonary injury
associated with COVID-19.
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. 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. It will be important to validate these findings
in other patient populations who are taking BTK inhibitors, including CLL patients.
Clinical trials examining the benefit of BTK inhibitors are being initiated by us
and other investigators in COVID-19 patients in pulmonary distress, and the outcome
of these prospective randomized studies will be needed to confirm these preliminary
observations.