Ibrutinib for chronic lymphocytic leukemia in the setting of respiratory failure from severe COVID‐19 infection: Case report and literature review

Abstract Ibrutinib, a known Burton's tyrosine kinase (BTK) and interleukin‐2 inducible T‐cell kinase (ITK) inhibitor, is used for the treatment of B‐cell disorders (chronic lymphocytic leukemia [CLL] and various other lymphomas) and chronic graft versus host disease following allogeneic hematopoietic cell transplantation. Because it is considered an immunosuppressant, continuation of ibrutinib is often debated when patients have an active infection, and this becomes an especially difficult decision in the setting of coronavirus disease 2019 (COVID‐19). Here, we describe a patient with CLL who was on ibrutinib then developed severe COVID‐19 infection requiring mechanical ventilation. We elected to continue ibrutinib the same day he was intubated, reasoning that BTK inhibition in myeloid immune cells has been shown to reduce or even reverse influenza‐mediated acute lung injury and that ITK inhibition in T cells has correlated with reduction in viral replication, and therefore may have an advantage in this setting. Ibrutinib also has been shown to block Src family kinases, which potentially could result in reduction of viral entry and the inflammatory cytokine response in the lungs. The patient was extubated after 9 days with a complex hospital course and eventually discharged on room air. The only way to rationally inform these decisions and explore similar potentially promising leads in this pandemic is to conduct carefully done clinical trials.

on ibrutinib then developed severe COVID-19 infection requiring mechanical ventilation. We elected to continue ibrutinib the same day he was intubated, reasoning that BTK inhibition in myeloid immune cells has been shown to reduce or even reverse influenza-mediated acute lung injury and that ITK inhibition in T cells has correlated with reduction in viral replication, and therefore may have an advantage in this setting. Ibrutinib also has been shown to block Src family kinases, which potentially could result in reduction of viral entry and the inflammatory cytokine response in the lungs.
The patient was extubated after 9 days with a complex hospital course and eventually discharged on room air. The only way to rationally inform these decisions and explore similar potentially promising leads in this pandemic is to conduct carefully done clinical trials.

K E Y W O R D S
acute respiratory distress syndrome, BTK inhibitor, COVID-19, chronic lymphocytic leukemia, Ibrutinib

INTRODUCTION
(FDA) for use in chronic lymphocytic leukemia (CLL), mantle cell lymphoma, marginal zone lymphoma, and chronic graft versus host disease (GvHD). In the ILLUMINATE study, which led to FDA approval of ibrutinib as front-line therapy for CLL, ibrutinib decreased inflammatory cytokines associated with infusion-related reactions when patients received the anti-CD20 antibody obinutuzumab [3]. Ibrutinib's immune suppressive activity was the basis of approval for chronic GvHD in allogeneic hematopoietic cell transplant patients (overall response rate 67%) [4]. However, there is concern that ibrutinib could exacerbate infection in susceptible patients. Treon et al described six patients with Waldenstrom macroglobulinemia who were on ibrutinib and diagnosed with COVID, and found that only one out of six patients required hospitalization [5]. Here, we describe a patient with CLL on ibrutinib, who developed severe COVID-19 infection, and we discuss the scientific rationale that informed our decision-making process at the bedside. there was concern that his clinical course would be more aggressive.

CASE DESCRIPTION
Ventilation was set for lung protective strategy targeting a tidal volume of 6 mL/kg ideal body weight with high positive end expiratory pressure, coupled with aggressive airway clearance.
After an interdisciplinary discussion, ibrutinib was resumed at a higher dose of 560 mg (starting day 2 of admission). Although inhibition of BTK with ibrutinib is covalent, inhibition of other immune-mediated kinases is noncovalent, and thus higher dose were used to achieve enough inhibition [6]. He also received one dose of hydroxychloroquine on admission, which was not continued, and two doses of tocilizumab on days 5 and 6 for recurring fever and increasing C-reactive protein (CRP). His fever resolved and CRP improved after tocilizumab (Figure 1A). D-dimer levels initially increased from 484 ng/mL on admis-F I G U R E 1 Laboratory data of CLL patient on ibrutinib with severe COVID-19 infection. A, Maximum temperature in 24 hours (T max ) (blue) and C-reactive protein (orange). B, D-dimer (blue) and platelet count (orange). C, White blood cell count (WBC) (blue) and absolute lymphocyte count (ALC) (orange) in relation to day of hospitalization. Green shaded areas: intubated. Yellow bar: ibrutinib use. T: tocilizumab sion to 6573 ng/mL, and declined after starting ibrutinib ( Figure 1B).
Similarly, the platelet count that was as low as 47 K/μL on admission improved to >100 K/μL. He also had normalization of leukopenia and lymphopenia after ibrutinib ( Figure 1C).  injury and pathogenesis observed [10]. Therefore, selective immunosuppression may modulate this response and improve outcomes.

Roschewski et al described 19 patients with COVID-19 that was
given another BTK inhibitor, acalabrutinib, off label [11]. They found that overall 10 out of the 19 patients who were hospitalized and needed supplemental oxygen or intubation were successfully discharged on room air. These patients had improved lymphocyte count similar to our patient after starting acalabrutinib. However, these patients were not previously on BTK inhibitors and did not have an underlying hematologic malignancy.

BTK inhibition reduces lung injury. In addition to expression on B cells,
BTK is expressed in myeloid immune cells including macrophages, monocytes, and neutrophils [12]. BTK binds and activates the toll-like receptor 4 (TLR4) pathway in these cells [13,14], which leads to induction of proinflammatory cytokines by the NFkB pathway [15]. Silencing BTK by intratracheal delivery of BTK siRNA caused suppression in NFkB, p38 MARK, and iNOS signaling pathways, which resulted in protection of acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) in a murine sepsis model [16]. and inflammatory infiltration compared with untreated mice in an ALI model [17]. Ibrutinib inhibition of BTK has also been shown to reduce myeloid cell inflammatory response during pneumococcal pneumonia induced ALI [18].
Furthermore, inhibition of BTK by ibrutinib rescued mice from lethal influenza-induced ALI [19]. In an influenza A virus-associated lung injury model, all mice treated with saline died or lost more than 30% of body weight, while ibrutinib-treated mice had a weight loss nadir at day 4 and recovered to normal by day 8-9. The ibrutinib-treated mice had less inflammatory cell recruitment on histology and reduced appearance of ground glass opacities on CT. These mice also showed less total protein and WBC in BAL fluid. Taken together, these results support the notion that BTK inhibition maybe a new drug target for viral-induced ARDS.

ITK inhibition reduces viral replication. ITK activation causes T-
cell activation, cytokine release, and rapid proliferation [20]. T-cellmediated immunity plays a role in clearance of viral infections [21].
ITK is upregulated on T-cell membranes after infection with influenza.
Importantly, g shRNA that targets and downregulates ITK leads to inhibition of influenza replication in infected T cells. Ibrutinib is an irreversible inhibitor of ITK and inhibits the formation of Th2 immunity, while Th1 CD4 T cell and CD8 T cells remain mostly active due to other redundant tyrosine kinases [22]. In CLL patients, as in our patient above, ibrutinib may maintain interferon-γ production from Th1 cells but with a reduction in IL-4 secreting Th2 T cells in peripheral blood.
Furthermore, ibrutinib was able to rescue antigen-specific CD8 T-cell response in an immune suppressive leukemia mouse model (EuTCL1).
CD8 T cells in CLL patients on chronic ibrutinib had less PD1 expression, allowing them to be more active [23]. In addition, up to 74% of CLL patients on ibrutinib were able to achieve seroprotective titer antibody response to influenza after receiving the vaccine [24]. These results suggest that ITK blockade with ibrutinib can reduce viral replication while maintaining important Th1 immunity to synergistically lead to elimination of the virus.
Ibrutinib also targets other kinases, which may contribute to better outcomes in viral infections. Src family kinase (SFK) inhibition blocks single-stranded RNA virion assembly and entry. Ibrutinib is known to inhibit HCK, part of the SRC family of kinases, which is expressed in lung tissue. Targeting of SFK with saracatinib led to inhibition of Middle East respiratory syndrome coronavirus (MERS-CoV) replication [25]. HCK regulates ADAM17 [26], which can cleave ACE2, freeing