Immunological effects of ibrutinib for patients with CLL and COVID-19

Chronic lymphocytic leukemia (CLL) is the most common type of leukemia in Western countries, predominantly affecting older patients and characterized by several alterations in the way the immune system functions. The advent of the SARS-CoV-2 pandemic has been challenging for patients with CLL, who are predisposed to infections due to the immunodeficiency related to the leukemia itself and to immunosuppression caused by cumulative treatments. The novel coronavirus activates a severe, aberrant, and uncontrollable inflammatory response, known as a cytokine storm, involving both innate and adaptive responses and leading to major acute clinical complications and high mortality rates for this high-risk group.

Ibrutinib is a Bruton’s tyrosine kinase (BTK) inhibitor with clinical efficacy for patients with relapsed/refractory CLL. Recent studies have suggested that ibrutinib could also offer protection against lung injury in patients with CLL and COVID-19 by moderating the hyperinflammatory state and managing better outcomes and shorter hospitalization. Despite this, BTK inhibitor treatment is often interrupted at the onset of COVID-19.

In a letter to the editor recently published in Haematologica, Stefania Fiorcari and colleagues examined the modulation of treatment with ibrutinib on the cytokines released by monocytes (CD14⁺) and T cells (CD3⁺) in patients with CLL and an active COVID-19 infection.¹

Study design

• Peripheral blood mononuclear cells (PBMCs) were isolated from patients with CLL who had not been infected with SARS-CoV-2.
• For the in vitro analysis, PBMCs from treatment-naïve patients with CLL were treated with ibrutinib or vehicle and then stimulated with SARS-CoV-2 peptides.
• For the ex vivo analysis, PBMCs from patients with CLL before and after 3 months of ibrutinib therapy were collected and stimulated with SARS-CoV-2 peptides.
• PBMCs were analyzed for TNF-α, IFN-γ, and IL-6 proinflammatory cytokine secretion.
• To identify the monocytic and T-cell population, PBMCs were stained with CD14⁺ and CD3⁺ antibodies, respectively.

Results

In vitro

Following stimulation of PBMCs from treatment-naïve patients with SARS-CoV-2 peptides, the investigators observed:

• a strong and significant secretion of proinflammatory cytokines, both by CD3⁺ T cells and CD14⁺ monocytes, characterized by a significant increase of TNF-α (p < 0.05) and IFN-γ (p < 0.01) release; and
• increased secretion of IL-6 (p < 0.05).

The following immunomodulatory modifications were reported following treatment with ibrutinib in the presence of stimulation with SARS-CoV-2 peptides:

• an increase of IFN-γ secretion by CD3⁺ T cells (p < 0.05);
• significantly impaired release of TNF-α and IFN-γ by CD14⁺ monocytes (p < 0.05); and
• a significant decrease of IL-6 secretion (p < 0.05).

Ex vivo

CLL patient samples before treatment and after 3 months of treatment with ibrutinib were evaluated to compare the response of CD3⁺ and CD14⁺ cells to SARS-CoV-2:

• there was no significant change in cytokine secretion from CD3⁺ T cells; however
• secretion of TNF-α and IFN-γ by CD14⁺ monocytes was significantly reduced after ibrutinib treatment, compared with pretreated cells (p < 0.05).

Conclusion

According to the available evidence, the inhibition of BTK, expressed by myeloid immune cells, does not seem to worsen the COVID-19-specific immune response, but rather it appears to mitigate inflammation through the NF-κB pathway and improve resolution of infection. The results of this study indicate a protective action of ibrutinib against COVID-19 by limiting the inflammatory cytokine storm and preventing lung injury, hence providing a rationale for continuation of ibrutinib treatment in patients with CLL who develop a SARS-CoV-2 infection.