BTK Inhibition Impairs the Innate Response Against Fungal Infection in Patients With Chronic Lymphocytic Leukemia

Abstract

Infections represent a cause of morbidity and mortality in patients affected by chronic lymphocytic leukemia (CLL). Introduction of new drugs in CLL clinical practice has showed impressive efficacy, in particular those targeting BTK. Among the consistent clinical data, an increasing number of reports describing the occurrence of unexpected opportunistic fungal infections has been reported during treatment with ibrutinib in the first 6 months of treatment. The reason underlying manifestations of invasive fungal infections in patients treated with ibrutinib is still under investigation. Our study aimed to understand the impact of BTK inhibition on immune response to fungal infection mediated by macrophages and CD14+ monocytic population obtained from CLL patients. Exposure to ibrutinib and acalabrutinib reduced signaling pathways activated by Aspergillus fumigatus determining an exacerbation of an immunosuppressive signature, a reduction of phagocytosis and a significant deficit in the secretion of inflammatory cytokines either in macrophages and monocytes isolated from CLL patients and healthy donors. These effects lead to a failure in completely counteracting conidia germination. In addition we investigated the biological effects of ibrutinib on monocyte counterpart in patients who were undergoing therapy. A significant impairment in cytokine secretion and a deficit of phagocytosis in circulating monocytes were detected after 3 months of treatment. Thus, our results uncover modifications in the innate response in CLL patients induced by ibrutinib that may impair the immunological response to fungal infection. KEYPOINTS BTK inhibition affects a productive immune response of CLL-associated macrophages (NLC) during Aspergillus fumigatus infection. Reduction of TNF-α secretion and phagocytosis are detected in monocytes isolated from CLL patients during ibrutinib therapy.

Comparative Analysis of BTK Inhibitors and Mechanisms Underlying Adverse Effects

“…A TLR9-dependent endosomally driven pathway was implicated to increase the susceptibility of patients on ibrutinib to IFI ( Bercusson et al, 2018 ). A recent report ( Fiorcari et al, 2020 ), shows that ibrutinib- or acalabrutinib-mediated BTK inhibition negatively affects CLL-associated macrophages during A. fumigatus infection. It was also reported that ibrutinib and acalabrutinib impaired M1 polarization in macrophages, a phenotype associated with an efficient anti−microbial immune response ( Colado et al, 2020 ).…”

“…Off-BTK effects in B- or non-B-cells have a therapeutic potential and they may also account for the observed AEs, since those cannot be explained by BTK inhibition alone. As will be discussed in greater detail below, binding to BTK in B-cell malignancies has a treatment effect, while inhibition of this kinase by BTKi in macrophages or neutrophils was suggested to impair the anti-fungal response ( Fiorcari et al, 2020 ). However, it should be pointed out that in X-linked agammaglobulinemia, defined by non-functional BTK, a similar overt propensity for invasive fungal infections is not seen, nor are there increased bleedings, skin manifestations, diarrhoeas or cardiovascular disease ( Smith and Berglöf, 1993 ; Ochs and Smith, 1996 ).…”

Nurse-Like Cells and Chronic Lymphocytic Leukemia B Cells: A Mutualistic Crosstalk inside Tissue Microenvironments

“…Recently, invasive fungal infections have been reported among patients receiving treatment with ibrutinib. In this scenario, ibrutinib is able to affect the ability of NLC to counteract Aspergillus fumigatus conidia germination due to reduced phagocytosis and the impairment of a productive inflammatory response with a decreased level of IL-1β and TNF-α [ 81 , 82 ].…”

BTK inhibitors for Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2): A Systematic Review

“…While BTK inhibition may supress the excessive in ammation caused by the innate immune response against SARS-CoV-2, it may also increase the risk for secondary infections. Fungal and other opportunistic infections such as pneumonia have been observed in CLL and other patients on ibrutinib [23,[50][51][52]. However concomitant use of CD20-depleting agents may confound such a risk since CD20-depleting agents are also associated with an increased risk of pneumonia [53].…”