Ibrutinib-based therapy impaired neutrophils microbicidal activity in patients with chronic lymphocytic leukemia during the early phases of treatment

Abstract

Ibrutinib is a tyrosine kinase inhibitor used in the treatment of a variety of lymphoid malignancies, including chronic lymphocytic leukemia (CLL). Drugs inhibiting B-cell-receptor (BCR)-associated kinases, including BTK inhibitors, act on B cells and on a wide spectrum of tissues and cells, including innate immunity cells. Thus, alterations in the Bruton's tyrosine kinase (BTK) kinase function could lead to an impairment of innate immune cells functions and to an increased infectious risk in patients receiving BTK inhibitors. We analyzed in vivo neutrophils oxidative burst, neutrophils granules release and cytokine production in relapsed/refractory CLL patients treated over time with ibrutinib as single-agent. We observed a dramatic reduction of neutrophils oxidative burst, Fc gamma receptors (FcγRs)-mediated degranulation and IL-8 plasma levels already after the first forty-eight hours of therapy with ibrutinib. However, ibrutinib treatment did not alter the surface expression of CD11b nor cytokine and proteinases release not mediated by FcγRs engagement. After three weeks, oxidative burst was still impaired, while degranulation and IL-8 levels were restored. In a group of CLL patients who survived for more than three years, all processes triggered by FcγRs completely recovered except the release of neutrophil elastase (NE) and IL-8. In conclusion, during the initial phases of ibrutinib therapy, the reduction of IL-8, NE, myeloperoxidase (MPO) levels and oxidative burst negatively impacted on mechanisms involved in neutrophils microbicidal activity.

Multifaceted Immunomodulatory Effects of the BTK Inhibitors Ibrutinib and Acalabrutinib on Different Immune Cell Subsets – Beyond B Lymphocytes

“…In line with its effects on receptor signaling pathways, ibrutinib treatment generally affects neutrophil activation in response to bacterial or fungal infection, which typically engage multiple TLRs, TREM-1 and NLRP3. Neutrophils purified from ibrutinib-treated CLL patients exhibit reduced E. coliinduced oxidative burst and bacteria killing capacity and slightly impaired neutrophil extracellular trap (NET) production Prevents allergen-IgE-mediated broncho-constriction in isolated human lung tissues Dispenza et al, 2020 Eliminates skin prick test reactivity in CLL patients Dispenza et al, 2017;Regan et al, 2017 Frontiers in Cell and Developmental Biology | www.frontiersin.org (Prezzo et al, 2019;Risnik et al, 2020). Ibrutinib treatment reduces systemic neutrophil activation and neutrophil influx in the lung during ceftriaxone-treated pneumococcal pneumonia in mice (de Porto et al, 2019).…”

“…Ibrutinib also inhibits FcγR signaling in neutrophils, causing reduced neutrophil degranulation and ADCP in response to opsonized pathogens and malignant cells. In the early phases of treatment, neutrophils purified from ibrutinib-treated CLL patients display decreased FcγR-mediated IL-8 production and degranulation in response to opsonized E. coli, leading to reduced release of neutrophil elastase (NE), myeloperoxidase (MPO) and lactoferrin (Prezzo et al, 2019). Ibrutinib potently inhibits ADCP of lymphoma cells opsonized with anti-CD20 (rituximab, obinutuzumab or ofatumumab) or tumor cells opsonized with anti-HER2 (trastuzumab) by fresh human neutrophils in vitro (Da Roit et al, 2015;Duong et al, 2015).…”

“…Given the lack of effects of acalabrutinib on FcγR-mediated ADCP in macrophages (Golay et al, 2017;VanDerMeid et al, 2018), it is not likely that acalabrutinib could inhibit FcγR-mediated ADCP in neutrophils, although direct evidence has not been reported. Thus, the inhibitory effects of ibrutinib on FcγR-mediated neutrophil activation and ADCP are likely mediated through its off-target inhibition on non-BTK TEC family kinases that modulate neutrophil functions (Prezzo et al, 2019). The exact target kinases and detailed molecular mechanisms of ibrutinib on FcγR signaling in neutrophils remain to be elucidated in future studies.…”

BTK inhibitors for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2): A systematic review

“…For example, ibrutinib has demonstrated a protective role against lethal influenza- and lipoteichoic acid-induced lung injury in mice, including the reduction of the inflammatory cytokine IL-6 [ 26 , 27 ]. Concurrent with the finding that neutrophilic expression of several granule proteins (myeloperoxidase, elastase, gelatinase) is BTK-dependent, CLL patients on ibrutinib had reduced neutrophil degranulation and rapid reduction of oxidative burst [ [28] , [29] , [30] ], which may account for the heightened risk of some BTKinib-treated patients to opportunistic fungal infections [ 31 ]. Other important roles recently observed include a possible role for BTK in NLRP3 inflammasome activation [ 32 ].…”

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

“…For example, ibrutinib has demonstrated a protective role against lethal in uenza-and lipoteichoic acidinduced lung injury in mice, including the reduction of the in ammatory cytokine IL-6 [18,19]. Concurrent with the nding that neutrophilic expression of several granule proteins (myeloperoxidase, elastase, gelatinase) is BTK-dependent, CLL patients on ibrutinib had reduced neutrophil degranulation and rapid reduction of oxidative burst [20][21][22], which may account for the heightened risk of some BTKinib-treated patients to opportunistic fungal infections [23]. Other important roles recently observed include a possible role for BTK in NLRP3 in ammasome activation [24].…”