Immunomodulatory effect of ibrutinib: Reducing the barrier against fungal infections

Abstract

The Bruton tyrosine kinase (BTK) inhibitor ibrutinib is increasingly used in the treatment of chronic lymphocytic leukemia (CLL). Moreover, very promising results have been reported in other B-cell malignancies, including primary central nervous system lymphoma (PCNSL). Although well-tolerated in the majority of patients, ibrutinib demonstrates in some cases troublesome toxicities, including invasive fungal infections (IFIs). In the present review, we summarize clinical manifestations of IFIs in patients treated with ibrutinib, generally characterized by an early onset, mild clinical manifestations, asymptomatic/low symptomatic pulmonary localization and high incidence of central nervous system (CNS) involvement. IFI risk appears particularly increased in patients receiving ibrutinib associated with other immune modulator agents, especially with steroids or immune-chemotherapy. Moreover, the immunomodulatory effect of ibrutinib is described, pointing the attention on the involvement of specific molecules targeted by ibrutinib in innate and adaptive response to fungal infection. Overall, the findings indicate the ibrutinib may rapidly impair innate immune cell functions, while concomitantly restoring an effective protective potential of adaptive immune compartment. A correct awareness, especially when other predisposing factors are present, is warranted about the potential risk of IFIs in ibrutinibtreated patients.

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

“…An unexpected high incidence of Pneumocystis jirovecii pneumonia has been described in CLL patients receiving single-agent ibrutinib ( 31 ). In addition cases of IA have been characterized by an early onset, mild clinical manifestations, asymptomatic/low symptomatic pulmonary localization, and high risk of CNS involvement ( 14 , 16 , 32 , 33 ). The reason why an association of IFI during treatment with ibrutinib was observed is still not completely clear.…”

COVID-19 severity and mortality in patients with chronic lymphocytic leukemia: a joint study by ERIC, the European Research Initiative on CLL, and CLL Campus

“…CLL is a paradigmatic example of malignancy associated with impaired immune responses to common pathogens in a context of a profound immune dysregulation reflected by hypogammaglobulinemia, qualitative and quantitative B-and T-cell defects, including impaired response to vaccination, and CD4 + lymphopenia, as well innate immune dysfunction and neutropenia [14,15]. This can be further exacerbated by antileukemic treatments that by definition impact on the host immune system, some applied continuously until progression [16]. This could arguably compromise the capacity of patients with CLL to clear the virus, with a possible higher infection risk for this population.…”

Non‐Aspergillus invasive mould infections in patients treated with ibrutinib

“…Therefore, CLL presents with features that could potentially correlate with increased risk for NAIMIs. An additive or synergistic contribution of IBR to the increased risk for IMIs may be driven by BTK‐dependent effects on innate and adaptive immunity, IBR off‐target effects, given that IBR is a non‐selective inhibitor of both BTK and other alternative kinases 29 . Several studies indicate that patients receiving IBR may be more susceptible to IFIs, secondary to inhibition of macrophage responses and neutrophil dysfunction 29,30 .…”

“…An additive or synergistic contribution of IBR to the increased risk for IMIs may be driven by BTK‐dependent effects on innate and adaptive immunity, IBR off‐target effects, given that IBR is a non‐selective inhibitor of both BTK and other alternative kinases 29 . Several studies indicate that patients receiving IBR may be more susceptible to IFIs, secondary to inhibition of macrophage responses and neutrophil dysfunction 29,30 . In a recent study, IBR impaired the functions and anti‐ Aspergillus responses of neutrophils obtained from 27 patients with lymphoid malignancies (mostly comprised of CLL patients, 72%), compared to those obtained from healthy donors, by decreased production of reactive oxygen species (ROS), impairment of their capacity to engulf Aspergillus and inability to efficiently kill germinating conidia 31 .…”

“…29 Several studies indicate that patients receiving IBR may be more susceptible to IFIs, secondary to inhibition of macrophage responses and neutrophil dysfunction. 29,30 In a recent study, IBR impaired the functions and anti-Aspergillus responses of neutrophils obtained from 27 patients with lymphoid malignancies (mostly comprised of CLL patients, 72%), compared to those obtained from healthy donors, by decreased production of reactive oxygen species (ROS), impairment of their capacity to engulf Aspergillus and inability to efficiently kill germinating conidia. 31 It is unknown, however, whether these effects also apply to non-Aspergillus moulds.…”