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 ibrutinib-treated patients.
Highlights
Invasive fungal infections (IFIs) are opportunistic diseases that can occur in hematological malignancies in the presence of multiple predisposing factors
Its use is indicated in chronic lymphocytic leukemia (CLL), both in first and subsequent lines of treatment, in mantle cell lymphoma (MCL), in marginal zone lymphoma (MZL) and Waldenstrom Macroglobulinemia (WM) [146]
Very promising results have been reported in other lymphoproliferative disorders, including primary central nervous system lymphoma (PCNSL) [56,57]
Summary
Invasive fungal infections (IFIs) are opportunistic diseases that can occur in hematological malignancies in the presence of multiple predisposing factors. New drugs targeting the B-cell receptor signaling pathway (BCR inhibitors, BCRi) have been introduced in the treatment algorithm of CLL and of other chronic lymphoproliferative disorders, demonstrating a high efficacy in relapsed/refractory patients and in high risk patients with TP53 deletion or mutations [10,11]. These small molecules were initially considered less immunosuppressive than chemo-immunotherapy and BCRi were reported, in some cases, to partially revert the immunosuppressive environment typical of CLL [12,13]. The topic of immunomodulatory effect of ibrutinib on adaptive and innate immune activation is addressed and some clinical recommendations are included in the last section
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