Ibrutinib‐associated invasive fungal diseases in patients with chronic lymphocytic leukaemia and non‐Hodgkin lymphoma: An observational study

Abstract

Summary Background Invasive fungal diseases (IFD) are life‐threatening infections most commonly diagnosed in acute leukaemia patients with prolonged neutropenia and are uncommonly diagnosed in patients with lymphoproliferative diseases. Objectives Following the initial report of aspergillosis diagnosed shortly after beginning ibrutinib for chronic lymphocytic leukaemia, a survey was developed to seek additional cases of IFD during ibrutinib treatment. Methods Local and international physicians and groups were approached for relevant cases. Patients were included if they met the following criteria: diagnosis of chronic lymphocytic leukaemia/non‐Hodgkin lymphoma; proven or probable IFD; and ibrutinib treatment on the date IFD were diagnosed. Clinical and laboratory data were captured using REDCap software. Result Thirty‐five patients with IFD were reported from 22 centres in eight countries: 26 (74%) had chronic lymphocytic leukaemia. The median duration of ibrutinib treatment before the onset of IFD was 45 days (range 1‐540). Aspergillus species were identified in 22 (63%) of the patients and Cryptococcus species in 9 (26%). Pulmonary involvement occurred in 69% of patients, cranial in 60% and disseminated disease in 60%. A definite diagnosis was made in 21 patients (69%), and the mortality rate was 69%. Data from Israel regarding ibrutinib treated patients were used to evaluate a prevalence of 2.4% IFD. Conclusions The prevalence of IFD among chronic lymphocytic leukaemia/non‐Hodgkin lymphoma patients treated with ibrutinib appears to be higher than expected. These patients often present with unusual clinical features. Mortality from IFD in this study was high, indicating that additional studies are urgently needed to identify patients at risk for ibrutinib‐associated IFD.

A case of CNS aspergillosis in a patient with chronic lymphocytic leukemia on first-line ibrutinib therapy

“…Since the introduction of ibrutinib to treat hematologic malignancies, multiple reports of IFIs emerged prompting larger studies to investigate the incidence of IFI with ibrutinib in the hematologic malignancy population. The prevalence reported in these studies ranged from 2.4% [6] to 4.2% [7], and the majority of these IFIs were due to Aspergillus with a trend towards CNS involvement.…”

“…Importantly, CNS infection is not common in invasive aspergillosis, only occurring in 2.7–6% of cases [11,12]. In patients on ibrutinib, however, a striking proportion (40–41%) of invasive Aspergillus cases involve the CNS [6,13]. The reasoning for this apparent dichotomy is incompletely understood; however, there are a few possible explanations for this [1]: Aspergillus species produce mycotoxins that can alter the blood-brain barrier, destroy neural cells, and evade phagocytosis and conidial opsonization and propagate CNS infection [2,14] ibrutinib-affected macrophages may transmit Aspergillus spores across the blood-brain barrier establishing CNS infection [6]; and [3] given its good CNS penetration, ibrutinib may inhibit CNS macrophages or microglial cells [5].…”

“…It should be emphasized that despite our patient's positive clinical outcome, CNS aspergillosis is frequently fatal even with mold-active therapy [15]. The attributable mortality rate of CNS aspergillosis in patients taking ibrutinib is a devastating 52–69% [6]. The precise treatment strategy and its length remain uncertain and empirical.…”

“…First, should ibrutinib should be held during the entire treatment of the CNS aspergillosis? While there is little evidence to guide such decision making, it is often the practice to do so [6]. We immediately stopped ibrutinib in our patient in hopes of optimizing his innate immune system's capacity to control his infection.…”

Disseminated cryptococcal disease during treatment with idelalisib and corticosteroids for follicular lymphoma

“…2 6 Interestingly, multiple cases of invasive cryptococcal disease in the absence of lymphopenia have recently been described in patients with chronic lymphocytic leukaemia (CLL) receiving treatment with ibrutinib, an oral tyrosine kinase inhibitor targeting Btk. 7 It is hypothesised that this susceptibility is mediated through off-target inhibition of kinases in T lymphocytes or myeloid cells. 8 However, to the best of our knowledge, invasive cryptococcal infection during idelalisib therapy has not previously been described.…”