Fungal infection in patients treated with Bruton tyrosine kinase inhibitor-from epidemiology to clinical outcome: a systematic review

Abstract

Background: The Bruton tyrosine kinase inhibitor (BTKi) has emerged as a key treatment for B-cell lymphomas. Despite its efficacy in the treatment of malignancies, numerous cases of invasive fungal infections (IFI) have been reported in patients receiving ibrutinib, a first-generation BTKi. Cases of invasive aspergillosis have also been reported with acalabrutinib and zanubrutinib.

Objectives: The objective of this study was to provide an overview of the pathogens involved, the time of onset of infections and factors influencing survival.

Methods: Data sources: PubMed, Embase and Web of Science databases were used, and the results were reported according to Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines.

Study eligibility criteria: Case reports, case series, clinical trials and cohort studies were included.

Participants: All reported cases of IFI in patients treated with BTKi were analysed. For case reports/case series, demographic, microbiological and outcome data were retrieved. Assessment of risk of bias: Given the significant heterogeneity in clinical trials/cohort studies, only epidemiological analysis was performed, without formal incidence analysis. Methods of data synthesis: Epidemiologic data were presented as descriptive statistics.

Results: In total, 25 215 patients from 92 retrospective and prospective clinical trials/cohort studies and 211 patients from 115 case reports/case series were included. Among clinical trials/cohorts, 736 IFI were reported, including 234 candidiasis (31.8%), 227 aspergillosis (30.8%) and 124 Pneumocystis jirovecii pneumonia (PJP) (16.8%). Among the case reports/case series, 155 (73.5%) had chronic lymphocytic leukaemia, and 56 (26.5%) had other malignancies. The main IFI were aspergillosis (n = 107, 50.7%), cryptococcosis (n = 33, 15.6%), PJP (n = 26, 12.3%) and mucormycosis (n = 23, 10.9%). The median delay between the initiation of BTKi and IFI was 2.3, 4.0, 3.0 and 3.0 for aspergillosis, cryptococcosis, PJP and mucormycosis, respectively. The survival rate improved when BTKi was discontinued during infection.

Conclusions: Targeted therapies in lymphocytic malignancies raised new issues concerning infectious complications. Monitoring IFI in patients receiving second- and third-generation BTKi is crucial for improving the management of these manifestations.

Keywords: Aspergillosis; Bruton tyrosine kinase inhibitor; Chronic lymphocytic leukaemia; Fungal infection; Opportunistic infection; Systematic review.