Bruton Tyrosine Kinase inhibitor (BTKi) emerged as 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.
The objective was to provide an overview of the pathogens involved, the time of onset of infections and factors influencing survival.
PubMed, Embase and Web of Science databases were used and the results were reported according to PRISMA guidelines.
Case reports, case series, clinical trials and cohort studies were included.
All reported cases of IFI in patients treated with BTKi were analyzed. For case reports/case series, demographic, microbiological and outcome data were retrieved.
Given the significant heterogeneity in clinical trials/cohort studies, no formal incidence analysis was performed, only epidemiological analysis.
Epidemiologic data were presented as descriptive statistics.
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 PJP (16.8%). Among case reports/case series, 155 (73.5%) had chronic lymphocytic leukemia and 56 (26.5%) had other maligancies. The main IFI were aspergillosis (n=107, 50.7%), cryptococcosis (n=33, 15.6%), Pneumocystis jirovecii pneumonia (n=26, 12.3%), and mucormycosis (n=23, 10.9%). The median delay between initiation of BTKi and IFI was 2.3, 4.0, 3.0 and 3.0 for aspergillosis, cryptococcosis, PJP and mucormycosis, respectively. Survival rate improved when BTKi was discontinued during infection.
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.