Abstract
As ibrutinib has become a standard of care in B-cell malignancies in monotherapy or in combination with other agents, definition of its safety profile appears essential. The aim of this study was to further characterize the safety profile of ibrutinib through the identification of potential safety signals in a large-scale pharmacovigilance database. All serious individual case safety reports (ICSRs) in patients aged ≥18 years involving ibrutinib suspected in the occurrence of serious adverse drug reactions or drug interacting from November 13th, 2013 to December 31st, 2020 were extracted from VigiBase, the World Health Organization global safety database. Disproportionality reporting was assessed using the information component (IC) and the proportional reporting ratio (PRR), with all other anticancer drugs used as the reference group. To mitigate the confounding of age, two subgroups were considered: patients aged<75 years and ≥75 years. A signal of disproportionate reporting (SDR) was defined if both IC and PRR were significant. A total of 16,196 ICSRs were included. The median age of patients was 72.9 years, 42.6% of ICSRs concerned patients aged ≥75 years, and 64.2% male patients. More than half (56.2%) of ICSRs resulted in hospitalization or prolonged hospitalization. Among 713 SDRs, 36 potential safety signals emerged in ibrutinib-treated patients, mainly ischemic heart diseases, pericarditis, uveitis, retinal disorders and fractures. All potential safety signals having arisen in this analysis may support patient care and monitoring of ongoing clinical trials. However, owing to the mandatory limitations of this study, our results need further confirmation using population-based studies.
Highlights
The Uppsala Monitoring Center (UMC) receives individual case safety reports (ICSRs) of suspected adverse drug reactions (ADRs) from national pharmacovigilance systems, which are stored in VigiBase, the World Health Organization (WHO) global database of ICSRs (Lindquist, 2008)
Among 806,474 patients aged ≥18 years experiencing serious adverse drug reaction (SADR) associated with anticancer drugs, 16,196 were receiving ibrutinib
Ibrutinib was the only drug reported as suspected in 84.7% of ICSRs
Summary
A first-in-class, oral, once-daily, Bruton’s tyrosine kinase (BTK) inhibitor, has been demonstrated as an effective treatment for chronic lymphocytic leukemia (CLL), mantle cell lymphoma (MCL), Waldenström macroglobulinemia (WM), marginal zone lymphoma and chronic graft versus host disease (Treon et al, 2015; Chanan-Khan et al, 2016; Miklos et al, 2017; Dimopoulos et al, 2018; Burger et al, 2019; Byrd et al, 2019; Moreno et al, 2019; Shanafelt et al, 2019). Discrepancies in discontinuation rates due to toxicity have been highlighted between initial pivotal clinical trials and realworld studies, where adverse drug reactions (ADRs) were responsible for 51, 29, and 21% of ibrutinib discontinuations in CLL, WM and MCL respectively (Gustine et al, 2018; Mato et al, 2018; Sharman et al, 2020). Higher treatment discontinuation for safety reasons in real-world settings is likely due to differences in patient characteristics. In a previously published cohort study (n 102 patients), patients aged ≥80 years were at higher risk of serious adverse drug reaction (SADR) within the first year of ibrutinib treatment (Allouchery et al, 2021)
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