2.4.2 BCR-Abl inhibitors
All BCR-Abl (breakpoint cluster region and Abelson) inhibitors are associated with peripheral edema (García-Gutiérrez & Hernández-Boluda, 2019) and serous effusions (García-Gutiérrez & Hernández-Boluda, 2019; Rizzo et al., 2015). The risk of peripheral edema is greater with imatinib and dasatinib both in terms of incidence (e.g., periorbital and/or extremity edema in 74-84% imatinib-treated patients (Kim et al., 2015)) and in terms of severity where they are grade 3/4 in 5-10% of patients (García-Gutiérrez & Hernández-Boluda, 2019). The precise molecular substrate remains elusive but could be related to both on-target effects on endothelial Abl kinases (affecting vascular permeability and cell-cell junction dynamics) (Rizzo et al., 2015) and off-target inhibitory effects (e.g., Src kinases, platelet-derived growth factor receptors) (Giles et al., 2009). Both Src kinases and platelet-derived growth factor receptors regulate vascular permeability; the latter also affecting interstitial hydrostatic pressure (Giles et al., 2009). Imatinib has been shown to induce CLS (Hinchcliff, Lomasney, Johnson, & Varga, 2016; Jeong et al., 2019). Pathophysiology involves a decrease in the oncotic reflection coefficient through the capillary wall. It is thought to be due to an endothelial dysfunction and weakening of endothelial cell-to-cell binding secondary to hypercytokinemia, resulting in rapid extravasation of albumin into the extravascular space (Druey & Parikh, 2017; Siddall et al., 2017). Because of its uncertain pathogenesis, the management of drug-induced CLS remains largely empiric and mainly based on drug discontinuation and corticosteroids therapy to reduce cytokine release (Siddall et al., 2017). Surprisingly, recent data suggest a potential benefit of imatinib in certain forms of capillary hyperpermeability syndromes, including Clarkson disease (Rizzo et al., 2015).