Dermatological Toxicities of Bruton's Tyrosine Kinase Inhibitors

The development of Bruton's tyrosine kinase (BTK) inhibitors represents a major breakthrough in the treatment of chronic lymphocytic leukemia and other B cell malignancies. The first-generation inhibitor ibrutinib works by covalent irreversible binding to BTK, a non-receptor tyrosine kinase of the TEC (transient erythroblastopenia of childhood) family that plays a critical role in the B-cell receptor signaling pathway. It also induces an 'off-target' inhibition of a range of other kinases including (but not limited to) epidermal growth factor receptor (EGFR), SRC, and other kinases of the TEC family (interleukin-2-inducible T-cell kinase [ITK], Tec, BMX). Dermatological toxicities are among the most common toxicities of ibrutinib, but remain of mild to moderate intensity in most cases and are readily manageable. Their incidence is highest during the first year of treatment and declines over time. In addition, it has been postulated that ibrutinib-related dermatologic adverse events are mediated by the direct binding to both BTK and other 'off-target' kinases. Bruising, ecchymoses, and petechiae represent the most characteristic dermatologic adverse events. Nail and hair changes are also common, as skin infections (opportunistic infections including herpes simplex and herpes zoster virus reactivations, and Staphylococcus aureus superinfection), folliculitis, and other types of rashes. Panniculitis, aphthous-like ulcerations with stomatitis, neutrophilic dermatosis, peripheral edema, and skin cracking can also occur. Next-generation BTK inhibitors, acalabrutinib and zanubrutinib, have been designed to optimize BTK inhibition and minimize off-target inhibition of alternative kinases (Tec, ITK, EGFR, SRC-family kinases). These drugs have been recently FDA-approved for relapsed or refractory mantle cell lymphoma. Although the overall incidence of their toxicities is expected to be more limited, acalubrutinib and zanubrutinib are associated with a range of dermatologic toxic effects that appear to be similar to those previously described with ibrutinib, including bruising and ecchymoses, panniculitis, human herpesvirus infections, cellulitis, and skin rash. In particular, both drugs induce skin bleeding events in more than 30% of patients treated. However, the available dermatological data are still rather limited and will have to be consolidated prospectively. This review article analyses the wide spectrum of dermatological toxicities that can be encountered with first- and second-generation BTK inhibitors. Finally, recommendations for appropriate treatment as well as a synthesis algorithm for management are also proposed.