The B-cell receptor signalling pathway plays a critical role in development of B-cell
malignancies, and the central role of Bruton’s tyrosine kinase (BTK) activation in this pathway
provides compelling rationale for BTK inhibition as a therapeutic strategy for these conditions.
Covalent BTK inhibitors (BTKi) have transformed the treatment landscape of B-cell malignancies, but
adverse events and treatment resistance have emerged as therapeutic challenges, with the majority of
patients eventually discontinuing treatment due to toxicity or disease progression. Non-covalent BTKi
have alternative mechanisms of binding to BTK than covalent BTKi, and therefore offer a therapeutic
alternative for patients with B-cell malignancies, including those who have been intolerant to, or
experienced disease progression during treatment with a covalent BTKi. Here, we summarise the
clinical data, adverse events and mechanisms of resistance observed with covalent BTKi and describe
the emerging data for non-covalent BTKi as a novel treatment for B-cell malignancies.