BTK mutations in patients with chronic lymphocytic leukemia (CLL) receiving tirabrutinib

There is now a plethora of inhibitors of Bruton’s tyrosine kinase (BTKi) in the clinic, with either covalent or non-covalent binding to BTK, for malignant and autoimmune indications. Which BTKi is optimal for specific indications currently remains unclear; both relative efficacy and toxicities of individual BTKi will depend on their precise mechanisms of action. Chemical variables include the mechanism of binding of the BTKi within the ATP binding site of BTK, and in the case of covalent inhibitors, the mechanisms and kinetics of binding of the BTKi to the exposed cysteine 481 residue. In the context of prolonged BTKi treatment required for CLL, variations in binding of BTKi to BTK may be reflected in differences in patterns of BTK mutation.  We read with interest the two recent publications in “Blood Advances” by Blombery et al.1 and Naeem et al.2, and the recent publication in the “New England Journal of Medicine” by Wang et al.3, describing patterns of BTK mutations associated with the covalent BTKi zanubrutinib and the non-covalent BTKi, pirtobrutinib.