Bruton tyrosine kinase (BTK) plays a key role in the B-cell receptor (BCR) pathway. Because the BCR pathway is regularly activated in chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), and mantle cell lymphoma (MCL), BTK is an attractive treatment target for these malignancies.
Covalent BTK inhibitors ibrutinib, acalabrutinib, and zanubrutinib form a covalent bond with the cysteine 481 (C481) residue of BTK, preventing it from activating the BCR pathway. As a result, malignant B cells stop proliferating, leading to tumor reduction. Because BTK inhibitors must be continuously administered to exert their therapeutic effect, resistance can emerge over time.
The most common resistance mechanisms are C481 point mutations that prevent covalent BTK inhibitors from binding to BTK. Accordingly, noncovalent BTK inhibitors, which do not bind to C481, may allow for continued inhibition of the BCR pathway. Noncovalent BTK inhibitors interact with BTK via hydrophobic interactions and hydrogen and ionic bonds. These mechanisms allow them to bypass resistance arising from C481 point mutations, whereas the weaker, reversible bonds may confer a more favorable toxicity profile than covalent BTK inhibitors.
Of the noncovalent BTK inhibitors, pirtobrutinib has demonstrated effectiveness in CLL, SLL, and MCL after prior covalent BTK inhibitor therapy, and it is approved for use after 2 prior lines of therapy. An investigational noncovalent BTK inhibitor, nemtabrutinib, also shows promising activity in CLL/SLL after prior covalent BTK inhibitor therapy.
After covalent BTK inhibitor therapy in CLL/SLL or MCL, would you continue BTK inhibition or switch to another treatment class?
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ALEXANDER BARSOUK1yrSwitch to non covalent BTK inhibitor pirotoburitinib
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Fernando De Zarraga1yrDepends on response to covalent BTK's and duration of response. If both were positive, I would switch to another BTK. If not, venetoclax.
