Can acalabrutinib be used after ibrutinib failure in relapsed/refractory mantle cell lymphoma?  

Acalabrutinib binds to the same pocket as ibrutinib on BTK. Theoretically, if a patient is ibrutinib resistant, acalabrutinib would not be effective. Ideally, there should have been a small trial testing this hypothesis. However, because of the theoretic concerns, nobody wants to do this trial. As w...

Acalabrutinib is much more potent and selective than ibrutinib. It is not unreasonable to ask whether it would work in patients who are progressing on ibrutinib. Although both agents bind the same region of Bruton's tyrosine kinase (BTK) and resistance mutations may have altered the binding site, on...

There are 3 covalent BTKi (ibrutinib, acalabrutinib, zanubrutinib) all of which bind BTK at the same binding site C481. When patients experience progression on any of these 3 approved covalent BTKi, they do not experience benefit from changing them to one of the alternative approved covalent BTKi. A...

Unfortunately, if the patient is progressing on full dose of ibrutinib, acalabrutinib or zanubrutinib are unlikely to prove effective. There are data with pirtobrutinib, however, which may rescue some patients who progress after ibrutinib. Other options include adding rituximab and/or venetoclax.

First-in-class ibrutinib, an irreversible BTK inhibitor which forms a covalent bond to a cysteine in the catalytic region of the kinase, has been followed by next generation inhibitors acalabrutinib and zanubrutinib. These BTK inhibitors, deactivate the enzyme by creating covalent, or irreversible, ...