Home > Focus Areas > Leukemia and Lymphoma Connect > Post
  • Saved

1yr
Overcoming resistance to covalent BTK inhibitors for B-cell malignancies

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?

  • 1yr
    Switch to non covalent BTK inhibitor pirotoburitinib
  • 1yr
    Depends on response to covalent BTK's and duration of response. If both were positive, I would switch to another BTK. If not, venetoclax.
  • 1yr
    ideally, would first switch to an alternative agent first such as venetoclax before changing to pirtobrutinib as there can be a long duration of response (several years). But having pirtobrutinib as a later option, is reassuring for patients to know about
  • 1yr
    I typically would switch to Venetoclax but 3rd line would go back to pirtorutinib
  • 1yr
    I will use pirtobrutinib only after failure to covalent BTK and BLC2 inhibitor, ventoclax
  • 1yr
    I would follow the current approval specifics - if I used BTK inhibitor first line, would switch to venetoclax based regimen and then use pirtobrutinib in the third line.
  • 1yr
    I would favor switching to pirtobrutinib. Pt most likely has done well for a while on covalent BTKi and sticking with this class before totally changing druf classes seems most reasonable
  • 1yr
    In CLL, Pirtobrutinib is approved after progression on a covalent btki and bcl2. Therefore I would use venetoclax in second line and then pirtobrutinib in third line.
    Similarly I would assume a covalent btki is used in second line in mcl and I would transition to Pirto in third line as a bridge to car-t cell therapy.
  • 1yr
    Ideally I would test for a C481 point mutations and switch to a Non covalent inhibitor
  • 1yr
    Will stay the course if pt has been on it and having no issues. However if any side effects or response change then will be quick to change, not just for efficacy but possible better side effects.
  • 1yr
    most mutations post btk specially with imbruvica are overcome by non covalent binder pirtobrutinib would use that
  • 1yr
    I would go with pirtobrutinib eventually but i typically would go with different MOA and pick Venclexta first. i think this patient would qualify for pirto at some point but i would use after Venclexta. agreed with my colleague that it's nice to have more options nowadays
  • 1yr
    I would switch to pirtorubtinib since it has efficacy in this population. It may continue to give a response.
  • 1yr
    I would favor switching to Jaypirca (pirtobrutinib).
  • 1yr
    I will go with pirtorutinib if can secure through insurance
  • 1yr
    Would switch to bcl2 inhibitor venetoclax and after progression on that would do non covalent BTk inhibitor with Pirtorutinib
  • 1yr
    After progression in BTKi I would usually change class of agents often to a venetoclax based regimen. At progression on venetoclax I would return to BTKi directed medication, using a non covalent BTKi such as pirtobrutinib. I would also try to find a clinical trial for my patients if they are eligible. This is an exciting time in CLL!
  • 1yr
    Switch to pirtorutinib

Show More Comments