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1yr
BTK inhibition in CLL/SLL: Where are we now?

Over the last decade, Bruton tyrosine kinase (BTK) inhibitors have transformed the treatment of chronic lymphocytic leukemia (CLL). Ibrutinib, the first approved covalent BTK inhibitor, improved patient outcomes compared with chemoimmunotherapy regimens, which were the previous standard of care. However, many patients must discontinue ibrutinib due to toxicity.

Second-generation covalent BTK inhibitors acalabrutinib and zanubrutinib were developed to address toxicity concerns. Although these therapies have an improved safety profile compared with ibrutinib, acquired resistance may limit treatment. Because all 3 covalent BTK inhibitors share common resistance mechanisms, switching from one to another upon disease progression is an ineffective strategy.

Noncovalent BTK inhibitors offer patients an opportunity to reestablish BTK inhibition following covalent BTK inhibitor therapy. Pirtobrutinib selectively and reversibly binds to the BTK protein, minimizing toxic off-target effects while bypassing key mutations that confer resistance to covalent BTK inhibitors. As such, pirtobrutinib demonstrates effectiveness in patients whose disease has progressed on a covalent BTK inhibitor. It is approved for use in adults with CLL or small lymphocytic lymphoma (SLL) who have received at least 2 prior lines of therapy, including a BTK inhibitor and a B-cell lymphoma 2 inhibitor. An investigational noncovalent BTK inhibitor, nemtabrutinib, also shows promising activity after prior exposure to covalent BTK inhibitor therapy.

How do you treat patients with CLL/SLL who progress on a covalent BTK inhibitor? Has the recent approval of pirtobrutinib in CLL/SLL altered your treatment decisions?

  • 1yr
    I would use venetoclax with or without obinutuzumab followed by Pirtobrutinib.
  • 1yr
    I mainly use venetoclax with obintuzumab and use Pirtobrutinib in third line
  • 1yr
    either venclexa plus cd20 monoclonal or jaypirca
  • 1yr
    First line zanibrutinib
    Second venetoclax gazyva
    3 rd line Pirtobrutinib
  • 1yr
    I will follow guidelines. Usually use Acalburitinb +/- ritruximab, then venetoclax based treatment +/- Gazyva, sometimes vice versa. Then will use pirtobrutinib in susbequent line. More non-chemotherapy choices for patients.
  • 1yr
    I would non covalent pirtobrutinib after prior use of 2nd gen BTK inhibitor and bcl-2 inhibitor. Yes, instead of recycling BTK inhibitors and BCL-2 inhibitors, I would use the new drug, pirtobrutinib.
  • 1yr
    for patients with CLL/SLL who progress on a covalent BTK inhibitor, I usually change to Venclexta + Rituximab as the 2nd line, and pirtobrutinib as the 3rd line therapy.
  • 1yr
    Would use venetoclax as second line therapy with a cd20 agent in the second line due to different moa. But pirto in 3rd line at a later date
  • 1yr
    I will use Venetia’s with Gaza in second line followed by pirtobrutinib a non covalent BTK in third line
  • 1yr
    yes, the availability of pirtobrunib has given us a much needed opportunity to use a non-covalent BTK inhibitor after the failure of a BTK inhibitor. This would be very useful in practice.
  • 1yr
    Venetoclax plus gazyva is my next option (2L), but then pritoburtinib after that in 3L
  • 1yr
    while pirtobrutinib is a reasonable option, my preference is to go another direction with different mech of action and go with BCL2 such as venclexta. have had decent success with this approach
  • 1yr
    I would like to use a non covalent BTK like Pirto, but based on approvals, likely use BCL-2 inhibitor venetoclax second line.
  • 1yr
    Yes if they fail a BTK - would use BCL2 next. If they progress on that would certainly consider a non-covalent inhibitor such as pirtobrutinib or nemtabrutinib,
  • 1yr
    if they fail acalabrutinib or zanu i will use pirtobrutinib or a venetoclax regimen.
  • 1yr
    I prefer time limited there in first line unless patient has high risk disease such as del17p where I choose zanu.
    If I use venetoclax in first line, then zanu would be my second line go to option and vice versa. Pirtobrutinib remains a third Iine option at this time.
  • 1yr
    I like to use Acalabrutinib first, then Zanu, then Piro which would be on-label as a 3rd line
  • 1yr
    First line for most pt's zanabrutinib
    Second line--- venetoclax + obinutuzumab
    Third line--- pirtobrutinib
  • 1yr
    I use a bcl2 inhibitor first, than Pirtobrutinib in 3rd line
  • 1yr
    depending on their risk profile either bcl2 inhibitors or pirtobrutinib
  • 1yr
    of course noncovalent is an important addition but the optimal sequencing needs to be worked out on the level of NCCN and other guidelines
  • 1yr
    Yes the use of noncovalent Pirtobrutinib

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