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FAQs: Refining CLL and SLL Tx
FAQs: Fine-tuning Contemporary Treatment for Patients With CLL/SLL

Released: July 21, 2023

Jeremy S Abramson
Jeremy S Abramson, MD, MMSc
Farrukh T Awan
Farrukh T Awan, MD, MS, MBA
Brian T Hill
Brian T Hill, MD, PhD
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Key Takeaways
  • The second-generation covalent BTK inhibitors zanubrutinib and acalabrutinib are now favored over ibrutinib because of their improved toxicity profiles.
  • The noncovalent BTK inhibitor pirtobrutinib should not be recommended in place of covalent BTK inhibitors but can be considered for patients with CLL/SLL who previously have received a covalent BTK inhibitor and usually venetoclax, as well.

In this commentary adapted from a discussion among Brian Hill, MD, PhD; Jeremy Abramson, MD, MMSc; and Farrukh T. Awan, MD, the experts address important clinical questions about how to fine-tune contemporary treatment for patients with chronic lymphocytic leukemia (CLL)/small lymphocytic lyomphoma (SLL).

What are the differences in the kinome mappings of the covalent BTK inhibitors ibrutinib, acalabrutinib, and zanubrutinib?

Farrukh T. Awan, MD:
The acalabrutinib kinome is more specific for BTK than zanubrutinib, and both acalabrutinib and zanubrutinib are more specific than ibrutinib. So, ibrutinib is less selective for BTK than the second-generation covalent BTK inhibitors acalabrutinib and zanubrutinib. Kinome mapping is also a visual way of predicting toxicities using these BTK inhibitors. Besides the kinome profiling, looking at the IC50/EC50 values for each agent is essential. If you evaluate that further, ibrutinib has a notable on-target effect, making it quite effective in targeting BTK, even though it has the most off-target effects and hence a higher incidence of toxicities.

Brian Hill, MD, PhD:
Certainly, the clinical toxicities observed with each of these covalent BTK inhibitors match their individual kinome profiles.  

When is the appropriate time to rechallenge with another covalent BTK inhibitor vs switching to venetoclax or a noncovalent BTK inhibitor?

Jeremy Abramson, MD, MMSc:
Patients who are responding to but intolerant of ibrutinib typically respond to either acalabrutinib or zanubrutinib, and the majority of these patients do not experience a relapse of the same toxicity that prompted treatment discontinuation. For most patients with responding disease who discontinued a covalent BTK inhibitor therapy because of intolerance, I would rechallenge with either acalabrutinib or zanubrutinib. Of importance, treatment decision also depends on the specific adverse event that led to treatment discontinuation. The risk of bleeding is lower with acalabrutinib and zanubrutinib compared with ibrutinib, but bleeding is a class effect of BTK inhibitors. So, if serious bleeding is the issue, I will not typically rechallenge with another BTK inhibitor if another good treatment option is available for that patient. Some unique adverse events, such as headaches, are specifically associated with acalabrutinib. The headaches usually resolve quickly in response to caffeine intake. If a patient is highly affected by acalabrutinib-induced headaches, switching to zanubrutinib is a reasonable approach because zanubrutinib is not associated with headaches. Arthralgias and diarrhea are less common with the second-generation covalent BTK inhibitors compared with ibrutinib. So, in this situation, I would be comfortable switching from ibrutinib to either acalabrutinib or zanubrutinib.

In a case where the patient achieved stable disease or is experiencing disease progression on any of the covalent BTK inhibitors, I would not rechallenge with another covalent BTK inhibitor because, in general, the covalent BTK inhibitors have similar efficacies. For such a patient, I would switch to venetoclax, a BCL2 inhibitor.

Would you use the noncovalent BTK inhibitor pirtobrutinib off label as a substitute option for a covalent BTK inhibitor for patients with CLL/SLL?

Jeremy Abramson, MD, MMSc:
It is not safe to simply assume that the newest BTK inhibitor is always the best. I will not use pirtobrutinib in place of zanubrutinib or acalabrutinib as the initial BTK inhibitor for patients with relapsed/refractory CLL. I would consider using it where the available data support its use, which is for patients who have progressed on or are intolerant to a covalent BTK inhibitor, and usually after patients also have received venetoclax. 

Farrukh T. Awan, MD:
Because the resistance mutations that might develop in patients who take pirtobrutinib without failing a prior covalent BTK inhibitor are unknown, I would not recommend its use before a covalent BTK inhibitor. Until data from head-to-head trials are available in earlier lines of therapy, I also would not recommend using pirtobrutinib before the failure of both a covalent BTK inhibitor and venetoclax. 

Jeremy Abramson, MD, MMSc:
I agree. The ongoing phase III BRUIN-CLL-314 is investigating pirtobrutinib vs ibrutinib in patients with BTK inhibitor‒naive CLL/SLL (NCT05254743).

Brian Hill, MD, PhD:
We cannot jeopardize BTK inhibitor efficacy by using pirtobrutinib before any of the covalent BTK inhibitors and venetoclax in the absence of any supporting evidence.

What are your thoughts on the current use of obinutuzumab in the COVID-19 era?   

Brian Hill, MD, PhD:
Of note, BTK inhibitors and the monoclonal antibodies negatively affect the immune system. So, I do not believe that monoclonal antibodies such as obinutuzumab should be avoided in the COVID-19 era.

Jeremy Abramson, MD, MMSc:
I am back to managing patients largely as I did before the COVID-19 pandemic. The evolving state of things reminds everyone that COVID-19 is still around. Recently, the FDA approved a second COVID-19 bivalent booster dose, and it is recommended that all patients with CLL/SLL receive this vaccine. Even if the B-cells are suppressed, T-cell responses can still be mounted in response to vaccination, which is protective for our patients.

Farrukh T. Awan, MD:
Given the limited incidence of COVID-19 and availability of effective treatments, our practice patterns have reverted to prepandemic procedures. The use of obinutuzumab is as per label within our practice.

Your Thoughts?
What are the challenges you experience in your practice when it comes to the use of BTK inhibitors for patients with CLL/SLL? Answer the polling question and join the conversation by posting a comment.

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Are you using pirtobrutinib for your patients with CLL/SLL who have previously received a covalent BTK inhibitor and venetoclax?

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