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Optimal Treatment of CLL
Expert Answers to Questions Regarding the Optimal Treatment of CLL

Released: January 21, 2025

Expiration: January 20, 2026

Danielle M. Brander
Danielle M. Brander, MD
Brian Hill
Brian Hill, MD, PhD
Sameer A. Parikh
Sameer A. Parikh, MBBS
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At a recent live symposium, experts provided thought-provoking answers to questions posed by healthcare professionals (HCPs) on optimal first- and later-line treatment for chronic lymphocytic leukemia (CLL).

How would you manage a 76-year-old man with CLL who received first-line therapy with venetoclax + obinutuzumab, then was treated with and progressed on acalabrutinib after 3 years? Testing revealed no del(17p) or TP53 mutation but a BTK C481S mutation was observed.

Brian T. Hill, MD, PhD: This mutation is commonly observed in patients who develop covalent BTK inhibitor resistance. Switching from one covalent BTK inhibitor to another will not be effective because all bind to the same BTK residue: cysteine 481. Data on pirtobrutinib, a noncovalent BTK inhibitor, have shown that this agent can be effective in treating CLL with a BTK C481 mutation. Pirtobrutinib has received accelerated FDA approval for adults with CLL/small lymphocytic leukemia (SLL) who have received 2 or more prior lines of therapy, including a BTK inhibitor and a BCL-2 inhibitor.

Danielle M. Brander, MD: From a logistical standpoint, a venetoclax-based retreatment regimen might, in theory, be an option for this patient; however, CLL with a BTK C481 mutation can progress rapidly, making it difficult to transition back to venetoclax. Pirtobrutinib can be helpful in this situation.

Is it possible to restart a covalent BTK inhibitor after progressing on pirtobrutinib, especially in the absence of a BTK C481 mutation?

Sameer A. Parikh, MBBS: I believe the short answer is that there are not enough data to answer this question. 

Brian T. Hill, MD, PhD: I think HCPs have anecdotally seen that a patient with a clone that was previously resistant and subsequently treated with another agent with a different mechanism of action might respond with retreatment. One possible explanation for this is that the resistant clone was eliminated with the alternative therapy. 

Danielle M. Brander: If enrollment in a clinical trial is not an option, this strategy could be considered, especially if you have seen a deep remission when switching to an agent with a different mechanism of action.

Are there patients for whom you consider using venetoclax beyond the recommended 12 months in the first-line setting? 

Sameer A. Parikh, MBBS: Yes. I typically use venetoclax in the frontline setting for the recommended 12 months, but in a very small proportion of patients with CLL with a TP53 aberration, we discuss whether it makes sense to continue with treatment. In the presence of a TP53 aberration, the median progression-free survival with venetoclax plus obinutuzumab is about 4 years, which is worse than that in patients without the aberration. Prospective data to address this question are needed, particularly as it relates to the role of MRD testing in determining the need for additional treatment.

Danielle M. Brander, MD: In patients with a TP53 aberration, I tend to target BTK. Though venetoclax allows patients to frequently achieve undetectable measurable residual disease (MRD), it is important to note that it is not yet standard of care to base treatment choices on MRD status, especially for patients with average risk CLL. I believe continuous venetoclax can be considered only for patients with a TP53 aberration.

Are there scenarios in which you add obinutuzumab to acalabrutinib? 

Danielle M. Brander, MD: I do so in patients in whom I am trying to achieve a response quickly, such as those with an effusion or severe cytopenias related to disease, or in the case of refractory autoimmune conditions. Of importance, in trials assessing the addition of obinutuzumab to acalabrutinib, patients were first started on acalabrutinib and obinutuzumab was not added until the second cycle. Therefore, I often wait a couple of cycles before adding obinutuzumab because if patients have a lower disease burden, if they have been treated with a BTK inhibitor, it lowers their risk for infusion-related reactions as well as their risk for obinutuzumab-related tumor lysis. There may also be other mechanisms for which starting a BTK inhibitor first lowers risk for infusion-related reactions with anti-CD20 antibodies.

In patients with relapsed/refractory disease, do you use MRD to guide treatment decisions? 

Sameer A. Parikh, MBBS: Unfortunately, at present, MRD does not help guide treatment duration or intensity. However, clinical trials currently underway should help address whether MRD can be used to either deintensify or intensify treatment options. I use MRD mostly as a prognostic tool. At the end of treatment, I assess MRD either by flow cytometry or next-generation sequencing. This allows me to have a discussion with patients about expectations going forward and how long remission may last.

Brian T. Hill, MD, PhD: I agree. There is probably some prognostic value to undetectable MRD at the end of venetoclax plus obinutuzumab treatment, but it does not currently influence treatment decisions. However, the MRD outcome after frontline VO treatment might be useful in the future if venetoclax retreatment is considered.

Can you comment on the safety of oral anticoagulants with the currently approved BTK inhibitors and how you counsel patients? 

Sameer A. Parikh, MBBS: I would likely preemptively reduce the dose of the BTK inhibitor in many patients to ensure they are able to tolerate both agents simultaneously and then potentially increase the dose of the BTK inhibitor if this is the case. In patients with bleeding issues, the dosage of zanubrutinib can be decreased to 80 mg twice daily (as opposed to the usual dosage of 160 mg twice daily), whereas it may be challenging to modify the dosage of acalabrutinib. Aspirin and clopidogrel and other antiplatelet agents should not be overlooked in patients who may have a drug-eluting stent or experience bleeding on BTK inhibitors. Generally speaking, warfarin should be avoided in conjunction with any covalent BTK inhibitor.

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