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MRD and BTKi Resistance in CLL
CLL Management: Testing for MRD and BTK Mutations

Released: November 05, 2024

Expiration: November 04, 2025

Jennifer R. Brown
Jennifer R. Brown, MD, PhD
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Emerging data with targeted therapeutics continue to refine our approach to chronic lymphocytic leukemia (CLL) management and generate new questions in the field. In this commentary, I discuss the usefulness and implications of routine testing for minimal residual disease (MRD) and BTK mutations in the management of CLL.

MRD Testing and How Results Influence Treatment Decisions
I perform MRD testing routinely for patients receiving time-limited therapy (typically venetoclax-based therapy), but I do this mainly for prognostic purposes. For patients receiving venetoclax plus obinutuzumab, I often test for MRD after around 9 months of treatment and at the end of treatment to understand the trajectory of this parameter. Most patients demonstrate undetectable MRD at both time points, but the trajectory is important because about half the patients who have detectable MRD at the end of venetoclax plus obinutuzumab have increasing levels of MRD, and the other half have decreasing levels.

Hypothetically, if most patients on venetoclax plus obinutuzumab achieve undetectable MRD at 1 year, then it might make sense to shorten treatment; however, this might not be a good plan. My concerns related to shortening treatment arise from the phase II BOVen trial of zanubrutinib plus obinutuzumab and venetoclax, in which MRD guidance was used to determine when treatment could be stopped. The median duration of treatment was only 10 months; however, the median time to MRD recurrence was around 30 months, which is not long for frontline treatment, and this may be because the treatment duration was not sufficient.

Data from both the phase III FLAIR and phase II CLARITY trials showed that MRD guidance may be effective with BTK inhibitor plus venetoclax combination therapy. However, as shown in FLAIR, some patients do not achieve undetectable MRD even after 3 years. How should these patients be managed? I am disinclined to continue therapy indefinitely, because that will mean that the patients are resistant to both drugs when they do eventually progress.  

Of note, in the phase III MAJIC trial of frontline acalabrutinib plus venetoclax vs venetoclax plus obinutuzumab, which has recently completed accrual, patients in each arm were evaluated for MRD at 1 year. Those with undetectable MRD stopped treatment, while those with detectable MRD continued treatment for 1 year, at which point treatment was stopped regardless of MRD status. This single timepoint of MRD guidance is simpler and has more potential for incorporation into standard of care. These results are anxiously awaited. Ultimately, I believe MRD guidance will be used to direct some therapies.

BTK Inhibitor Plus Venetoclax Combination Therapy and Treatment Sequence Following Relapse
There are very limited data on patients who progress on first-line BTK inhibitor plus venetoclax combination therapy. The mechanisms of resistance are not clear, and there are no treatment data. I have not used frontline BTK inhibitor plus venetoclax combination therapy because based on noncomparative data from clinical trials of ibrutinib plus venetoclax and venetoclax plus obinutuzumab, 3-year progression-free survival (PFS) rates are very similar with these regimens, so I prefer to hold back 1 class of therapy for use at relapse.

Treatment following BTK inhibitor plus venetoclax therapy depends on whether patients complete treatment, relapse, or progress during treatment. If patients complete treatment and then relapse, the same treatment could be repeated. One would expect that a continuous BTK inhibitor would also be effective. A venetoclax-based, time-limited regimen could also work as long as the patient had been in remission for some time off therapy, but as yet there are limited data to support this. Pirtobrutinib is another option, and perhaps the best, given that it is approved for patients exposed to both drugs. CAR T-cell therapy, while obviously more challenging in terms of the effort required by the patient, is also approved and could be considered for the very early progressors. I encourage any healthcare professional (HCP) who has a patient progress on dual BTK inhibitor plus venetoclax combination therapy to consider a biopsy because of the relatively high rate of transformation events among those with early relapse.

BTK Inhibitor Resistance Mutations and How They Inform Decision-Making
I usually test for BTK inhibitor resistance mutations when there is evidence of clinical progression on either a covalent BTK inhibitor or pirtobrutinib. If a patient has been on a BTK inhibitor for some length of time and I am not quite sure if they might be progressing (eg, if their white count goes up), it can be potentially helpful to check for the resistance mutations, although I won’t stop the drug unless there is clear clinical progression, even in the presence of a resistance mutation.

For patients on a covalent BTK inhibitor for whom subsequent treatment with either venetoclax or pirtobrutinib is being considered, the resistance mutations are irrelevant—clinical trials of both agents showed high response rates regardless of their presence. In this context, testing for BTK inhibitor resistance mutations is not that clinically useful. However, as more patients progress on second-generation covalent inhibitors like acalabrutinib and zanubrutinib, we are going to see more mutations that can also give rise to pirtobrutinib resistance. Hence, it may be prudent to know whether resistance mutations are present when considering the next line of therapy. However, the presence of a mutation does not necessarily mean a patient will not respond to treatment. For example, if the mutation has a very low allele frequency and is therefore present in only a small percentage of cells, the patient could still respond. It is unclear how HCPs can use this information to direct therapy at the moment but more information will likely emerge in the next few years.

Your Thoughts?
In your patients with CLL, do you routinely test for MRD and/or BTK inhibitor resistance mutations? How do you use this information? Get involved in the discussion by answering the polling question and posting a comment.

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