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Novel BTKi for CLL/SLL
Our Experiences and Considerations With Current and Emerging BTK Inhibitors for R/R CLL/SLL

Released: December 26, 2023

Jennifer R. Brown
Jennifer R. Brown, MD, PhD
Florence Cymbalista
Florence Cymbalista, MD, PhD
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Key Takeaways
  • Currently approved covalent BTK inhibitors—acalabrutinib, ibrutinib, and zanubrutinib—are standard treatment options for patients with chronic lymphocytic leukemia (CLL).
  • Pirtobrutinib is a noncovalent BTK inhibitor recently approved by the FDA for relapsed/refractory CLL; it is well tolerated and may be considered for patients with CLL who have progressed on standard therapy.
  • Novel BTK inhibitors under investigation, including nemtabrutinib, have the potential to significantly alter the treatment paradigm in relapsed/refractory CLL.

There are currently 3 covalent BTK inhibitors approved for chronic lymphocytic leukemia (CLL): acalabrutinib, ibrutinib, and zanubrutinib. Therapy selection often is driven by toxicity profile as well as patient comorbidities. Recently, noncovalent BTK inhibitors have demonstrated efficacy following progression on covalent BTK inhibitor therapy and have shown favorable toxicity profiles. Jennifer R. Brown, MD, PhD, and Florence Cymbalista, MD, PhD, respond to audience questions from a live event on BTK inhibitors for the treatment of relapsed/refractory (R/R) CLL.

How do you currently select between acalabrutinib and zanubrutinib?

Jennifer R. Brown, MD, PhD:
Ever since the ALPINE trial demonstrated improved efficacy with zanubrutinib when compared with ibrutinib, my preference has been to use zanubrutinib. Although acalabrutinib and zanubrutinib can be considered relatively equal, I feel that the level of data that we have with zanubrutinib is superior. However, one exception is if I wanted to give the patient obinutuzumab, as I do like the combination of acalabrutinib plus obinutuzumab as a first-line regimen, particularly for patients in whom I want a rapid response or in younger patients, where the incremental PFS benefit will make a greater difference.

Florence Cymbalista, MD, PhD:
As acalabrutinib has been approved for longer than zanubrutinib and we have longer follow-up data, I have more experience with acalabrutinib. Therefore, I tend to use acalabrutinib, though I do not feel there are significant differences between these 2 BTK inhibitors.

Are there patients for whom you are using ibrutinib plus venetoclax up front?

Jennifer R. Brown, MD, PhD:
This combination is not currently approved in the US nor am I using it. Looking at the available data, the progression-free survival appears similar for both the combination of ibrutinib plus venetoclax and venetoclax plus obinutuzumab. My preference is to avoid ibrutinib due to toxicity, and therefore I tend to use the combination of venetoclax plus obinutuzumab.

Florence Cymbalista, MD, PhD:
I agree, I am not currently using that combination. I would like to see trials demonstrating a benefit with ibrutinib plus venetoclax before using it up front.

How are you using pirtobrutinib for patients with CLL/small lymphocytic leukemia (SLL) in clinical practice?

Florence Cymbalista, MD, PhD:
As pirtobrutinib is not currently approved for CLL in Europe, we have only been able to access it via compassionate use, which has been difficult.

Jennifer R. Brown, MD, PhD:
Pirtobrutinib has been included in the NCCN guideline recommendations, and was approved by the US FDA on December 1, 2023 for patients with CLL/SLL who have received at least 2 previous treatments, including a BTK inhibitor and a BCL-2 inhibitor. Initially, after the approval of pirtobrutinib for mantle cell lymphoma in the US, I had some difficulty obtaining the drug. However, more recently it has become easier to get access to pirtobrutinib for patients with CLL, especially for those who have experienced disease progression on both a covalent BTK inhibitor and venetoclax. You can potentially use pirtobrutinib prior to venetoclax, though there has not been much data on the optimal sequence, and it may prove more difficult to obtain from an insurance standpoint prior to FDA approval. With the recent FDA approval of pirtobrutinib for CLL in the third-line setting and beyond, pirtobrutinib should be much easier to obtain within the US.

What has been your experience with pirtobrutinib in terms of tolerability and adverse event (AE) management?

Florence Cymbalista, MD, PhD:
I have not had many patients on pirtobrutinib, but my experience is that it is quite well tolerated. However, I do think that we need to be cautious as the follow-up on the trials thus far is not very long. It is possible that we will see the development of more AEs over time.

Jennifer R. Brown, MD, PhD:
In my experience, pirtobrutinib is remarkably well tolerated, and the majority of my patients have had essentially no AEs. I have not seen much neutropenia. If it does occur, my typical practice is to administer granulocyte-colony stimulating factor without interruption of pirtobrutinib, and often the neutropenia does not recur. Certainly, we always like to see longer follow-up to understand potential long-term AEs. At the most recent data cut-off, we did see some cardiac AEs, namely atrial fibrillation. So this is an area we will need to continue to monitor.

Where do you see the potential role of nemtabrutinib, if approved?

Jennifer R. Brown, MD, PhD:
Similar to pirtobrutinib, the investigational agent nemtabrutinib is a noncovalent, reversible inhibitor of both wild-type and C481S-mutant BTK. Phase I/II data showed an overall response rate of 56% with an AE profile more similar to the covalent BTK inhibitors. A number of trials with nemtabrutinib are ongoing (including NCT05624554, NCT05947851), so it will depend on what the data show. There is potentially an option to use nemtabrutinib in the double-refractory population. We are seeing slightly higher toxicity with nemtabrutinib than we have observed with pirtobrutinib, particularly hypertension, so that will be one aspect to keep in mind as these agents progress. Although pirtobrutinib is highly specific for BTK, nemtabrutinib inhibits more kinases, which may contribute to the difference in toxicity profiles.  

Florence Cymbalista, MD, PhD:
It is difficult to say, as I would be interested to see comparative data with nemtabrutinib and pirtobrutinib.

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