Treatment selection based on patient and treatment factors

William Wierda, MD, PhD: We talked about 3 irreversible inhibitor options for our patients if we chose to put a patient on BTK [Bruton tyrosine kinase] inhibitor. Can you explain to us some of the things you think about in terms of which of these 3 you select? How do you make this decision, this choice of treatment, for your patient that you have decided to treat with a BTK inhibitor?

Jacqueline Barrientos, MD, MS: Based on the ELEVATE-RR trial comparing acalabrutinib [Calquence] against ibrutinib [Imbruvica] in high-risk patients with relapsed/refractory disease, I extrapolate the data to the frontline. Similarly, with the data we have on second-generation zanubrutinib [Brukinsa] versus ibrutinib, I also extrapolate that in terms of considerations for my patients. For the most part in my practice I use second generation BTK inhibitors due to tolerance issues. This is based on data from these clinical trials, but also what I see in my clinical practice is that patients end up having a lot more toxicities – adverse effects like arthralgias, rashes and bleeding events similar. They have more grade 1 bruising events, and it’s getting concerning.

Overall, I look at the patient’s characteristics and profile. If they have problems with a PUP [proton- pump inhibitor], I can choose or select zanubrutinib because the drug acalabrutinib may have an interaction and may not be observed well if you are taking a PPI. This could be overcome in the future as the data also comes out with a tablet, not just a capsule. But right now a PPI is a problem because many patients are taking a PPI. If patients develop toxicity such as an intolerable headache with the use of acalabrutinib, which usually occurs within the first 3 months, then I might choose zanubrutinib. For the most part insurance will cover this even though it is not fully approved for use in CLL patients [chronic lymphocytic leukemia]. But based on published and abstract data, we can appeal.

For which patients should I consider using ibrutinib? I have used it in patients who have co-existing solid cancer because using ibrutinib may have better results for these patients. But I recently had a patient with CLL who had large kidney cell cancer. In order for it to undergo surgical resection, the surgeon asked me to reduce it as quickly as possible, and I thought that ibrutinib might be better based on the data from the trial comparing ibrutinib and ibrutinib. acalabrutinib. Other than that, most of my patients are currently being treated with a second generation BTK inhibitor.

William Wierda, MD, PhD: Anthony, 1 question that my patients ask me is: “I am starting acalabrutinib. How long will I follow this treatment? I’m sure you’ve heard this question before. How do you usually respond?

Anthony Mato, MD, MSCE: To start the drug according to the standard of care, this is a stepwise treatment strategy. Sure, we’re looking at great front-line data from the ELEVATE-TN, but we don’t have a median. I am grateful that I cannot quote a median progression-free survival [PFS] for them, but I can cite a low dropout rate due to adverse events. And I’m commenting that in our practice, most of the patients we treat with acalabrutinib as first line receive it with obinutuzumab as part of an MRD [minimal residual disease]– piloted and time-limited approach. This is probably the future of BTK [Bruton tyrosine kinase] combination therapies based on inhibitors with CD20. But for standard of care, we start it with the intention of stopping it only if there is clinical progression or intolerance, two relatively rare events.

William Wierda, MD, PhD: You have a lot of experience with real world data. I’m sure you’ve looked at data that indicates patients are still receiving first-line chemoimmunotherapy. In the US, we have a ton of data supporting improved outcomes, at the very least progression-free survival, and in a few trials overall survival with first-line therapy with BTK inhibitors . We haven’t talked about it at all, but targeted therapy with venetoclax and BCL2 inhibitors is also an option. What do you think of when you think of first-line therapy as standard treatment? How do you make a recommendation and discuss these options with your patients?

Anthony Mato, MD, MSCE: The conversation about chemoimmunotherapy is, for the most part, irrelevant in our practice. Apart from the minority of these ideal candidates for FCR [fludarabine, cyclophosphamide, rituximab]— I don’t need to tell you who they are because you defined this population — we offer that. But most of the time, patients prefer targeted therapies, given the excellent data we have from the ECOG trial, for example, vs FCR [fludarabine, cyclophosphamide, rituximab]. We have two options: continuous treatment with BTK inhibitors versus time-limited venetoclax-obinutuzumab. For the most part, my practice has been limited to using acalabrutinib as the BTK inhibitor of choice and based on standard of care, primarily monotherapy. I told you about the trial.

The hardest part – and we all know this – is that there are very few notable front-line controlled trials comparing modern targeted therapies. None of us can cite data to support one strategy over another, so it comes down to age, comorbidities, molecular genetic profile, patient preference. You go through that list, then the patient, and you usually end up with the same conclusion about which is the best choice. But I don’t have a profile where I absolutely favor venetoclax over acalabrutinib or acalabrutinib over venetoclax. It’s on the table under all circumstances.

William Wierda, MD, PhD: Debbie, what are your critical factors when putting a patient on treatment? What do you need to know about a patient in terms of the prognostic factors that we have had over the years?

Deborah M. Stephens, DO: It comes up over and over again. For me, the initial decision point that needs to be made on treating patients comes from their immunoglobulin heavy chain variable [IGHV] status. For example, if a patient has a mutation HVSI status, they still have all the treatment options open. These may be patients who may benefit from chemoimmunotherapy. For patients with an unmutated mutation HVSIstandard chemoimmunotherapy has been repeatedly shown to result in much shorter progression-free survival and less durable responses in this population.

If I had to pick just one, that would be the one I would ask for. The good thing is that it never changes. You can order it once for a patient and never have to order it again throughout their CLL. It also provides important prognostic information about the pace of their illness and how quickly they are likely to progress to therapy. The second most important thing is to know their status del(17p) or TP53 mutation status. There is not as much data on these patients because there are not as many of these patients. In the first line, this represents approximately 10% of the patient population. It becomes more prevalent as part of the relapse, maybe 25% or more.

Data is limited, but based on the available data, I would favor the use of a BTK inhibitor in these patients because the more data there is, the longer progression-free survival for these patients. This is always a decision point for young patients with del(17p) or TP53, if you want to consider preparing them for the possible need for an allogeneic stem cell transplant if they have relapsed after several therapies. These are the 2 essentials for me.

William Wierda, MD, PhD: I heard 3. I heard HVSI mutation status, del(17) by FISH [fluorescence in situ hybridization]and mutation status for TP53. To the right?

Deborah M. Stephens, DO: To the right.

William Wierda, MD, PhD: Others? Anyone else have any other must-haves? Jackie, could there have been a summary presented to ASH [American Society of Hematology Annual Meeting] with regards to the 17p frontline in the longer term follow-up with the ALLIANCE A041202 trial that Dr. Jennifer Woyach provided and the results for 17p patients in the ibrutinib arms versus non-17p patients and how they were similar. Do you want to comment on this updated data?

Jacqueline Barrientos, MD, MS: The data looks very good. We had initially seen some of this progression free survival which looked very encouraging from the small group being treated at NIH [National Institutes of Health] first-line in approximately 30+ patients, where PFS appeared to be similar to patients with lower-risk disease. When Dr. Woyach took stock of these patients with del(17p), they found the same thing: these patients have better PFS compared to previous historical cohorts treated with any other treatment regimen. For those patients with 17p by FISH or TP53-mutated disease, continuously administered BTK inhibitors continue to be my first-line choice.

William Wierda, MD, PhD: You mentioned earlier the availability of a new formulation of acalabrutinib, so we can give and not worry about co-administering with a PPI.

Jacqueline Barrientos, MD, MS: Yes. An abstract was presented at this year’s ASH [American Society of Hematology Annual Meeting], finding the drug to be safe and tolerated, was able to be absorbed without having a concomitant PPI in use. I await it with impatience. I don’t know when the FDA will give its approval, but I understand the company is moving forward with this formulation, and patients on PPIs won’t have to choose a different drug if acalabrutinib is the drug of choice.

William Wierda, MD, PhD: I often find myself changing, and most of the time it’s not a problem. Occasionally, but rarely, stopping their PPI is a problem for some patients. It will be useful for our patients.

Transcript edited for clarity.

Martin E. Berry