Frontline Therapy for CLL: Treatment Selection Based on Patient and Treatment Factors

Variables that impact which Bruton tyrosine kinase inhibitor is most appropriate as frontline therapy for patients with newly diagnosed chronic lymphocytic leukemia and the role of patient and disease factors in treatment selection.

William Wierda, MD, PhD: We’ve talked about 3 irreversible inhibitor options for our patients if we’ve chosen to put a patient on a BTK [Bruton tyrosine kinase] inhibitor. Can you walk us through some things you think about in terms of which 1 you select among those 3? How do you make that decision, that choice of treatment, for your patient who you’ve decided to treat with a BTK inhibitor?

Jacqueline Barrientos, MD, MS: Based on the ELEVATE-RR trial that compared acalabrutinib [Calquence] against ibrutinib [Imbruvica] in high-risk patients in relapsed/refractory disease, I’m extrapolating the data to the front line. Similarly, with the data we have coming out of second-generation zanubrutinib [Brukinsa] against ibrutinib, I’m also extrapolating that in terms of considerations for my patients. For the most part, in my practice, I’m using second-generation BTK inhibitors because of the tolerability 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 much more toxicities—adverse effects like arthralgias, rashes, and similarly bleeding events. They have more events of grade 1 ecchymosis, and it becomes concerning.

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

For which patients do I consider using ibrutinib? I’ve used it in patients that have a coexisting solid cancer, because the use of the ibrutinib may have better outcome for these patients. But I recently had a patient present with CLL who had a large renal cell cancer. For him to have surgical resection, the surgeon asked me to debulk him as fast as possible, and I felt that ibrutinib might be better based on data from the trial comparing ibrutinib and acalabrutinib. Short of that, most of my patients are being treated with a second-generation BTK inhibitor at this time.

William Wierda, MD, PhD: Anthony, 1 question I’m asked by my patients is, “I’m starting on acalabrutinib. How long am I going to be on this treatment?” I’m sure you’ve heard that question before. How do you usually answer?

Anthony Mato, MD, MSCE: For starting the drug based on the standard of care, it’s a treat-to-progression strategy. Of course, we’re looking at excellent frontline data from the ELEVATE-TN, but we don’t have a median. I’m thankful that I can’t quote a median progression-free survival [PFS] for them, but I can quote a low discontinuation rate due to adverse events. And I comment that in our practice, most patients we’re treating with acalabrutinib in the frontline setting receive it with obinutuzumab in the context of an MRD [minimal residual disease]–driven, time-limited approach. That’s probably the future for BTK [Bruton tyrosine kinase] inhibitor–based combination therapies with CD20s. But for standard of care, we start it with the intent to stop it only with clinical progression or intolerance, both of which are relatively rare events.

William Wierda, MD, PhD: You have a lot of experience with real-world data. I’m sure you’ve reviewed data that indicate that patients are still getting first-line chemoimmunotherapy. In the United States, we have a ton of data favoring improved outcomes, at the very least progression-free survival, and in a couple of trials overall survival with frontline BTK inhibitor–based therapy. We didn’t talk at all about it, but venetoclax and BCL2 inhibitor–targeted therapy is also an option. What are the things that you think about when you’re thinking about first-line therapy as a standard treatment? How do you make a recommendation and discuss those options with your patients?

Anthony Mato, MD, MSCE: The conversation about chemoimmunotherapy is, for the most part, off the table in our practice. Outside the minority of these ideal candidates for FCR [fludarabine, cyclophosphamide, rituximab]—I don’t need to tell you who they are because you guys have defined that population—we offer that. But most of the time patients favor targeted therapies, given the great data we have from the ECOG trial, for example, vs FCR [fludarabine, cyclophosphamide, rituximab]. We have a couple of options: continuous BTK inhibitor–based therapy vs time-limited venetoclax- obinutuzumab. For the most part, my practice has narrowed down to use of acalabrutinib as the BTK inhibitor of choice and based on the standard of care, mostly monotherapy. I told you about the trial.

The hard part—and we all know this—is that there are very few comparative trials of note in the frontline setting comparing modern targeted therapies. None of us can quote data to support 1 strategy over another, so it’s about age, comorbidities, molecular genetic profile, patient preference. You go down this list, and then the patient and you usually end up with the same conclusion about which choice is better. But I don’t have any profile where I absolutely favor venetoclax over acalabrutinib or acalabrutinib over venetoclax. It’s on the table in all circumstances.

William Wierda, MD, PhD: Debbie, what are your must-have factors when you’re starting a patient on treatment? What do you need to know about any patient in terms of the prognostic factors we’ve had available over the years?

Deborah M. Stephens, DO: This comes up time and again. For me, the original 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 mutated IGHV status, they still have all therapy options open. They might be patients who can benefit from chemoimmunotherapy. For patients with an unmutated IGHV, it’s been shown time and again that standard chemoimmunotherapy results in much shorter progression-free survival and less durable responses in that population.

If I had to pick only 1, that would be the 1 that I would ask for. The nice thing is it never changes. You can order it once on a patient and never have to reorder it throughout the course of their CLL. It provides important prognostic information too, about the pace of their disease and how quickly they’ll probably progress to needing therapy. The second most important thing is knowing their del(17p) status or TP53 mutational status. There aren’t as much data on these patients because there aren’t as many of these patients. In the frontline setting, this is about 10% of the patient population. It becomes more prevalent in the relapsed setting, maybe 25% or higher.

There are limited data, but based on the data available, I would favor using a BTK inhibitor in these patients because the most data is there, the longest progression-free survival for these patients. It’s still a decision point for young patients with del(17p) or TP53, whether you want to consider getting them prepared for the possible need of an allogeneic stem cell transplant if they’ve relapsed after multiple therapies. Those are the 2 must-haves for me.

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

Deborah M. Stephens, DO: Right.

William Wierda, MD, PhD: Any others? Does anybody else have any other must-haves? Jackie, could there was an abstract presented at ASH [American Society of Hematology Annual Meeting] with regard to 17p front line in the longer-term follow-up with the ALLIANCE A041202 trial that Dr Jennifer Woyach provided and outcomes for the 17p patients in the ibrutinib arms vs the non-17p patients and how they were similar. Do you want to comment on that data that were updated?

Jacqueline Barrientos, MD, MS: The data are looking very good. We had originally seen some of this progression-free survival that seemed very encouraging from the smaller group treated at the NIH [National Institutes of Health] in the front line in about 30-plus patients, where the PFS seemed to be similar to patients with less-risk disease. When Dr Woyach gave her updates on these patients with del(17p), they saw the same: these patients have better PFS compared with prior historical cohorts treated with any other treatment regimen. For these patients with 17p by FISH or TP53-mutated disease, BTK inhibitors on continuous dosing continues to be my first-line choice.

William Wierda, MD, PhD: You mentioned earlier the availability of a new formulation of acalabrutinib, so we’ll be able to give and not be concerned about coadministration with PPI.

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

William Wierda, MD, PhD: I frequently find myself switching, and most of the time it’s not a problem. Occasionally, but uncommonly, stopping their PPI is a problem for some patients. That will be helpful for our patients.

Transcript edited for clarity.

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