Individualizing Fixed-Duration Therapy in Treatment-Naive CLL

As treatment options expand in chronic lymphocytic leukemia (CLL), the benefits and limitations of fixed-duration regimens in the frontline setting remain a key area of clinical uncertainty. In a virtual Case-Based Roundtable event, Catherine Coombs, MD, hematologist and oncologist at UCI Health, discussed these considerations and emerging data with oncologists from Ohio.

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This article is part 2 of a 2-part series from a Case-Based Roundtable event.

DISCUSSION QUESTIONS

• After reviewing the updated data from the AMPLIFY trial (NCT03836261), how do you feel about fixed-duration approaches in treatment-naive CLL, including BTK inhibitor (BTKi) + BCL2 inhibitor and venetoclax (Venclexta) + obinutuzumab (Gazyva)?
• In your experience, which patient types are most appropriate for a fixed-duration approach, and which patients are less ideal candidates?
• When considering fixed-duration therapy, do you find that specific datasets are more compelling?
  • Or do the outcomes feel comparable, with your final treatment choice driven more by practical considerations?

Catherine Coombs, MD: So now, after reviewing the updated data, how do you feel about fixed-duration approaches in treatment-naive CLL, including BTKi plus BCL2 inhibitor and venetoclax-obinutuzumab? ...Maybe we can also weave in the second question of which patients [to whom] you are most excited to offer fixed-duration, and then who’s not an ideal candidate.

Adarsh Vennepureddy, MD: I will do the fixed-duration [approach] in mutated IGHV and wild-type deletion 17p.

Coombs: I totally agree, [Dr Vennepureddy]… I love giving [fixed-duration] to mutated [IGHV patients]; they have great outcomes, and why be on something indefinitely if you can avoid it? But you have to convince them to come, so how often is it an issue for your patients to get to and from clinic for the monitoring and for the infusions? Is that a barrier?

Vennepureddy: No, not really.

Coombs: Not a common barrier for you? What about others?

Ike Onwere, MD: No.

Coombs: All right. So now, when considering fixed-duration therapy, do you find that certain datasets are more compelling? [Regarding] AMPLIFY, for example, are you all sold on that, or is 3 years’ follow-up a little short? Do you want more data on retreatment?

Kasra Karamlou, MD: I think one area where AMPLIFY data look OK is, if you're thinking of fixed-duration therapy in an unmutated IGHV, it seems like the acalabrutinib [Calquence]-venetoclax arm may be the best out of the arms in that particular study.¹ But then you also have to put that in the context of the increased toxicity with the addition of obinutuzumab. So I think maybe, if I'm thinking of fixed-duration and an unmutated IGHV patient, that regimen would maybe be something that I'll go to.

Coombs: Would you give that to a 75-year-old with unmutated IGHV with a couple comorbidities?

Karamlou: Probably not.

Coombs: What if they were 55 with no comorbidities?

Karamlou: I would probably consider it.

Coombs: Yes, me too. I agree with you. I think [for] unmutated, I don't think acalabrutinib-venetoclax looks as good, but I think acalabrutinib-venetoclax looks pretty good for mutated. Everything looks good for the mutated patients, though, because they do well. But yeah, I think that's an important subset to consider.

Allison Winter, MD: I think it's [worth] at least noting that we're missing one important comparator in that study, which is venetoclax-obinutuzumab. I'm not convinced that, without data, acalabrutinib-venetoclax is worth the extra toxicity when it's not compared with our tried and true fixed-duration regimen, which is venetoclax-obinutuzumab.

Coombs: I agree, the comparator arm left some efficacy to be desired. And the standard of care wasn't exactly standard when the study was accrued. You're probably aware of this, but there is an ongoing study called MAJIC [NCT05057494] that'll compare acalabrutinib-venetoclax with venetoclax-obinutuzumab. That might read out in the next year...but it's not exactly standard of care. It's acalabrutinib-venetoclax vs venetoclax-obinutuzumab, but patients actually have an option to continue another year if they're MRD [minimal residual disease]-positive.

And that was another surprise from the AMPLIFY study; the rates of undetectable MRD with acalabrutinib-venetoclax were really low compared with I think what some people thought they would have been.¹ It was only 30% undetectable, and it was worse than chemoimmunotherapy. And so to me, it's a really good argument for why MRD is not a universal end point in CLL, because there's this decoupling, where you don't have low MRD with acalabrutinib-venetoclax, yet the progression-free survival [PFS] is better. And I prefer PFS as my end point [vs] MRD; MRD is just a number. So anyway, I don't know; this is complicated.

DISCUSSION QUESTIONS

• When deciding on frontline therapy in CLL, whether a fixed-duration regimen or continuous BTKi monotherapy, what are the most important factors and considerations influencing your choice?
• How much does patient preference, ie, desire for time-limited therapy vs ongoing disease control, ultimately influence your treatment decision in CLL?

Coombs: Do you all offer these regimens to patients and then see what their preference is, or do you try to guide them one way? Or does it depend on what the markers and comorbidities are like? Could anyone give me an example of a conversation with the patient?

D’Anna Mullins, MD: I had a patient recently [where] it was twisting his arm to get him to decide to proceed with treatment. We built up to this knowing that it was coming based on his symptoms and the trajectory of his lymphocyte count. From the time of prescribing the BTKi, 3 months later, he actually started this medication. Now, this patient would have been an excellent candidate for a fixed-duration [regimen]. There was no way I would be able to get him on board with it. So, I think knowing your patient is half the battle with this. It wasn't even worth discussing fixed-duration, because it was never going to happen.

Coombs: I have absolutely seen those patients in my clinic multiple times, and I totally hear what you're saying. There are some people who just will not get on board. You need a compliant and motivated patient. And CLL is a weird malignancy; they sit with this for years being told to just watch and wait, and then to think about treatment. It's [overwhelming], whereas with a patient [with acute myeloid leukemia might say], “Okay, doc, whatever you say.” So we have these long conversations; it's totally different. But I see that frequently myself.

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DISCLOSURES: Coombs previously disclosed receiving consulting fees from AbbVie, AstraZeneca, BeiGene, Octapharma, Lilly, MEI Pharma, TG Therapeutics, Janssen, Genentech, Allogene, Mingsight; research funding from AbbVie, CarnaBio, and Lilly; payments for lectures from AbbVie, Genentech, AstraZeneca, and BeiGene; payment for developing educational materials from Achilles Therapeutics Aptitute Health, BioAscend, Cardinal Health, Clinical Care Options, Curio, DAVA Oncology Mashup, MJH Life Sciences National Association of Continuing Education OncLive, Oncoboard, Physicians Education Resource Peerview, PRIME Education, LLC Prova Education, and Targeted Oncology; holding stock in Pfizer and Bluebird Bio; and receiving fees for serving on data monitoring boards from Octapharma and AbbVie.

REFERENCE

1. Brown JR, Seymour JF, Jurczak W, et al. Fixed-duration acalabrutinib combinations in untreated chronic lymphocytic leukemia. N Engl J Med. 2025;392(8):748-762. doi:10.1056/NEJMoa2409804