Experts Weigh Fixed-Duration Approaches in Frontline CLL

The frontline treatment landscape for chronic lymphocytic leukemia (CLL) continues to evolve with expanding options for continuous and fixed-duration therapy. In a virtual Case-Based Roundtable event, a group of oncologists from Ohio moderated by Catherine Coombs, MD, hematologist and oncologist at UCI Health, discussed how patient age, comorbidities, and emerging clinical data influence frontline treatment selection and the emerging role of fixed-duration combinations.

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EVENT RECAP

Prior to reviewing any trial data, the group was polled on their preferred frontline treatment approach for 2 patients with CLL lacking a 17p deletion or TP53 mutation but differing in age and comorbidities. For an 83-year-old patient with hyperlipidemia and mild CKD most respondents (72.2%) selected continuous zanubrutinib (Brukinsa) monotherapy, with smaller proportions favoring acalabrutinib (Calquence) plus venetoclax (Venclexta) and obinutuzumab (Gazyva; 11.1%), zanubrutinib plus venetoclax (11.1%), or acalabrutinib with or without obinutuzumab (5.6%). When presented with a younger, 66-year-old patient with hyperlipidemia but no CKD, zanubrutinib remained the preferred option for most participants (61.1%). However, there was greater interest in time-limited combination regimens, with 16.7% selecting zanubrutinib plus venetoclax and 11.1% choosing venetoclax plus obinutuzumab. An additional 11.1% favored acalabrutinib with or without obinutuzumab. Overall, the polling suggested a strong preference for second-generation Bruton tyrosine kinase (BTK) inhibitor–based therapy across both scenarios, while younger, fitter patients prompted greater consideration of fixed-duration combination approaches.

Following the voting, the group reviewed the data of the phase 3 SEQUOIA (NCT03336333) and phase 3 ELEVATE-TN (NCT02475681) trials and discussed selection of BTK inhibitors.

DISCUSSION QUESTIONS

• Among fixed-duration combination approaches, which strategies are you most interested in learning more about, or are already incorporating into practice?
• In which patient types do fixed-duration strategies feel most appropriate in your practice?
  • Younger/fit patients
  • Older patients prioritizing time-limited therapy
  • High-risk cytogenetics
  • Patients strongly preferring treatment-free intervals

Catherine Coombs, MD: Among the fixed-duration combination approaches, which strategies are you most interested in learning more about, or are you already incorporating them into practice? We haven't covered AMPLIFY [NCT03836261] yet, but that's the acalabrutinib-venetoclax plus/minus obinutuzumab. But also, you have venetoclax-obinutuzumab, and these smaller zanubrutinib-venetoclax or acalabrutinib-venetoclax-obinutuzumab [minimal residual disease (MRD)]-guided regimens. Has anyone already started adapting those? Or are you curious and want to learn more?

Neeraj Mahajan, MD: Curious. Just started 1 patient [on a fixed-duration combination]. It's taking time, it's a very complicated schedule you have to make. And [there’s an] order set in the [electronic medical record (EMR)]; certain things start on day 1, certain things start on day 28. But I guess going forward, if we can get it approved, this may be more commonly used.

Coombs: When we're thinking about fixed duration, it seemed like, based on the voting, there's more appeal for younger, fit patients. What about an old patient who just had terrible cardiac comorbidities but good renal function? Would you ever think about venetoclax-obinutuzumab in an older patient, or maybe they had recurrent gastrointestinal bleeding—some reason that [would make them] not a good candidate for a BTK inhibitor? Or maybe they just want to be on something indefinite—maybe they travel a lot and don't want to be on a drug when they go on their cruises for a year.

Allison Winter, MD: I think there is an older patient with certain cardiac medications that make me favor venetoclax-obinutuzumab. I've used it safely for people on antiplatelets, and I've used it safely for people on anticoagulation. But there's the every-once-in-a-while patient—especially at Cleveland Clinic Cardiology, capital of lots of referrals—[who is on agents like] rivaroxaban [Xarelto] and clopidogrel [Plavix] plus a BTK inhibitor; that's where I get nervous. It's not even rivaroxaban plus baby aspirin; it's the clopidogrel that makes me nervous about bleeding. Or the patient, every once in a while, who is still on warfarin [Coumadin] for a heart valve.

Coombs: That's a great point, too. I have this patient who is on dual antiplatelet, also [has] significant CKD and had multiple strokes. Anyway, I said that I don't want to give him anything, but I was thinking about just acalabrutinib, and I was able to get the neurologist to say, “You don’t need antiplatelet anymore,” [and had done] imaging just to get a baseline. [The patient] had a dissection, and [the neurologist] said he had to go to the ER. And I said, “This patient’s just not going to die of his CLL.” And then he was admitted with aa new stroke. And I'm like, this is bad, but he does need CLL treatment, but it's just not the priority… You just then have to figure all that out. So that's my toughest comorbid case.

Shyamal Bastola, MD: A quick question—when do you ever use a single agent and CD20 like obinutuzumab by itself? I think I've had some patients respond really well for some time.

Coombs: For patients who just aren't good candidates for anything, I've done it every once in a while. I did think about that with my patient who had so many comorbidities. I even worry about infusion reactions and him going to the [emergency department] with that. But I would say, very infrequently, someone who I'm convinced is going to die from something other than their CLL, because the progression-free survival [PFS] is probably only a couple of years with the CD20. It's way worse than any of our good therapies, but if they just are totally not a good candidate for any of them, I have done it, but not often. There are data for obinutuzumab in the front line as a monotherapy, and I think the PFS is around 2 years.¹ So it'll work; it won't work for that long.

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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.

REFERENCES

1. Byrd JC, Flynn JM, Kipps TJ, et al. Randomized phase 2 study of obinutuzumab monotherapy in symptomatic, previously untreated chronic lymphocytic leukemia. Blood. 2016;127(1):79-86. doi:10.1182/blood-2015-03-634394