Thinking Beyond Efficacy When Selecting BTK Inhibitors in Relapsed CLL

For patients with relapsed/refractory chronic lymphocytic leukemia (CLL), selection between second-generation Bruton tyrosine kinase (BTK) inhibitors may come down to individual toxicity concerns rather than major differences in efficacy. In a virtual Case-Based Roundtable event, Mazyar Shadman, MD, MPH, deputy chief medical officer for classical hematology, hematologic malignancies, transplant and immunotherapy at Fred Hutchinson Cancer Center, moderated a discussion with oncologists in San Diego, California, on approaches to second-generation BTK inhibitor selection and sequencing in relapsed/refractory CLL.

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This is part 2 of a 2-part series. Read part 1.

EVENT RECAP

The group reviewed the efficacy and safety data from 2 trials in the second-line setting: ALPINE (NCT03734016) and ELEVATE-RR (NCT02477696).

DISCUSSION QUESTIONS

How do findings from ALPINE and ELEVATE-RR influence your selection of a BTK inhibitor in the second-line setting?

When reviewing these trials, which end points (eg, progression-free survival [PFS], safety and tolerability over time, treatment discontinuation rates) are most meaningful for your real-world decisions in second-line CLL?

In patients with specific clinical features like cardiovascular morbidities, advanced age, or prior treatment exposure, do these datasets push you toward one BTK inhibitor over another?

Sam Huang, MD: If I have a patient for whom I think the bleeding risk is higher, then I'm probably going to use acalabrutinib [Calquence]. I think both [acalabrutinib and zanubrutinib (Brunkinsa)] are superior to ibrutinib [Imbruvica]; I don't use ibrutinib anymore. In the relapsed/refractory setting, if a patient is going to have very high blood pressure that’s not under control as well as higher bleeding risk, I would be more inclined to use acalabrutinib, whereas if a patient has a lot of headaches, I am more likely to use zanubrutinib instead of acalabrutinib.

Mazyar Shadman, MD, MPH: Did you say that for bleeding, you believe that acalabrutinib is your preferred drug if someone has bleeding risk?

Huang: I've had more problems with zanubrutinib with bleeding, so the answer is yes.

Ben Goldenson, MD: I think these results reinforce my thoughts about how effective the BTK inhibitors are, even in the second line. [As for] end points, the improved PFS and treatment discontinuation rates stand out.

Shadman: When you look at these studies, there are a number of end points, anywhere from overall response to PFS to time to next treatment to overall survival. From an efficacy standpoint, which one do you care most about? When you look at the study, do you look at overall response at all? What is that one efficacy end point that you look for?

Mykola Onyshchenko, MD: I would say duration of response. That would be my end point for efficacy. As for safety, it's hard to choose one second-generation BTK inhibitor over another. There are some data; [zanubrutinib and acalabrutinib are] borderline different. I would say it's more important to see what exactly the cardiovascular comorbidity degree is. It's important to talk to cardiologists and see when exactly the stent was placed [and] how long the patient was on dual antibiotics, for example.

Shadman: I think that's a great point, and to summarize the cardiovascular risk: To me, atrial fibrillation should never be a reason not to use a BTK inhibitor. We can use BTK inhibitors and treat atrial fibrillation, including anticoagulation. That's number 1. Number 2, any other dysrhythmia or arrhythmia, I get a cardio-oncologist involved and get their green light before I start someone on a BTK inhibitor.

[Regarding] hypertension, the one study that shows [a similar] rate of hypertension compared with ibrutinib is ALPINE [with zanubrutinib].¹ We respect the trial, and I would agree that if somebody's problem is hypertension, meaning that if you have a patient on 4 antihypertensive drugs and is still challenging [to manage], of course, zanubrutinib would not be the first choice for that patient. Most of the time, these patients are rare; blood pressure is well controlled, and I say that because…I think a well-controlled hypertension, at least for me, is not a reason not to use zanubrutinib.

Same with headache. It's true that the headache with acalabrutinib is real, and more than half of the patients will get it. But it's usually safe, self-limited, and in the first few weeks, maybe. Again, yes, if somebody's problem is headache, that's obviously the deciding point. But I guess my point is, for both conditions to be balanced between the 2 drugs, these are pretty rare situations where you have patients whose major problem is hypertension or headache.

To me, efficacy is important, and obviously safety. I don't know personally if the bleeding risk between the 2 drugs is different. I'm sure we all have personal experiences, and that usually trumps everything else that we see in data. But I think that from the data standpoint, I'm not aware of a difference in terms of bleeding risk between the 2 drugs.

DISCUSSION QUESTION

When a patient develops intolerance on a covalent BTK inhibitor, what’s your typical next move?

Shadman: Has anyone switched between zanubrutinib and acalabrutinib for intolerance? I think ibrutinib to second generation is pretty obvious, but any experience switching between the 2 second-generation BTK inhibitors?

Xinting Fu, MD: I did it the other way around, but it's for diarrhea.

Huang: [I have experience] going from acalabrutinib to zanubrutinib because of headaches.

DISCUSSION QUESTIONS

In the relapsed/refractory setting, where are you currently positioning noncovalent BTK inhibitors in your treatment algorithm?

Are you reaching for them after covalent BTK inhibitor progression, after BCL2 inhibitor progression, or only after both?

Shadman: Let’s hear from one colleague about their pirtobrutinib [Jaypirca] experience.

Kentson Lam, MD: I haven't had the chance to give it yet, but I would do the BTK and then the fixed-duration venetoclax [Venclexta]; switch them if it's the other way around, and then pirtobrutinib would probably be my next option.

Shadman: You actually answered my next question: After covalent BTK inhibitor, now we have the option of going to venetoclax-based therapy and then pirtobrutinib, or go directly to pirtobrutinib. Would anybody go directly from covalent to noncovalent and skip the BCL2 inhibitor, or would you rather go with the sequence that is better studied?

Fu: I actually did that. [I did] not really go straight from the covalent to noncovalent, but my patient did not tolerate the venetoclax that well, so that's why we just did the pirtobrutinib. But at that time, it was not in the NCCN guidelines yet. But I can see [the possibility to go directly to pirtobrutinib]. Why not? You should be okay. They just tolerate it better.

Shadman: I think you're right for patients who are progressing, and if it's easier to switch them to covalent to pirtobrutinib rather than just bring them the bringing the patient for CD20 antibody or ramp-up. I think there is a room for both options. I tend to go with covalent BCL2 and then noncovalent, but I've also done that in, I would say, 60%/30% in favor of BCL2.

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DISCLOSURES: Shadman previously disclosed serving a consulting or advisory role with AbbVie, Genentech, AstraZeneca, Pharmacyclics, BeiGene, Bristol Myers Squibb/Celgene, MorphoSys, Kite Pharmaceuticals, Fate Therapeutics, Lilly, Regeneron, Genmab, Merck, and Nurix.

REFERENCE

1. Brown JR, Eichhorst B, Hillmen P, et al. Zanubrutinib or Ibrutinib in Relapsed or Refractory Chronic Lymphocytic Leukemia. N Eng J Med. 2023;388(4):319-332. doi:10.1056/nejmoa2211582