Oncologists Discuss a Second-Generation BTK for Relapsed/Refractory CLL

Daniel A. Ermann, MD

Hematologist/Oncologist

Division of Hematology & Hematologic Malignancies

Huntsman Cancer Institute

Salt Lake City, UT

CASE SUMMARY

History and Presentation

• A 70-year-old White man with asymptomatic lymphocytosis, identified 4 years ago
• Initially monitored; 2 years later, he developed anemia, night sweats, and splenomegaly
• Treated with venetoclax (Venclexta) plus obinutuzumab (Gazyva)
• Relapsed 24 months later
• ECOG performance status: 1
• Palpable splenomegaly
• CT of the chest, abdomen, and pelvis showed the largest node at 4.2 × 2.8 cm; all others < 3 cm.

Comorbidities

• Coronary artery disease
• High cardiovascular risk due to history of non–ST-elevation myocardial infarction, status post 2 stents

Medications

• Simvastatin
• Amlodipine
• Clopidogrel, aspirin

Diagnostic Workup

• White blood cell count: 35.0 × 10³ cells/μL
• Absolute lymphocyte count: 22.0 × 10³ cells/μL
• Hemoglobin level: 9.5 g/dL
• Platelet count: 80 × 10³/μL
• Lactate dehydrogenase level: 255 U/L
• Karyotype: complex, 4 abnormalities
• Fluorescence in situ hybridization (FISH): 11q deletion (del[11q]), without 17p deletion (del[17p])
• IGHV: unmutated
• Mutations of interest: unmutated TP53
• Largest node on imaging: 4.2 × 2.8 cm

PEERS & PERSPECTIVES IN ONCOLOGY: What methods do you use to evaluate patients such as this with chronic lymphocytic leukemia (CLL)?

ERMANN: One thing I recommend at diagnosis is FISH testing and DNA sequencing. The reason is that when patients relapse, their disease can change, so FISH testing and DNA sequencing can change. I would recommend doing it at diagnosis and then at relapse. Patients can have both del(17p) and TP53 or have one, but TP53 lives on the 17p chromosome, and both of those are unfavorable risk. Del(11q) is also unfavorable; trisomy 12 intermediate and del(13q) tend to be favorable. There are certain complex karyotypes that predict a more favorable response, but, in general, the more complexity, the more aggressive the CLL and the worse the outcomes in general. As a blanket statement, 3, 4, and 5 or more variables would be unfavorable; every time you add on complexity, the outcomes are worse.

If you’re going to proceed with observation up front, would you still send for testing at the beginning if it’s not changing the management?

In my opinion, sending it early can let you know how often you may need follow-up for the patient. Let’s say you do FISH and mutational testing, and it comes back with TP53 mutated, del(11q), and unmutated IGHV, so high risk. That’s someone who you can put on your radar. Maybe instead of every 6 months, you set them up sooner. I counsel my patients at diagnosis. I say each one of these tests is [a part of] a jigsaw puzzle and paints the picture of how their CLL will behave. It lets you, as their treating physician, understand what their disease biology might be and how the disease will behave.

I use a risk score called the CLL-IPI [International Prognostic Index for Chronic Lymphocytic Leukemia], which looks at all the risk factors and can predict, pretty reliably, the time to first treatment in CLL. It gives you an insight…at diagnosis before patients need treatment. Usually what happens is by the time someone does need treatment, you’re rushed to get treatment, and then you can forget to order something, so it’s good to get it done when things are calmed down. [However], IGHV, you don’t have to repeat. That will rarely ever change.

Do you use stimulated metaphase karyotype or regular cytogenetic testing for your patients with CLL?

I do regular cytogenetics. The only time you’d do a specialized one is if you’re looking to rule out mantle cell lymphoma, which you can do with an interphase [chromosome flow] FISH for translocation 11;14 because sometimes CLL and mantle cell lymphoma will overlap.

If you use Tempus testing, Tempus xT Heme does free next-generation sequencing testing, essentially free. There’s no cost to the patients, and I do that for everyone I see; I’ve never had a patient have a bill. That will pick up TP53 as well, and then there are some other higher-risk mutations that don’t influence treatment. But things like NOTCH1 can predict Richter transformation, and there are some other higher-risk ones that can be somewhat valuable to know.

What are the recommended first-line therapies for patients with CLL without del(17p)?

In the preferred regimens, ibrutinib [Imbruvica] is missing, and that’s mainly because ibrutinib has fallen out of favor due to the higher rates of adverse events [AEs] seen with ibrutinib compared with the second-generation Bruton tyrosine kinase [BTK] inhibitors acalabrutinib [Calquence] and zanubrutinib [Brukinsa]. Because of that, if you can, it’s generally advised not to use ibrutinib. Keeping a patient on ibrutinib or if you do choose to use it, it’s not wrong; it just has a bit more AEs, including the risk of sudden cardiac death, which the other ones have much lower rates of.¹

CASE UPDATE

Due to progression of disease after a BCL2 inhibitor, the decision was made to initiate therapy with a BTK inhibitor.

What BTK options are available for this patient?

For second-line therapy, there is acalabrutinib, venetoclax/ rituximab [Rituxan], and zanubrutinib.² It does say venetoclax/rituximab for second line and beyond, and that’s how it was studied with the phase 3 MURANO trial [NCT02005471]. However, using obinutuzumab is generally what most CLL physicians will do. Very few will use venetoclax plus rituximab, and that’s mainly due to frontline data showing…better outcomes when you use venetoclax/obinutuzumab.³ So, even in the relapse setting, I would use the obinutuzumab [over] rituximab. The NCCN says the preferred BTK inhibitors are acalabrutinib and zanubrutinib.²

Of note, chimeric antigen receptor T-cell therapy is now FDA-approved for CLL. It was approved in March 2024 and had an accelerated approval, so that is also an option in the third-line plus setting.

What were the trial data behind zanubrutinib in this space?

It’s called the ALPINE trial [NCT03734016]. This was a phase 3 trial comparing zanubrutinib to ibrutinib. For patients to be eligible, they had to be relapsed/refractory to 1 or more therapies with CLL, and they excluded Richter transformation and prior BTK. So mainly patients were treated with chemotherapy, and the primary end point on this study was overall response rate and the secondary end point was progression-free survival [PFS]. Of note, this was a superiority study, looking at superiority of zanubrutinib to ibrutinib.⁴

The patient characteristics were relatively well balanced [with] similar rates of high-risk del(17p), TP53, and del(11q) between the groups, with most patients having 1 prior line of treatment.

What were the efficacy and toxicity seen on ALPINE with long-term follow-up?

What we saw in this phase 3 study was a statistically significant PFS benefit of zanubrutinib compared with ibrutinib in the relapsed setting, with a median follow-up of 36 months. The [36-month] PFS rate was 66% to 54%, so it was a pretty significant PFS benefit.… [The benefit was observed] regardless of risk status.⁵

When we look at [AEs] with zanubrutinib compared with ibrutinib, it’s notable that in this study, there were a significant number of COVID-19–related deaths. That’s one of the pitfalls of having a study during the COVID-19 era. You’re going to have a lot of patients who [died during the pandemic], and this is one of those trials. But if we look at the rest of the AEs—ibrutinib is known for its toxicity. When we look at this, if you put a patient on zanubrutinib, it’s comparing what you are going to expect. You would expect similar rates of neutropenia with zanubrutinib, similar rates of hypertension, but lower rates of some of these other AEs such as diarrhea and arthralgias.

Looking at the AEs of interest, the big AEs with ibrutinib include hypertension and atrial fibrillation. Atrial fibrillation and some cardiac death were the 2 big ones with ibrutinib. Sixteen percent of all-grade atrial fibrillation is very high compared with zanubrutinib. The second generations are significantly lower with essentially 7% all-grade and only 3% grade 3 or more atrial fibrillation. Of note, zanubrutinib seems to have a lot of neutropenia, so keep that in mind. When I see that, I usually utilize granulocyte colony–stimulating factor [G-CSF] to counter the neutropenia seen with zanubrutinib.

How do you decide how often you give that G-CSF? Do you do it as needed for blood counts? If so, how often do you check the blood counts?

I do it as needed for blood counts. When I start a patient on [zanubrutinib], I usually see them 2 weeks after starting for a toxicity check. I would say the neutropenia starts around cycle 2, and what I will usually do is see them every cycle, once a month. And usually once a month I’ll give them pegfilgrastim [Neulasta] if their neutrophil count is low. It’s a little bit tough because when you start a BTK, you see the white blood cell count increase, and there can be some spurious neutropenia. It’s hard to know whether it’s real or not, but if I see neutrophils of 0, I treat it with long-acting G-CSF. I usually do that once a month as needed. Then after the white blood cell count starts to come down, around month 3, the neutropenia usually resolves.

With the risk of major bleeding, how do you manage this with patients who are on anticoagulation? Does that play a role in your decision?

It does; it makes it hard. Warfarin [Coumadin] is essentially contraindicated with any BTK inhibitor. They’re always excluded from all the trials. For anyone on warfarin, unfortunately, you either get them on a different medication like a direct oral anticoagulant or you have to find something else for them. But yes, you can use BTK inhibitors in patients on dual antiplatelet therapy. It’s not a blood thinner; it just increases their rates of bleeding, so you can do it.

While they’re on just direct oral anticoagulants, you can put patients on a BTK. Just be mindful of any surgeries [or] procedures, or if they have any other comorbidities that predisposes them to bleeding. You can run into tough situations. Zanubrutinib seems to [cause] more bleeding than acalabrutinib, in my experience. If you’re worried about bleeding, I think acalabrutinib might be a bit of a better… second-generation BTK.

When we look at atrial fibrillation rates, they’re significantly reduced in zanubrutinib compared with ibrutinib with significantly lower cumulative incidence rates.

_REFERENCES

_{1. Diamond A, Bensken WP, Vu L, Dong W, Koroukian SM, Caimi P. Ibrutinib is associated with increased cardiovascular events and major bleeding in older CLL patients. JACC CardioOncol. 2023;5(2):233-243. doi:10.1016/j.jaccao.2023.02.001}

_{2. NCCN. Clinical Practice Guidelines in Oncology. Chronic lymphocytic leukemia/ small lymphocytic lymphoma, version 1.2025. Accessed November 12, 2024. https://www.nccn.org/professionals/physician_gls/pdf/cll.pdf}

_{3. Eichhorst B, Niemann CU, Kater AP, et al. First-line venetoclax combinations in chronic lymphocytic leukemia. N Engl J Med. 2023;388(19):1739-1754. doi:10.1056/NEJMoa2213093}

_{4. Brown JR, Eichhorst B, Hillmen P, et al. Zanubrutinib or ibrutinib in relapsed or refractory chronic lymphocytic leukemia. N Engl J Med. 2023;388(4):319-332. doi:10.1056/NEJMoa2211582}

_{5. Brown JR, Eichhorst B, Lamanna N et al. Extended follow-up of ALPINE randomized phase 3 study confirms sustained superior progression-free survival of zanubrutinib versus ibrutinib for treatment of relapsed/refractory chronic lymphocytic leukemia and small lymphocytic lymphoma (R/R CLL/ SLL). Presented at: 65th ASH Annual Meeting and Exposition; December 9-12, 2023; San Diego, CA.}