Lipsky Reviews High-Risk Genetic Features That Impact Treatment With a BTK Inhibitor in CLL

Andrew Lipsky, MD

Assistant Professor of Medicine

Columbia University Medical Center

New York, NY

History and presentation

• A 70-year-old White man with asymptomatic lymphocytosis was identified 4 years previously.
• Initially monitored; after 2 years, developed anemia, night sweats, and splenomegaly
• Treated with venetoclax (Venclexta) plus obinutuzumab (Gazyva)
• Relapsed 13 months later; current status: ECOG performance status: 1
• Palpable splenomegaly
• Largest node, 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

Lab values

• White blood cell count: 35.0 × 10³ cells/μL
• Glycated hemoglobin A1_C: 22.0 × 10₃ cells/μL
• Hemoglobin: 9.5 g/dL
• Platelets: 80 × 10³ /μL
• Lactate dehydrogenase: 255 U/L
• Karyotype: complex, 4 abnormalities
• Fluorescence in situ hybridization: del(11q); without del(17p)
• IGHV: unmutated
• Mutations of interest: unmutated TP53
• Largest node on imaging: 4.2 × 2.8 cm

Targeted Oncology: What would you consider before further treatment if you encountered a patient case like this?

LIPSKY: When we think about a patient who has relapsed and [we are] selecting therapy for them…[there are certain patient] features I have in mind when deciding what to treat [them with]. In the relapsed setting, the most important [feature by far is knowing] their prior line of therapy. In this [hypothetical] case, the patient was given obinutuzumab and venetoclax. The other [factors that] I think about—and these are [factors] that are relevant for first-line treatment, too—[are the patient’s] comorbidities and disease characteristics.

[Those are factors] intrinsic to the tumor, such as mutations and karyotype. The last main factor to consider is patient preference, which is important in treating patients with chronic lymphocytic leukemia [CLL]. We have the luxury of having so many treatments that work so well now [in this space], that this is something we can discuss with patients [and find out their preference for treatment].

CASE UPDATE

Due to progression after BCL-2 treatment, a decision was made to start Bruton tyrosine kinase inhibitor (BTKI) treatment.

How do you factor the National Comprehensive Cancer Network (NCCN) guidelines into your treatment schema?

If you start with first-line treatment, you get [several] choices of BTKIs plus or minus anti-CD20 therapy.1 The 2 treatment paradigms [to consider are] indefinite therapy with a BTKI or time-limited therapy with venetoclax and obinutuzumab. If the patient has a response after treatment, which [the patient in this case] did…the NCCN [advises] to observe the patient until relapse or wait for indications for retreatment. Technically, by the NCCN guidelines, it is acceptable to either retreat [the patient] with venetoclax with an anti-CD20 therapy or give a BTKI. According to the NCCN guidelines, if your patient responded initially— which this patient did—then you can wait until you have a treatment indication and select a therapy, and retreatment might be something you could think about.¹

What data show the efficacy for treatment with venetoclax and obinutuzumab?

The 6-year progression-free survival [PFS] with venetoclax and obinutuzumab is…[approximately] 53%, [according to results from the CLL-14 study (NCT02242942)].² Most of the patients on [this combination] get a lot of time out of it…and I would expect if [I choose a patient at random] in frontline [treatment], they would probably get an average of [approximately] 6 years [of response to treatment with venetoclax and obinutuzumab], which is great. For 1 year of therapy, all of a sudden they’re getting 6 years [of survival] out of it.²

Do you see a role for assessing minimal residual disease (MRD) in patients with CLL?

MRD does make a difference in terms of how patients do, but the role of MRD assessments in clinical decision-making [in the CLL space] is a difficult topic. I do think there is a potential role there, although most clinicians would agree at this point that you shouldn’t be using MRD to decide to treat a patient, because there’s certainly a long interval between loss of MRD negativity in that context and a need to treat [the patient in a timely manner], as per the International Workshop on Chronic Lymphocytic Leukemia [IWCL].³

What are the preferred second-line regimens for this patient, according to the NCCN?

Both acalabrutinib [Calquence] and zanubrutinib [Brukinsa] have a category 1 preferred indication.¹ However, you don’t see the addition of an anti-CD20 therapy for acalabrutinib [in the guidelines].¹ For patients who, let’s say, may have received a BTKI in the first line and you want to switch them to venetoclax, then [that is] partnered with an anti-CD20 antibody such as rituximab [Rituxan]; that comes from the MURANO trial [NCT02005471].⁴ [Acalabrutinib and zanubrutinib] are the 2 preferred BTKIs, [and recent studies] have compared these 2 agents individually [with] ibrutinib [Imbruvica].

Does the dosing differ between these generations of BTKIs?

[Yes], ibrutinib has a dosing schedule of 420 mg [given] daily, and acalabrutinib is dosed at 100 mg twice a day. Acalabrutinib also has a new tablet formulation.⁵ With zanubrutinib, you have the option of twice-daily dosing at 160 mg or once-daily dosing at 320 mg…. All these are approved as continuous treatment until [disease] progression or unacceptable toxicity.

How does factoring in gene mutations like del(17p) and TP53 impact this patient population?

When you get genes from your mom and dad, you get 2 copies. The TP53 gene is the guardian of the genome, [which] prevents [the patient’s] cells from going crazy and entering the cell cycle if they have a deleterious mutation. You have 2 copies of it, and to get [to the patient’s] CLL, you need to affect both copies of the gene. But because that gene lives on the 17th chromosome, on the short arm—the P arm—one way to impact that gene is to delete the entire short arm of the 17th chromosome. The other way is just to make a mutation exactly where the TP53 gene lives.

It turns out [that] in CLL, [the patient] can have all combinations of these. [The patient] can have loss of the short arm of both chromosomes or they can have loss of the short arm of 1 chromosome and mutation of the other. They can have mutation of just the gene and a different mutation on the other chromosome. If we’re only checking del(17p) by fluorescence in situ hybridization and not checking the TP53 mutation status by something like next-generation sequencing, we miss TP53 aberrations. That’s why the NCCN and the IWCL criteria recommend not just checking to see whether the patient lost the short arm of the chromosome, but [they recommend to] sequence the gene at that point to figure out whether the patient has a mutation [in their disease], because you’ll miss it if you don’t do it.^1,3

What was the design and baseline characteristics of the phase 3 ALPINE (NCT03734016) study?

ALPINE was a phase 3 trial that was a 1:1 randomization of [652 patients] on either zanubrutinib [n = 327] or ibrutinib [n = 325] in the [intention-to-treat population].⁶ These were relapsed and refractory patients who had at least 1 line of therapy and measurable disease. They didn’t have Richter syndrome, and they couldn’t be on warfarin because of bleeding. The first patients on the original ibrutinib trials had intracerebral hemorrhage, and [some of them] died. Since then, we haven’t allowed patients to be on warfarin from concomitant PKC inhibitor usage. [Patients on this] trial were stratified by age, geographic region, refractory status, and del(17p) and TP53 mutation status. The primary end points were overall response rate [ORR] and investigator-assessed complete response rate. The secondary end points included [PFS], incidence of atrial fibrillation, duration of response, and overall survival.⁶

In this trial…the median number of prior lines of therapy was 1 [range, 1-6] in the zanubrutinib arm and 1 [range, 1-12] in the ibrutinib arm…. The risk feature breakdown of this patient population—knowing that some of those higher-risk features [will also show up as you] continue to treat patients—showed that [approximately] 23% of patients in this trial have those adverse risk genetic features, del17p and TP53 mutation status, with 13.8% of patients on zanubrutinib displaying del17p with or without the TP53 mutation [vs 15.4% in the ibrutinib arm], whereas patients with just a TP53 mutation [made up 9.2% of the zanubrutinib group and 7.7% of the ibrutinib group].⁶

What other high-risk features were noticeable for patients on this trial?

The other high-risk feature [we should consider] is a complex karyotype…[which] means many different things in different spaces. [In the CLL space], the technical definition of complex karyotype is 3 or more abnormalities on a karyotype.⁷ Now, what is a karyotype? CLL cells don’t like to divide, and it’s very hard to get them to divide, so you need to stimulate those cells in a lab, get them to divide, do a karyotype, then see 3 or more recurrent abnormalities [to know whether the patient has a complex karyotype]. We can also stratify this into high complexity and low complexity, with high complexity being more than 5 abnormalities and low complexity being 3 or 4 abnormalities.⁷

What were the response and PFS results of this trial?

In the intention-to-treat population, there was a PFS difference [between those on [zanubrutinib vs ibrutinib].⁶ With zanubrutinib, the estimated PFS at 24 months was 78.4% and for ibrutinib, it was 65.9%. So, there was a substantial PFS difference. If you look at the HR for comparing the second-generation BTKI to the first-generation BTKI, it was 0.65 [95% CI, 0.49-0.86]. [The HR] was a statistically significant result, with a P value of .002, so [this showed a clear] PFS difference. This is a pretty impressive [result], and in the highest-risk population group, patients with del(17p), TP53, or both mutations had longer PFS results on zanubrutinib [HR 0.53; 95% CI, 0.31-0.88].⁶ Investigator-assessed ORR also favored the second-generation BTKI vs ibrutinib, at 83.5% [95% CI, 79.0%-87.3%] vs 74.2% [95% CI, 69.0%-78.8%] [Figure⁶].

_REFERENCES

_{1. NCCN. Clinical Practice Guidelines in Oncology. Chronic lymphocytic leukemia/small lymphocytic lymphoma, version 3.2023. Accessed September 25, 2023. https://tinyurl.com/5yw9jnvk}

_{2. Fischer K, Al-Sawaf O, Bahlo J, et al. Venetoclax and obinutuzumab in patients with CLL and coexisting conditions. N Engl J Med. 2019;380(23):2225-2236. doi:10.1056/NEJMoa1815281}

_{3. Hallek M, Cheson BD, Catovsky D, et al. iwCLL guidelines for diagnosis, indications for treatment, response assessment, and supportive management of CLL. Blood. 2018;131(25):2745-2760. doi:10.1182/blood-2017-09-806398}

_{4. Seymour J, Kipps TJ, Eichhorst B, et al. Venetoclax–rituximab in relapsed or refractory chronic lymphocytic leukemia. N Engl J Med. 2018;378(12):1107-1120. doi:10.1056/NEJMoa1713976}

_{5. Kemp A. Calquence tablet formulation approved in the US across current indications. Press release. AstraZeneca. August 5, 2022. Accessed September 25, 2023. https://bit.ly/3P42p9r}

_{6. 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}

_{7. Visentin A, Bonaldi L, Rigolin GM, et al. The complex karyotype landscape in chronic lymphocytic leukemia allows the refinement of the risk of Richter syndrome transformation. Haematologica. 2022;107(4):868-876. doi:10.3324/haematol.2021.278304}