Saba Analyzes the Importance of Considering a Patient’s Health History When Using BTK Inhibition in R/R CLL

Nakhle Saba, MD

Associate Professor of Clinical Medicine

Tulane University School of Medicine

Tulane Cancer Center

New Orleans, LA

At a live virtual event, Nakhle Saba, MD, discussed the role of Bruton tyrosine kinase (BTK) inhibitors for patients with relapsed or refractory (R/R) chronic lymphocytic leukemia (CLL), especially in patients with a poor health history. Specifically, he looked at how they could impact the case of a 70-year-old patient who has coronary artery disease and high cardiovascular risk and who relapsed after 2 years of treatment on venetoclax and obinutuzumab. According to Saba, it’s important to factor in the patient’s health history as they move to BTK inhibition treatment. Here, he discusses how he would proceed and what therapy he would look to use and lowering toxicities.

Assessing the Patient

[In this case], the patient was diagnosed with classic CLL and relapse [that followed]. So, the discussion here [would be whether] we are going to re-treat this patient with venetoclax [Venclexta]- based treatment vs going to a BTK inhibitor. [However, we should be] concerned about bleeding if a patient like this is on Plavix and aspirin and [what their] cardiotoxicity could be if the patient has stents [and a poor health history regarding their heart]. When we see a patient like this, a lot of them [are still taking] aspirin for no reason. I stop aspirin [in most cases], and definitely stop when I’m considering giving them a BTK inhibitor, and I will call the cardiologist to tell them that taking this drug can cause bleeding, so [does the patient still] need Plavix and aspirin? If so, for how long, and can we drop one or the other? These are important points [to address early] that can potentially save the patient’s life [from serious adverse events (AEs)].¹ If someone is tolerating ibrutinib [Imbruvica] well without serious [AEs], and [is] not willing to switch therapy, then it’s OK to continue ibrutinib. But for the newcomers, [we should be] using the newer generation of BTK inhibitors for their treatment.

Measuring Effectiveness of Therapy

You really want to see good overall survival [OS] data in a chronic disease like CLL. We have seen some very long follow-ups of earlier novel agent trials, but with the more recent data it might be too early [to make an OS determination]. So, can we use progression-free survival [PFS] as a good surrogate, or do we really want to see OS before considering which therapy is better? [The answer is] yes, PFS is an important primary or key secondary end point for CLL trials [and we can use it to determine which therapy has a more ideal efficacy in these patients].²

The response rate is [also] important, and some trials [of BTK inhibitors in this space] used the overall response rate [ORR] as the primary end point. Regarding the depth of response, it’s not really fair to measure the efficacy of BTK inhibitors by the minimal residual disease [MRD] rate, but it is fair [to use MRD as a benchmark] for those therapies that kill the disease cells right away, such as venetoclax. This is why we can use venetoclax-based treatment for a fixed duration, because it’s achieving a deep response.

The deeper the better, and the MRD-negative aspect is positive for [venetoclax-based treatment] as opposed to a single-agent BTK inhibitor where you’re [reducing] the disease further. These cells are pushed out of the lymph node to the blood, where they’re going to die slowly from basically a lack of stimulation. So, it’s not fair to measure the efficacy of a continuous therapy [by using MRD rates]. If you combine a BTK inhibitor with a BCL2 inhibitor for a fixed-duration therapy, and this is what the newer trials are addressing, then yes, MRD will probably play a role [in determining the effectiveness of the therapy] and will probably play a role in how we determine treatment options for these patients in the future.

Results With Newer BTK Inhibitors

The initial median follow-up [in the phase 3 ALPINE study (NCT03734016)] was 29.6 months, so a little short, but the ORR was higher with zanubrutinib [Brukinsa], which was the primary end point [of this study], but PFS was surprisingly higher with zanubrutinib too.³ The median PFS with zanubrutinib was not reached…as opposed to 34 months with ibrutinib. The 2-year PFS rate was 78% [for zanubrutinib compared with] 65% on ibrutinib, and [that difference] was statistically significant [HR, 0.65; 95% CI, 0.49-0.86; P = .002]. The median duration of follow-up here was more than 3 years, at 36.3 months, and the updated median PFS…[was better for both therapies], and this statistically significant difference in PFS was obtained after adding 1 year of follow-up.⁴ So, the 3-year PFS rate was 65.8% for zanubrutinib vs 54.3% for those on ibrutinib [HR, 0.67; 95% CI, 0.52-0.86; P = .002].⁴

There were some subset analyses to compare; for example, [patients with CLL positive for] deletion 17p, a TP53 mutation, or both, were in both cohorts [of therapies] and even in this subgroup [the 2-year PFS rate with]… zanubrutinib continued to do much better than ibrutinib did [at 72.6% vs 54.6%, respectively (HR, 0.53; 95% CI, 0.31-0.88)].³ If you exclude patients who stopped treatment for AEs and just focus on those patients who progressed or died while on treatment, this difference also was maintained favoring zanubrutinib whether they dropped treatment due to AEs or COVID-19.³ No matter how you look at these data, even from a different angle, you still see the same results [favoring treatment with zanubrutinib]. We were all surprised to see it, but it does maintain efficacy in the long run and hopefully we’ll continue to see a longer follow-up of this trial.

If you look at grade 3 or higher AEs, 67.3% of patients in the zanubrutinib arm had a grade 3 AE [compared with] 70.4% in the ibrutinib arm.³ The rest of the toxicity profile was pretty much the same and, surprisingly, [when you combine] hypertension and increased blood pressure events, [the number of events] was the same between the 2 arms, which was surprising [Table³]. The main difference in toxicity [between zanubrutinib and ibrutinib] was atrial fibrillation [AFib].⁴ Remember, this was a secondary end point, and the investigators were doing [electrocardiograms] at every clinic visit, so they captured all AFib [events], whether it was symptomatic or asymptomatic. Reports of high-grade AFib were 6.2% with zanubrutinib vs 16.0% with ibrutinib, and that was statistically significant [between the 2 arms (P < .0001)].⁴ If you look at all serious AEs, they’re also lower [in the zanubrutinib arm], along with cardiac events leading to dose reduction or discontinuation [at 0.6% in the zanubrutinib arm compared with 4.6% with ibrutinib].³ Grade 5 toxicities were 10% with zanubrutinib and 11% with ibrutinib and most were due to infection, but this study was conducted during the height of [the COVID-19 pandemic], [which should be kept in mind].³

REFERENCES:

1. Brown JR. How I treat CLL patients with ibrutinib. Blood. 2018;131(4):379-386. doi:10.1182/blood-2017-08-764712

2. Niemann CU. BTK inhibitors: safety+ efficacy= outcome. Blood. 2023;142(8): 679-680. doi:10.1182/blood.2023020974

3. 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

4. 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). Blood. 2023;142(suppl 1):202. doi:10.1182/ blood-2023-174289