Patient KM is a 72 y/o woman.
- PMH: Hypertension (well controlled on medication)
- SMH: Does not smoke; drinks occasional glass of wine in social setting; Walks with friends 2-3 times weekly.

Clinical Presentation:

In October 2022, KM visited her PCP for her annual checkup. She reported having persistent fatigue and recent occurrences of night sweats.

Clinical Workup and Diagnosis:

WBC: 186,000; 80% lymphocytes
Hgb, 9.4 g/dL
Platelets, 85 x 109/L
ECOG PS 0
Elevated serum beta-2-microglobulin
Flow cytometry, CD5+, CD20+, CD23+
TP53 mutation status – unmutated; IGHV mutation status – unmutated
Bone marrow biopsy confirms diagnosis of chronic lymphocytic leukemia (CLL)

Current Treatment:

After discussions with her family and clinical team, KM was initiated on fixed duration of venetoclax + obinutuzumab.
- KM was started on obinutuzumab at 100 mg IV Day 1, followed by 900 mg IV on Day 2, then 1000 mg IV on Days 8 and 15 of Cycle 1; Currently infused with 1000 mg IV on Day 1 of remaining cycles.
- She was initiated on a ramp-up dosing schedule of venetoclax starting on C1D22 and currently taking the recommended dose of 400 mg PO daily.

Transcript:

John Allan, MD: We’re talking about venetoclax-obinutuzumab, but we have other treatment options, like BTK [Bruton tyrosine kinase] inhibitors. There have been some exciting updates in the past few years, including recently at ASH [American Society for Hematology Annual Meeting], showing really good long-term results with these agents. They’ve established themselves as an alternative therapy—maybe just as good, maybe better, but a great agent and really effective for patients with CLL [chronic lymphocytic leukemia]. With ibrutinib, we’ve seen 8-year follow-up data published. It has set the bar for the expectations of what we want to see with a BTK inhibitor. At 8 years, we still haven’t met a median progression-free survival [PFS] in the frontline setting; it’s about 57%. This is with ibrutinib, which has toxicity issues. We’ve seen very few discontinuations after year 3 or 4. If you get through the first 3 years, you’re probably not going to discontinue this drug due to toxicity.

That said, less than half the patients are remaining on the drug. Most have come off the agent due to toxicities and adverse events. But it’s shifted the game. We see overall survival [OS] at this 8-year mark of about 80% or 85%, and patients are doing phenomenally well. We see new agents come onto the block as well. There was another analysis done at ASH that looked at age-matched controls without CLL, and patients who were age 65 or older on ibrutinib from the RESONATE-2 study had the same survival. For the first time, we’ve seen the same survival 8 years later as an age-matched control without CLL. Basically, we’ve shifted patients up to a normal life expectancy. In a sense, you can look at it like that. It’s a chronic illness. They’re taking medication, and CLL isn’t necessarily the cause for an earlier demise. Patients are living as long as their counterparts without CLL.

Other studies have been updated. The ELEVATE-TN study has been published and updated to 5 years of data. ELEVATE-TN used acalabrutinib. This study was interesting because it looked at acalabrutinib monotherapy vs acalabrutinib-obinutuzumab, and then obviously the inferior control arm, chlorambucil-obinutuzumab. What’s interesting is that with the longer-term follow-up, acalabrutinib-obinutuzumab had an OS benefit compared with chlorambucil-obinutuzumab. And chlorambucil-obinutuzumab had very similar survival as acalabrutinib monotherapy. With longer-term follow-up, we might see OS benefits by obinutuzumab addition over monotherapy acalabrutinib.

This study was important in that obinutuzumab seems to add some benefit to acalabrutinib monotherapy. What we see are higher complete remission rates. Earlier on, we see higher MRD [minimal residual disease]–negativity rates. About 30% of patients are becoming MRD negative in the peripheral blood by the addition of obinutuzumab. This has seemingly translated into a PFS benefit. The study was not powered to show a PFS benefit between acalabrutinib-obinutuzumab vs acalabrutinib monotherapy. But at this 5-year mark, we’re seeing about 87% PFS at 5 years compared with around 77% or 78%. That’s almost a 10% to 12% PFS difference by the addition of the obinutuzumab, which is relatively modest. There’s no OS benefit. That’s a relatively large number needed to treat patients with obinutuzumab who do have issues.

There were increased infections with this agent addition. Many patients do phenomenally well just with monotherapy. We’d love to think that high-risk patients should be the ones for whom we escalate the therapy, but unfortunately the TP53 complex karyotype patients aren’t benefiting from the addition of obinutuzumab. It doesn’t make much sense to add the drug to those patients because it’s adding toxicity and not adding benefit. Unmutated IGHV patients, mutated IGHVpatients, and basically any other patients who don’t have these high-risk features are the ones who seem to have this PFS benefit, however modest.

How we’re viewing this and how we incorporate anti-CD20s with continuous-therapy BTK inhibitors continues to evolve. I favor monotherapy approaches because of the headaches you sometimes run into with severe B-cell depletion from the anti-CD20. But if we start to see OS benefits and continual long-term differentiation of these curves, that’s going to cause me to rethink—maybe when I’m using acalabrutinib, we should be using obinutuzumab.

The third big update was the SEQUOIA study. SEQUOIA was zanubrutinib vs bendamustine-rituximab in a phase 3 clinical trial. Zanubrutinib showed PFS benefit over BR [bendamustine, rituximab]. Not that this is a surprise, but this got its approval in the frontline setting. This study has a follow-up of 30-plus months, almost 2 years, showing 2-year PFS of 85% vs 70%. That’s a 15% difference already. No OS benefit was noted.

SEQUOIA is notable because it has a cohort: del(17p) patients were excluded from the randomized portion but put into 2 other cohorts. One cohort was zanubrutinib monotherapy. That arm will look at 110 patients with a deletion 17p being prospectively studied on a single arm with zanubrutinib monotherapy, and it will be the largest prospective group of patients on a single study being followed. It’s going to be a very important data set to set the bar because all the data—and the expectations for what we see with BTK inhibitors in del (17p) patients—come from pooled studies, small numbers from 4 or 5 different studies pooled. Ultimately, that bar is about a 74% PFS rate at 4 years. Zanubrutinib is tracking along at this 30-year mark with close to 87% of patients progression-free at this 30-year mark. Will it be better? That remains to be seen, but at least it’s tracking well historically. Zanubrutinib is another great option for our patients with BTK inhibitors.

Transcript edited for clarity.