AV Gives CLL Patients a Fixed-Duration Oral Path: Adam Kittai, MD

The FDA’s February 2025 approval of acalabrutinib plus venetoclax (AV) marks the first all-oral, time-limited frontline regimen for chronic lymphocytic leukemia (CLL) in the US. Phase 3 AMPLIFY data (NCT03836261) demonstrated that AV improved progression-free survival (PFS) and overall survival vs chemoimmunotherapy, with a notably favorable safety profile. Atrial fibrillation (AFib) or flutter occurred in just 0.7% of patients, and tumor lysis syndrome (TLS), a hallmark concern with venetoclax, arose in only 1 of 291 patients, attributed to the 2-cycle Bruton tyrosine kinase (BTK) inhibitor priming strategy.

Adam Kittai, MD, of NYU Langone Health; director, CLL Program, Perlmutter Cancer Center; and director, Lymphoma Program, Perlmutter Cancer Center - Long Island, sees AV as a strong fit for patients committed to avoiding both indefinite therapy and infusions. “If somebody was coming in really committed to time-limited therapy and wanted oral therapy without the infusion, that'd be somebody I would be fine doing it [in],” he said.

He does, however, counsel caution in TP53-aberrant or immunoglobulin heavy-chain variable (IGHV)–unmutated disease and remains vigilant about bleeding risk in patients on concurrent anticoagulation, noting he may engage cardiology when anticoagulation seems potentially avoidable.

This interview was lightly edited for clarity.

AJMC: How was the AMPLIFY trial designed to evaluate AV?

Kittai: The AMPLIFY study was a phase 3 clinical trial that had 3 arms: AV, AV plus obinutuzumab (AVO), vs investigator’s choice chemoimmunotherapy with either fludarabine/cyclophosphamide/rituximab or bendamustine/rituximab. The study was powered to look for a PFS benefit, and it was powered to test AV vs chemoimmunotherapy and AVO vs chemoimmunotherapy, but not AV vs AVO, so that’s something to note. In this particular treatment, patients received 2 cycles of acalabrutinib lead-in and then got 12 cycles of the combination of AV. That was for the AV arm. For the AVO arm, the A and the V were given the same, except the obinutuzumab was added at cycle 2 and given for 6 cycles with a standard ramp-up.

This study looked to see if patients receiving AV did better than chemoimmunotherapy or receiving AVO compared with chemoimmunotherapy. In general, a couple of notes about the patient population. Number 1, patients with deletion 17p (del17p) and TP53 were not allowed on this study because by the time that this study was developed, we knew that patients with the TP53 aberrations did poorly with chemoimmunotherapy, so it wasn’t going to be fair to put them onto a chemotherapy arm in a randomized study. Additionally, the other thing to note is, because one of the arms was chemoimmunotherapy, the median age for this study was a little bit lower than what we typically see, at 61. Those are the 2 main comments about the patient population that enrolled. Otherwise, this is a pretty standard randomized phase 3 study that included a general normal CLL population.

AJMC: With efficacy data showing improved PFS vs chemoimmunotherapy, how do you see this shifting the treatment paradigm vs continuous BTK inhibition?

Kittai: The study found that time-limited AV led to a PFS benefit compared with chemoimmunotherapy and an overall survival benefit compared with chemoimmunotherapy. What this didn’t show was a benefit compared with continuous BTK inhibitor therapy because it didn’t test that, and it also didn’t show a benefit compared with venetoclax plus obinutuzumab because it didn’t test that.

What I think this does is it adds an extra treatment option into our armamentarium for treatment options for patients with CLL, where it offers the opportunity for someone to get an all-oral therapy that is also time-limited. This is the first time that we’ve had an all-oral time-limited therapy approved by the FDA in the US. There was the GLOW study (NCT03462719), which studied ibrutinib plus venetoclax, but that did not get approval by the FDA and was actually only approved ex-US.

So now that we have this approval of an all-oral time-limited therapy, the question then becomes, is this going to replace patients who otherwise would have gone on continuous BTK inhibitor therapy or is it going to replace patients who otherwise were on venetoclax plus obinutuzumab? It is yet to be determined how this is going to be adopted. When I think about the patient that I would put on this particular regimen, I would think about somebody who has good risk features because in this study, patients with TP53 aberrations were excluded, so we don’t have the information for how patients would have done if they had a del17p or TP53.

So for those patients, they still would favor a continuous BTK inhibitor. Additionally, the patients who had IGHV unmutated status appeared to have worse outcomes with AV than I otherwise would have expected. And so I also might give pause to give AV in patients with unmutated IGHV. That being said, if a patient wanted to come in and they were like, “Listen, I really want time-limited therapy, but I don’t want the infusion” and they also have high-risk features, I still probably would give it to them. I always have a conversation with them about how maybe this wouldn't be what I would favor for them, but if they were still insistent on getting time-limited therapy and they didn’t want the infusion of obinutuzumab, this is something I would move forward with in that regard.

AJMC: How are you counseling patients when choosing between fixed-duration therapy and indefinite BTK inhibitor treatment?

Kittai: We don’t have head-to-head data long term. What we do have is the CLL17 study (NCT04608318), which compared ibrutinib to ibrutinib plus venetoclax to venetoclax plus obinutuzumab, and the efficacy looked overlapping. It was the same. We can extrapolate a little bit here and say that AV at least likely will have similar efficacy to continuous BTK inhibitor therapy. But we don’t know for sure, and so we’re doing a lot of extrapolation from that.

What I usually talk about with patients is that continuous BTK inhibitor therapy, 1 oral pill or twice-a-day pill that you take, is really super convenient and very well tolerated. However, for younger patients, they might have some cumulative toxicity over time that we might want to avoid. Let’s say we have a patient who is younger, maybe in their 50s, who has a strong family history of cardiac disease, might be prediabetic, might be a little bit overweight. I’m not sure if I really want to add more hypertension to that person, which we do see over time with continuous BTK inhibitor therapy. That would be something I would talk to them about.

With A plus V, since it’s given only for 14 cycles, we’re not going to see that cumulative hypertension over time. The safety profile in AMPLIFY looked quite good, where we didn’t see the classic BTK inhibitor adverse effects as much. For instance, there was only 0.7% AFib or flutter, and major hemorrhage only occurred in 1% of patients. Additionally, the adverse effect that we worry about with the venetoclax, which is TLS, only happened in 1 patient out of 291 patients, really showing that priming patients with that BTK inhibitor for 2 cycles mitigates that risk for TLS a lot, which makes us less worry about it.

I think that I would counsel them on AV as being a very safe regimen, one that we can give for a time-limited manner; however, we don’t have long-term follow-up on it. We don’t have direct comparison of AV to continuous therapy or VO yet, but we will soon. Additionally, at least right now, giving it for high-risk features may not be the best idea. Although, as I said, if somebody was coming in really committed to time-limited therapy and wanted oral therapy without the infusion, that’d be somebody I would be fine doing it [in]. Just talking to them about it first and letting them know that maybe it’s not what I prefer.

AJMC: What are the most important safety consideration when using acalbrutinib plus venetoclax, especially in community practice settings?

Kittai: I would say that the safety profile of AV looked really good, and it’s really nice that it’s only done for 14 cycles. That being said, the 2 main things that I think about are the classic BTK inhibitor side effects. I’m less worried about long-term hypertension, and in the particular study, the AFib rate wasn’t very high, too, so I’m less worried about those 2 things given that you’re only giving the acalabrutinib for 14 cycles.

But what I do still worry [about] is that bleeding component. We know that when patients are on multiple different anticoagulants, such as aspirin, Plavix [clopidogrel], and acalabrutinib, that’s what makes me nervous. I would say that anybody who has to be on concurrent anticoagulants, you want to see if you can either do a dose reduction or a dose hold, or talk to the cardiologist if they’re mandating it because they have AFib at baseline or something like a recent stent that required Plavix and aspirin. And so I think that bleeding risk is something I still pay attention to, at least for the acalabrutinib for sure. With the venetoclax, it’s the standard TLS, which, as I said, was very low here. But it still requires that dose ramp-up.

Now, the one thing I didn’t cover is infection, where even though AV had a grade 3 infection rate of 12.4%, which is actually pretty similar to chemotherapy at 10.0%, that’s still a 12.4% grade 3 infection rate. So I do counsel my patients that if they suspect a fever or aren’t feeling well, they should just definitely talk to me about it. I do monitor their cytopenias pretty closely when they’re getting the venetoclax. I check labs at least once per month. That’s how I would approach the different adverse effect profile for AV, which is slightly different than what we’ve seen in the other medications.