Catherine C. Coombs, MD, is a hematologist-oncologist and associate clinical professor in the Department of Medicine of the Division of Hematology/Oncology at University of California Irvine Health.

 Let’s turn to new treatments. One drug that’s furthest along in development is called pirtobrutinib, which Anthony updated at ASH [American Society of Hematology Annual Meeting] 2021. Anthony, can you introduce reversible inhibitors of BTK [Bruton tyrosine kinase] and summarize the update on pirtobrutinib? Then we’ll have Callie discuss nemtabrutinib as another drug within that category of reversible inhibitors.

As an intro to the topic, these molecules are meant to bind in a noncovalent way to an alternative binding site on BTK to circumvent the main and known mechanism of resistance to covalent inhibitors, which are Cys481 mutations. Pirtobrutinib is a specific noncovalent BTK inhibitor that works as well in wild type preclinically as it did in mutated CLL [chronic lymphocytic leukemia] in models. It looks to be an ideal BTK inhibitor from the perspective of minimal off-target effects and addresses the main unmet need, which is resistance to covalent inhibitors that are utilizing a treat until progression strategy.

The update to the BRUIN study focused on patients who had prior covalent BTK inhibitors, about 252 patients. The take-homes are simple. It’s active. Response rate was 68%. It got better with time. It seemed to be similarly active, no matter how you looked at patients’ prior therapies, high-risk features, and reasons for discontinuation. Remissions were durable. The median PFS [progression-free survival] was not reached with a short follow-up of 9.4 months. In the double-exposed patients, the median PFS was 18 months. The third point I want to make is that it was safe.

Very few AEs [adverse events] occurred at 15% or higher. BTK-associated adverse events were minimal. AFib [atrial fibrillation] was only 2% in more than 600 patients treated on the trial. The major take-home in terms of safety was a discontinuation rate of less than 1% in the population. We know from other covalent BTK inhibitors that the discontinuation rates with similar follow-up can range from 10% to 20%. Overall, it seemed to be safe and effective, and it addressed an unmet need. It’s a promising molecule, and we’ll probably hear a lot more about this in the future.

Nemtabrutinib has had a lot of names. Formerly it was ARQ 531. Now it’s owned by Merck, so it’s MK-1026 or nemtabrutinib. This is another noncovalent BTK inhibitor. Dr Jennifer Woyach presented the results from the single-arm phase 2 trial, which had several expansion cohorts. This trial hasn’t enrolled anywhere near as many patients, and the report from the abstract was that a little over 100 participants had been enrolled, including patients with a variety of B-cell NHLs [non-Hodgkin lymphomas] but also CLL.

They did present efficacy data that show this drug is also efficacious. They quote a response rate of 58% for patients with CLL—22 of 38 patients—who are primarily PR [partial response] or PRL [PR with treatment-induced lymphocytosis]. The 1 difference with this drug is that it appears that grade 3 adverse events are a bit higher: 68% of patients had grade 3 or higher treatment-emergent AEs. There were a few grade 5 events, specifically in 6% of participants, though those were more commonly because of disease progression in 3 of 7 patients that died. This is an interesting compound that appears to be active but not as many patients and maybe not as low of a toxicity profile when doing a cross-trial comparison of the pirtobrutinib data. It will be interesting to follow what happens with more time and patients on this trial.

 Other reversible inhibitors are in development, perhaps not as far along as pirtobrutinib and nemtabrutinib, which we’ll most likely be hearing about.

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Recommendations for applying information from clinical trials presented at oncology and hematology conferences in 2021 into routine clinical practice when managing patients with chronic lymphocytic leukemia.

Noncovalent BTK Inhibitors in CLL

 Let’s talk about sequencing. It’s a tough subject. Anthony, can you comment? It’s a complicated topic. There aren’t data that say 1 strategy over another is better in terms of starting with a BTK [Bruton tyrosine kinase] vs starting with BCL2. Can you summarize some of the general concepts around sequencing? If you start with a BTK, do you treat to progression and then switch to a BCL2? Also, comment on where chemoimmunotherapy would be in that sequence.

I agree that there are no data to support 1 strategy over another. But if you start with a covalent BTK inhibitor, there are 2 options. You’ll treat to progress. If they progress, they’re generally resistant. That takes covalent BTK inhibitors off the table because of the known mechanism of resistance, or you’ll discontinue because of an adverse event [AE]. That’s a relatively common event with ibrutinib, less common with acalabrutinib and zanubrutinib. If you discontinue because of an adverse event, you could think about what the AE was. There’s a strong rationale to switch and stay within class to another covalent BTK inhibitor, like switching from ibrutinib to acalabrutinib.

Upon progression from a covalent BTK inhibitor, the standard of care is venetoclax-based therapy, time-limited with venetoclax re-treatment as the next most reasonable line of therapy. BTK to BTK to venetoclax to venetoclax is 4 different lines of therapy before you need to do anything experimental or consider a PI3K. If you start with venetoclax, everybody gets a year and then stops. That’s what happens for most people when it’s given with obinutuzumab.

And then the question is whether you do venetoclax again or a BTK inhibitor. Most people think about venetoclax again, particularly if the remission duration was long. You would do venetoclax, venetoclax re-treatment, switch to a covalent BTK inhibitor, and then treat to progress or do the same strategy regarding intolerance if possible. You can stretch the BTK and BCL2 inhibitors over 2 to 4 lines of therapy and then consider PI3K vs experimental therapies like noncovalents. That’s how I think about sequencing. That being said, no matter which strategy you pick, on average, you get 10 to 12 years of median progression-free survival [PFS]. That’s pretty good going from monotherapy to monotherapy.

 I agree. Nicole, do you do anything different from what Anthony said, in a patient with deletion 17p, realizing that’s 5% to 8% of frontline patients?

 We have longer data in the front line, particularly for ibrutinib, because the BTKs were the first to market. As mentioned earlier, about the progression-free survival of the patients with 17p appear, compared to venetoclax-obinutuzumab, appear longer. We have some nice data, over 5 to 6 years, on some of those patients with 17p or 

 mutation, and it seems that the PFS curves are longer. For high-risk patients, I tend to continue monotherapy.

When we talk about the combination of a BTK plus venetoclax, will that be an advantage for high-risk patients? I’m looking forward to some of the data from the SEQUOIA study to see if that will be better in our high-risk-patient population so we can truncate their therapy vs continuous, which is what I’m currently doing on my high-risk individuals: giving continuous BTK for the 17p population until we see data.

I agree with Anthony that we just have more data because the BTKs were used first. We know we can sequence patients when they relapse to venetoclax, and patients do well. We have emerging and mounting data for the patients who might have gotten venetoclax-obinutuzumab in the front line and then can be salvaged with a BTK in the opposite fashion, and whether those responses will be as robust over time. From the IV [intravenous] combinations, there are certain patients who, if they’re multiple relapsed and have a BTK plus venetoclax, their responses aren’t as good. This speaks to the fact that these multiple-relapsed patients are going to be trickier to salvage. We’ll need other therapies, which I’m sure we’re going to touch on shortly, to salvage some of those guys whose PFS and overall survival will be shorter in that setting.

I’ve been thinking about this a lot with the 17p’s. There’s no obvious reason why a patient has to have a BTK inhibitor. The median PFS for venetoclax-obinutuzumab is about 40 months for 17p.

If you get half as good a remission out of re-treatment, which is a general rule of thumb with chemotherapy, you’re looking at a 70-month median progression-free survival. That will rival any BTK inhibitor for that patient population. To me it’s a wash.

It could be. We need to see, right? That’s what we hope, but we just need to see those data. Unfortunately, there’s a lag. That doesn’t mean it won’t be that way.

I would argue that we make decisions to use, let’s say, ibrutinib as a standard of care for del(17p) based on like a handful of patients treated at NCI [National Cancer Institute] with the longest-term follow-up. The data are just as scanty for BTK inhibitors as they are for venetoclax. They’re both completely fine. I’m spicing it up now on the 

® debate, but it’s a wash. I don’t think there’s an obvious strategy for which is better.

 I agree. We need data. One thing we would all agree on is no genotoxic therapy—ie, chemotherapy—for patients with 17p or mutated 

Factors that impact decisions for frontline and subsequent lines of therapy for patients with chronic lymphocytic leukemia.

Novel Therapies for CLL: Sequencing Strategies

 We touched a lot on ibrutinib plus venetoclax. There’s also data with zanubrutinib plus venetoclax. We touched on that and acalabrutinib (ACALA) plus venetoclax (VEN). Debbie, maybe you can highlight there was an abstract that was reported with a randomized trial design of ACALA-VEN. And then there’s also been single-arm phase 2 data reported for ACALA-VEN-OBIN (obinutuzumab) and zanubrutinib (ZANU)-VEN-OBIN. Can give your thoughts on those trials, and what your thoughts are on if there’s clinical benefit that we might see with a triplet compared with a doublet?

Yes, this is based on a couple of things. If acalabrutinib and zanubrutinib are less toxic than ibrutinib, why not combine them with venetoclax instead of ibrutinib? It’s also based on the fact if 1 drug is good, 2 drugs are better, or 3 drugs even better. And we’re trying to figure out where the balancing point is with all of that because certainly it does appear that toxicity is added the more drugs you add. And we must catch that balancing point of keeping the efficacy without causing significant toxicity. We haven’t even touched upon financial toxicity in this yet, because, of course, all these agents are expensive drugs. And that also factors in. If you have 3 of them, is it 3 times the cost of what it would cost to just take 1 of these therapies? But all in all, all these trials are showing great response, good rates of MRD [minimal residual disease] undetectability of approximately 70%. Usually, those time points are at 12 to 15 months after starting therapy.

One of the studies Dr Mato has been involved in developing is this upcoming MAGIC study. And it also looks at a different spin on this, looking at acalabrutinib plus venetoclax vs venetoclax plus obinutuzumab, which is the standard-of-care arm. This study, of course, will look at progression-free survival (PFS), and it’s going to be a big study with plans to enroll about 600 patients. One of the things I like about the design is it allows for a way to make these regimens MRD guided. And most of you saw the data that was presented last year at ASH [American Society of Hematology meeting 2021] and now published on the CLL14 study that showed that after that year of venetoclax and obinutuzumab, all MRD-detectable remissions are not equal. They looked at clonal dynamics, and some of [the cases in which] those patients with CLL chronic lymphocytic leukemia) were positive had been continuously increasing before that set time point. It’s possible those patients might never achieve MRD undetectability because their MRD was already escalating on the combination. Then there were also patients for whom MRD was still positive, but you could see a decline before that set time point that they checked it. And that was showing that maybe further therapy would help these patients.

In this upcoming study, on both of the arms you get 1 year of the combination therapy and then MRD is assessed. If it’s undetectable, then the patient can stop all therapy. If it’s still detectable, the patient can continue therapy until a time at which the MRD becomes undetectable. This is a good study combining all the strategies that we’ve seen before. As of right now, clinically, MRD is not quite as useful but once we see the results of studies like this that use that data from MRD to drive what your next step is, it will give us a real reason to start checking MRD status.

 We talked about CD20. Callie, we can come to you in terms of what your recommendations are for CD20 antibody use in the setting of BTK [Bruton tyrosine kinase] inhibitors? And then maybe you could touch on the setting of BCL-2 inhibitor and whether you prefer 1 of the CD20 antibodies over another in either setting.

In the context of BTK inhibitors, I’ll first tackle ibrutinib. We have 2 randomized trials showing no meaningful added benefit from the addition of rituximab (RITUX) to ibrutinib. And when I use ibrutinib, I use it as a monotherapy, given that the addition of RITUX adds cost, adds infusion chair time without improving PFS or OS [overall survival]. ACALA is a different story. We have the ELEVATE CLL TN trial, which was a nicely done trial, a 3-arm trial of patients with newly-treated CLL who got either ACALA monotherapy, ACALA with obinutuzumab, or the comparator arm of chlorambucil and obinutuzumab. With some longer-term follow-up, it does seem that the curves for PFS are separating in favor of the obinutuzumab arm.

At this point, I am still not widely adding it, mainly because when I’m discussing up-front therapy with a patient, it’s either do you want kind of an intensive, time-limited therapy option with the addition of obinutuzumab? But then, I would add it with venetoclax to do the CLL14 regimen. And then the patients that are opting for a less intense, indefinite therapy option are generally the ones who don’t want to add an IV [intravenous] therapy. I don’t think it’s the wrong thing to do, and I do think there is a modest PFS benefit, but it comes with these other nuances, which is having to come in for an infusion; and then there are the infusion reactions with obinutuzumab which, admittedly, are quite a bit less when they’re on a concurrent BTK inhibitor as compared with getting it by itself kind of as part of the lead-in for combining it with venetoclax.

The last thing I’ll mention with combinations of BTK inhibitors is that obinutuzumab has also been combined with ibrutinib in the iLLUMINATE study. Unfortunately, we don’t have randomized data between ibrutinib with obinutuzumab and ibrutinib by itself, but I generally do not add obinutuzumab when I’m doing ibrutinib. Who knows, we don’t have that comparator. The ACALA data is provocative, but I’m not at this point sure that the added inconvenience of doing the IV therapy is worth that modest benefit in PFS.

The next thing you asked was the addition of a CD20 with venetoclax. For me, it’s beneficial. We have, of course, several studies looking at that. In the frontline, we’ve spoken about the CLL14 data that shows excellent rates of MRD. I was, of course, impressed with the CLL13 trial, where we see how much better OBIN is compared with rituximab in the frontline setting with the 1 year of venetoclax. And then, of course, we have these favorable results from the long-term follow-up of the MURANO trial, which are different than CLL13. And this starts with venetoclax and then the RITUX is added in, and it’s 2 years of venetoclax, but a really impressive median PFS for a relapsed trial of just under 54 months.

What we don’t have is head-to-head data of VEN vs VEN plus an anti-CD20. The VEN monotherapy data doesn’t look quite as good, and VEN monotherapy in general is a treat-to-progression. Could we get MRD negative with VEN alone? I mean maybe, but the studies of VEN monotherapy are in such highly refractory patients. The rates were low. Would that be different now in a modern population where patients aren’t so quite refractory? Maybe, maybe not. But I, in general, do add it to VEN, a CD20, and I typically do obinutuzumab in the front line. And I have been doing RITUX in the relapsed setting, again just reflecting upon the favorable results from MURANO. Of course, some people—I wonder if they’ll extrapolate from CLL13 and just everyone switch to OBIN in the relapsed setting. I’m not quite ready to do that, but I certainly would wonder what other people think.

I’m going to agree, absolutely. Regardless, if you’re using a BTK inhibitor or VEN, VEN is different because it’s time limited and you’re combining the monoclonal antibodies and the benefit that we’ve seen with the data already presented. It’s time limited. We’ll, of course, combine it with a CD20 monoclonal. If I’m going to give it as monotherapy, they’re staying on it anyway. But for the BTK inhibitors, agreed, unless there’s a certain circumstance, maybe an autoimmune issue, we need to quickly get in those counts because they have an autoimmune problem, and it won’t improve that quickly with a BTK inhibitor. Then maybe I’ll front-load them with the antibody and then do the BTK inhibitor. But those are rare circumstances. If they’re going to be on a BTK inhibitor as monotherapy, I often don’t include the CD20. But certainly, the acalabrutinib-obinutuzumab data is intriguing, and I’m looking forward to a longer follow-up to see how that PFS curve goes over time but typically not giving it routinely.

 My preference is to give obinutuzumab whether it’s in the front line or the relapsed setting. Obinutuzumab is approved in the frontline setting. It’s not approved technically in the relapsed setting, but that doesn’t prevent me from using it, and it is in the NCCN (National Comprehensive Cancer Network) guidelines, [so] we usually can get it covered. It does have to have more toxicity associated with it; cytopenias. I’ve had transaminitis, but it for sure it is a more potent antibody in terms of disease, treating disease, and eliminating leukemia cells in CLL, in my own experience.

Recommendations for combining an anti-CD20 antibody with a Bruton tyrosine kinase inhibitor or venetoclax in doublet or triplet regimens for the treatment for chronic lymphocytic leukemia (CLL).

Treating CLL With Anti-CD20 Antibody Regimens

 Nicole, I’m going to give you the task of introducing and reviewing large randomized trials that the German CLL [Chronic Lymphocytic Leukemia] Study Group has been doing, and the first report was this ASH (American Society of Hematology) meeting on the CLL13 trial that was done by the German CLL Study Group. Can you review that and the highlights of what was found with that study?

This was a nice study, although I wanted 1 more arm.

You did too, right? Glad I’m not the only 1.

 That [second arm] is in CLL17. It’s coming.

Excellent. This is looking at fixed duration with venetoclax-based combinations vs chemoimmunotherapy in previously untreated patients with CLL. The combinations were randomized to 4 different arms, so you had either FCR (fludarabine, cyclophosphamide, rituximab) or BR (bendamustine, rituximab) depending upon your age and comorbidities, vs venetoclax-rituximab as an arm vs venetoclax-obinutuzumab as an arm, and then the fourth arm of venetoclax-ibrutinib and obinutuzumab. A nice randomization. The arm that I’m assuming all of you also wanted was monotherapy with a BTK [Bruton tyrosine kinase] inhibitor, correct?

I wouldn’t mind I plus V (ibrutinib- venetoclax).

Monotherapy, maybe. I’m greedy, but I would take both.

But a nice, large, randomized study, of course. One of the things was to look at not just response but levels of undetectable MRD (minimal residual disease) between the arms, as well as adverse effects and toxicities over time. And in terms of the undetectable MRD, looking at both peripheral blood and bone marrow, believe it or not, not surprisingly, the arms that had venetoclax with obinutuzumab or venetoclax with ibrutinib and obinutuzumab had a higher level of undetectable MRD in the peripheral blood compared to traditional chemoimmunotherapy, upwards anywhere from 87% to 92% vs 50% in the chemoimmunotherapy arms.

The venetoclax-rituximab vs chemoimmunotherapy were more similar: in the 50% range for peripheral blood undetectable MRD. In the obinutuzumab arms, we saw a difference between that with the combination of venetoclax vs rituximab and venetoclax. Similarly, the adverse events and toxicities between all the treatment arms were much more similar to neutropenia, thrombocytopenia—all the things we see with chemoimmunotherapy. But obviously, with the combinations with the antibodies and venetoclax, cytopenias were also observed. The toxicities and adverse events were more similar in all the treatment arms. There were slightly higher hematologic malignancies in the chemoimmunotherapy arms but nonhematologic malignancies in the other arms; a little bit of [an outlier] in terms of that.

Obviously exciting data….We’re going to need longer follow-up to see how things settle out between the arms, but certainly there’s no doubt that we saw greater depth of undetectable MRD with the obinutuzumab-venetoclax–treated arms compared to chemoimmunotherapy. And we just need to stay tuned for that.

May I add 1 comment just in terms of arms? Instead of thinking I wanted 1 more arm, I was thinking I wanted 1 less arm. The chemoimmunotherapy arm was—I don’t know—I would have rather seen either of the arms you guys proposed for a 1000-patient study. One of the clever things about CAPTIVATE, [although] I sometimes criticize GLOW or CAPTIVATE, but the CAPTIVATE fixed-duration arm where they bothered to use the CLL, it was the data from CLL10 for FCR as a historical control; I think it was so clever to spare patients the randomization vs FCR. The primary comparison were CR [complete response] rates of FCR with I plus V. If they did that for CAPTIVATE, it would have been wise to do it again to spare patients chemoimmunotherapy in this setting.

I bet you’re not the only 1. You saw that there were patients that decided to get off the trial once they were randomized to chemotherapy.

Yes, I’m with them. I probably wouldn’t have been on board for that.

Key takeaways of the CLL13 (GAIA) clinical trial based on highlights presented at ASH 2021.

Chemotherapy-Free Regimens as Frontline Therapy in CLL

 If we’re talking about fixed-duration therapy, the other alternative standard of care would be venetoclax plus obinutuzumab. I wonder if anybody is willing to comment on their choice between these 2 and what might drive how to choose between these 2 regimens, assuming that they’ll both be available as standard treatment for first line. Anybody willing to share?

I’m happy to stake an opinion to start the debate. If both are approved, I’ll still lean toward using venetoclax-obinutuzumab. The rationale is that the safety profile is better in a similar patient population between GLOW and CLL14. That would be 1. The second is that MRD [minimal residual disease] rates are comparable or more favorable for the venetoclax-obinutuzumab combination. Third, we have so much data for use of a BTK [Bruton tyrosine kinase] inhibitor following venetoclax that show that not only is venetoclax-obinutuzumab quite effective, but the median isn’t reached. Also, venetoclax re-treatment is a viable strategy. On top of that, BTK inhibitors like acalabrutinib would be a great choice based on the data we’ve seen updated in the relapsed/refractory setting. From a sequencing perspective in a noncurative strategy, where palliation obviously is the approach, you can get a lot more miles out of venetoclax-obinutuzumab and probably a safer regimen. I’m not convinced that I+V [ibrutinib, venetoclax] is safe in an older-patient population. That’s 1 side of the coin. Maybe someone else feels different.

I’ll throw in my 2 cents. I agree with what Anthony said. I may have some temptation to use I+V [ibrutinib, venetoclax] if it is approved in some scenarios, specifically a younger, fitter patient who’s desiring an all-oral regimen. That would be 1 advantage. During the COVID-19 pandemic, all these agents affect immunity, but the CD20s are the hardest on impairing vaccine response and annihilating one’s ability to make meaningful antibodies. That’s 1 attractive view, but I use a lot of venetoclax-obinutuzumab. It is safe and has a lot of experience with older patients. I do have concerns with BTK inhibition in cardiac toxicity. But for patients who are young and fit, the cardiac toxicities are much lower in younger-patient populations. To me ,that wouldn’t be as much of a concern, and it has the advantage of being an all-oral regimen.

The only thing that would sway me fully to use it in a combination up front is if we see that certain patients are cured or at least functionally cured. I haven’t seen data to support that this combination is curing people. Of course, if you could give something up front and cure the patient, and they don’t have to worry about CLL [chronic lymphocytic leukemia] ever again, then that’s 1 thing. But it seems like the sequential, powerhouse drugs in this space are the BCL2 inhibitors like venetoclax and the BTK inhibitors. In a setting of not being able to cure the patient, we want to give them the longest time possible, and using them sequentially makes a lot of sense in this population.

 comes up, I reflect on the FCR [fludarabine, cyclophosphamide, rituximab] data and how long it was before we were able to appreciate a plateau on the PFS [progression-free survival] curve. That was more than 10 years. We started the FCR [fludarabine, cyclophosphamide, rituximab] trials in 1998, 1999, and it wasn’t until nearly 2010 that we and also the German CLL study group realized that there was plateau. It may be awhile before we get the data that show a cure fraction. I’m optimistic that there probably is 1. I’ll be looking closely at the time to MRD relapse as an early indicator because we do tend to see an association of features correlating across the time to event. If we’re talking about time to MRD relapse, time to progression, time to next treatment, etc., they all correlate. Time to MRD relapse is meaningful.

The rationale for investigating the fixed-duration, all-oral combination regimen of venetoclax with obinutuzumab as treatment for chronic lymphocytic leukemia.

Fixed-Duration Therapy in Frontline CLL: Venetoclax Plus Obinutuzumab

 We talked about BTK [Bruton tyrosine kinase] inhibitors. There have been recent updates. Obviously, it’s a highly active, highly effective group of drugs. We’ll talk a little about them later when we talk about the reversible inhibitors to BTK, but let’s move on to the evolving landscape of treatment options and where the field is going. We’ll start with you, Anthony. We had an update at ASH [American Society of Hematology Annual Meeting] on the CAPTIVATE study that Dr Paolo Ghia presented. Could you summarize the study, the design, and what the updated data revealed?

CAPTIVATE is a complicated study in that it’s 2 studies in 1. Essentially, it’s looking at the combination of ibrutinib [Imbruvica] plus venetoclax [Venclexta], and it’s treating 2 different strategies for administering that combination. One is the strategy of a fixed-duration schedule. Everyone gets 3 months of ibrutinib, everyone gets 12 months of combination, then they stop. The second strategy is MRD [minimal residual disease] driven, where everybody gets 3 months of ibrutinib, 12 months of combination, and then an MRD test. If you’re undetectable on that study, you were randomized to ibrutinib vs placebo. If you were detectable, a sensitivity of the 10-4, you were randomized to ibrutinib vs I+V [ibrutinib plus venetoclax]. The primary end point of the MRD-driven study was the 1-year rate of disease-free survival with a comparison between the placebo-vs-ibrutinib curve. And the 1-year disease-free survival was nearly identical for both groups: 100% vs 95%-something. 

The update at ASH and the headline—maybe somebody could comment if there’s any more information to it—was that they had another year’s worth of follow-up and, in particular, that cohort demonstrated no events in either arm. The 2-year disease-free survival was the same as the 1-year disease-free survival—2 for the price of 1. If you memorize those numbers, you’ll be right at either time point. Those values were not significantly different, of course. The take-home was that with I+V [ibrutinib plus venetoclax], particularly for an MRD-undetectable patient, 15 months of total therapy is enough. You can stop. You’re fine. There’s no reason to continue ibrutinib as a maintenance strategy, regardless of your molecular genetic profile.

Data for the MRD-detectable patients is a different story. There, the headline has been and remains that probably 15 months’ worth of therapy is not enough. If you want to deepen your remissions, you need to have venetoclax as part of the backbone for further deepening of MRD response.

 I would add that, for the other arm, the unconfirmed undetectable MRD arm, those patients could continue ibrutinib monotherapy vs continued combined therapy. What you see with the follow-up in that group is a larger improvement in undetectable MRD status favoring those patients who continue combined therapy. We’ve seen that in our own trial at [The University of Texas] MD Anderson [Cancer Center], where we were giving routinely 2 years and we modified the protocol to allow 3 years. [We saw] continued improved responses with continued therapy in those patients who hadn’t converted after 12 cycles. That highlights that the jury is out about optimal duration of treatment. We need trials designed with MRD end points to get better clarity around what the optimum duration of treatment is with an objective to achieve undetectable MRD status.

As mentioned, we did a trial with ibrutinib-venetoclax at MD Anderson. The CAPTIVATE study that Anthony just reviewed was a multicenter international trial. There was also the randomized phase 3 GLOW trial, which included the investigational arm of ibrutinib plus venetoclax. Callie, can you talk about the GLOW study? There was an update of the GLOW study at ASH.

The main thing to keep in mind about GLOW, is that it’s a randomized study. That’s an important distinguishing feature. The other is that the patient population was different. CAPTIVATE had a maximum age of 70. GLOW had a minimum age of 65. If patients were younger than 65, they had to have a high SEER [Surveillance, Epidemiology, and End Results] score. So it was largely an unfit patient population.

This is a randomized study of ibrutinib plus venetoclax at the same schedule of the fixed-duration cohort of CAPTIVATE, a 3-cycle ibrutinib lead-in, followed by 12 cycles of the I+V [ibrutinib plus venetoclax] combination. This was an unfit older-patient population. The median age was 71, and the SEER score was an 8 or a 9 depending on the arm; it was a sick group. We see that this regimen is effective and, in comparison with chlorambucil-obinutuzumab, quite superior with respect to PFS [progression-free survival] and rate of undetectable MRD. They measured MRD in 2 ways: NGS [next-generation sequencing] testing and by flow. The rates by flow were 10-4 or a little over that—50% of patients in the I+V [ibrutinib plus venetoclax] arm attained MRD negativity. It was lower when using NGS and going down to 10-5.

They don’t have a long follow-up in this cohort, but it does look like patients are attaining deep remissions without many relapses. The abstract quotes greater than 90% are progression free with the limited amount of follow-up that they have. There seems to be a bit higher discontinuation in this trial. It was just over 10% because of toxicity, and that may be related to the slightly less fit and older-patient population with comorbidities having some more tolerance issues, which is not unexpected.

 Great. We have several trials with combined ibrutinib-venetoclax. We didn’t report any safety concerns on our trial. I did appreciate that there were no safety concerns identified on the other trials with ibrutinib-venetoclax—only those that we expect to see with either agent, but no safety or adverse events that would indicate significant concern or toxicity with the combination. Fast-forward a year or so, and the FDA has reviewed the data and feels that it would warrant approval for the combination.

Key takeaways from the CAPTIVATE and GLOW trials of ibrutinib plus venetoclax as fixed-duration frontline therapy for chronic lymphocytic leukemia.

Fixed-Duration Therapy in Frontline CLL: Ibrutinib Plus Venetoclax

: Let’s talk about second-generation and subsequent-generation BTK [Bruton tyrosine kinase] inhibitors. Ibrutinib [Imbruvica], first generation. We have a second generation which is acalabrutinib [Calquence®], also an irreversible inhibitor or BTK. Callie, can you introduce us to the drug and some of the features of acalabrutinib, which differentiates it from ibrutinib, and are particular factors that we think about before we start a patient on acalabrutinib?

Sure. Acalabrutinib is a second-generation BTK inhibitor, also irreversible. Some of the main distinguishing features about it are that number 1, it is a bit more selective for BTK and appears to have less off-target activity. And that potentially gives it a better adverse effect profile. Some of the other distinguishing features are that it is given as a twice daily [BID] drug, and one of the reasons that I may not use it is if a patient needs a PPI [proton pump inhibitor], given that concurrent PPI use can affect absorption. We saw a few updates on acala [acalabrutinib] data in this past year, and one of them that was important is, of course, we finally saw the head-to-head data with ibrutinib in the relapsed setting. And so that was presented at ASCO [American Society of Clinical Oncology annual meeting] in 2021 and was published in JCO [

It’s great to see head-to-head data on these 2 drugs, and what we can see is that acalabrutinib has a lower rate of all-grade atrial fibrillation when compared to ibrutinib. The acala [acalabrutinib] rate was 9% and ibrutinib was around 15%. The other advantage of acala [acalabrutinib], as far as adverse effect profile, is that it has lower rates of hypertension which of course is a particularly bothersome adverse effect of these drugs as a class, but the rate seems lower. Then there’s also some improvement in other low-grade toxicities, such as these myalgias and arthralgias that have already been mentioned. Acala [acalbrutinib] does have 1 kind of unique adverse effect that’s more commonly seen than ibrutinib [and] that’s specifically headaches. Fortunately, headaches don’t appear to be a longstanding issue. Usually, they occur early on over the patient’s treatment in the first month or 2 and often resolve with caffeine.

The other data that we saw at ASH [American Society of Hematology annual meeting] was some longer-term follow-up from the ASCEND trial. This trial you may remember was our first novel agent to novel agent comparator. One arm, this again was a relapsed trial, 1 arm was acalabrutinib monotherapy and then the other arm was the investigator’s choice of either idelalisib [Zydelig®] with rituximab [Rituxan®] or bendamustine [Treanda®] and rituximab. The oral presentation discussed now we have 3 years of follow-up on this trial, and we see continued improvement in the progression-free survival [PFS] rate of acala [acalabrutinib] compared to that investigator choice regimen, which was mostly the idela [idelalisib]. Though there were some patients that got BR [bendamustine, rituximab], but those were the minority. Interestingly, the response rates are similar, and all these agents are active, but the big difference is that the toxicity and the rates of discontinuation appear quite a bit higher for the idela [idelalisib]-treated patients. The PFS with more follow-up now out at 3 years continues to favor acalabrutinib in this study.

Features that distinguish acalabrutinib, a second-generation Bruton tyrosine kinase inhibitor, from ibrutinib as frontline therapy for patients with chronic lymphocytic leukemia.

Acalabrutinib as Frontline Therapy for CLL

 entitled, “Recent Advances in the Treatment of Chronic Lymphocytic Leukemia.”

I’m Dr William Wierda, professor of medicine in the Department of Leukemia and section head for chronic lymphocytic leukemia [CLL] at The University of Texas MD Anderson Cancer Center in Houston, Texas.

I’m joined today by a panel of experts in CLL and I would like to welcome them and invite each of them to introduce themselves. We’ll start with Jackie Barrientos.

Hi, my name is Jacqueline Barrientos, and I am professor of medicine at the Zucker School of Medicine at Hofstra/Northwell [New Hyde Park, New York]. I do work at the CLL Research and Treatment Program in Long Island, New York.

Hi there, I’m Callie Coombs. I’m at the University of North Carolina [Chapel Hill, North Carolina], where I work as an assistant professor of medicine within the Department of Hematology mostly caring for patients with CLL.

Hi, my name is Nicole Lamanna. I’m at Columbia Universality Medical Center [New York, New York] on the Leukemia Service and director of the CLL Program here.

Hi everybody, Anthony Mato from Memorial Sloan Kettering Cancer Center [New York, New York], director of the CLL Program and very happy to be here today.

Hi, I’m Debbie Stephens. I’m at the Huntsman Cancer Institute at the University of Utah [Salt Lake City, Utah], and I direct the CLL Program here.

: Great. Welcome everybody and thank you for joining me today. We’re going to discuss a number of recent updates in the treatment of CLL that were presented at conferences over 2021, particularly focusing on the ASH [American Society of Hematology meeting] 2021 updates. We’ll discuss the data in the context of standards of care and guidelines for treatment and how these updates impact on our management of our patients with CLL.

We’ll start with targeted therapy, which began with [the] Bruton tyrosine kinase [BTK] inhibitor, ibrutinib [Imbruvica®], which has been available for several years now. We’ve learned over the years that CLL cells are dependent on the kinase activity of Bruton tyrosine kinase for survival, and ibrutinib was the first small molecule inhibitor that was developed, first in the laboratory and then clinically in treatment of patients with CLL. This is an irreversible inhibitor, meaning that it binds covalently to BTK at the cysteine 481 moiety and in doing so it blocks the ATP [adenosine-triphosphate]-binding pocket and inactivates BTK irreversibly. And the only way to replace functional BTK would be resynthesis.

The rationale for using Bruton tyrosine kinase inhibitors, such as the first-generation option, ibrutinib, as first-line treatment for chronic lymphocytic leukemia.

Catherine C. Coombs, MD

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