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Hematology oncologist, Allison Winter, MD, joins the Cancer Advances podcast to discuss the latest innovations in treating chronic lymphocytic leukemia (CLL). Listen as she explains how the treatment for CLL has evolved over the past decade, with a shift towards using novel therapies such as BTK inhibitors and venetoclax, as well as the concept of time-limited therapy. Dr. Winter also shares insights into ongoing clinical trials like the MAJIC trial, which compares different treatment combinations.

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Exploring Novel Strategies for Chronic Lymphocytic Leukemia

Podcast Transcript

Dale Shepard, MD, PhD: Cancer Advances, a Cleveland Clinic podcast for medical professionals exploring the latest innovative research and clinical advances in the field of oncology. Thank you for joining us for another episode of Cancer Advances. I'm your host, Dr. Dale Shepard, a medical oncologist here at Cleveland Clinic Directing the Taussig Early Cancer Therapeutics Program and Co-Directing the Cleveland Clinic Sarcoma Program. Today I'm very happy to be joined by Dr. Allison Winter, an associate staff here at the Cancer Institute working in the lymphoid malignancies and cellular therapy programs. She's here today to talk to us about innovations in chronic lymphocytic leukemia treatment. So welcome back.

Allison Winter, MD: Thanks for having me.

Dale Shepard, MD, PhD: And incidentally, you've had a couple of other episodes that people can look up and listen to still.

Allison Winter, MD: I have indeed.

Dale Shepard, MD, PhD: So remind us, what do you do here at the clinic?

Allison Winter, MD: So I work in our lymphoid malignancies department, which means I specialize in lymphomas as well as some chronic indolent leukemia such as CLL and hairy cell leukemia. I'm also a member of our cellular therapy program where I mostly do autologous stem cell transplant as well as CAR T-cell therapy and bispecific therapies.

Dale Shepard, MD, PhD: Excellent. Well, we are going to focus today on chronic lymphocytic leukemia. And so we're going to talk about some of the newer things going on. So lots of different people might be listening in, may have a little bit different of historic perspective. Give us an idea where we've come from in terms of treatments.

Allison Winter, MD: The treatment for CLL has evolved over the last decade. I remember when I started in training, there was still a lot of use of chemotherapy. And since the approval of ibrutinib, which was one of the first novel therapies for CLL to BTK inhibitor, things have rapidly shifted in terms of treatment. So I almost never use chemotherapy at this point, and I'm using novel agents right up front for the first-line treatment.

Dale Shepard, MD, PhD: And tell me a little bit about what are some of those novel treatments. You mentioned the BTK inhibitors, those are still really important. What other things are we looking at?

Allison Winter, MD: BTK inhibitors are still very important. We started with the approval of ibrutinib, but we now have several other BTK inhibitors on market. So the second-generation BTK inhibitors include acalabrutinib and zanubrutinib. And then more recently we have a non-covalent BTK inhibitor, which was just approved for CLL in the last year. These drugs are still very important, but we also have novel agents such as venetoclax, which is the BCL-2 inhibitor that's currently commercially available. And then we often still combine some of these therapies with things such as monoclonal antibodies, most notably rituximab and obinutuzumab. What I think is really interesting is how we have pretty much gone to using just novel therapies in the frontline setting and we're shifting towards trying to go back to time-limited therapy. So years ago when patients had chemotherapy, it was only so many cycles, and then patients were able to come off of therapy. So now our focus in CLL in the frontline setting is coming back to how do we do time-limited therapy and get patients off of treatment for some time.

Dale Shepard, MD, PhD: I guess just to be really, really clear with everyone kind of listening in, when you say time-limited therapy, what exactly are you talking about?

Allison Winter, MD: Good question. So generally, when I'm treating a CLL patient for the first time, I consider two approaches. So one is to do a BTK inhibitor, usually as monotherapy. There are a couple of instances where I might add something like obinutuzumab in. So it's usually monotherapy. And with the BTK inhibitor monotherapy strategy, we really need to do indefinite therapy. We need that continuous inhibition. The other strategy I'll use is what I referred to as time-limited therapy. So commercially available is venetoclax plus obinutuzumab. And the reason it's called time-limited therapy is because after a combination of 12 months, patients are able to stop both drugs entirely and just go back to the monitoring phase.

Dale Shepard, MD, PhD: And what sort of drives that ability to stop treatment? So oftentimes we think, you have a tumor, you're suppressing something, you're sort of minimizing risk if it comes back, even if your scans look good. What's different about this disease? What's different about these drugs that allow us to do that?

Allison Winter, MD: So when we're doing the BTK inhibitor monotherapy, we're not getting deep enough remissions where we're able to stop therapy. When we're doing a venetoclax-based regimen, we are getting deeper remissions. We're able to get MRD undetectable states, which is why we're able to stop therapy.

Dale Shepard, MD, PhD: Okay. So I'm going to just throw out there. I'm very jealous because you talk about a deep remission and I don't as a sarcoma guy get to get remissions much at all. So deep remission, well, how are you defining deep remission?

Allison Winter, MD: So this is where the strategies are changing. So for commercially available venetoclax plus obinutuzumab, I do get MRD testing at the beginning because I use clonoSEQ where I have to get ID testing. I do get it at the end of the combination 12-month therapy, but I don't necessarily dictate what I do. I stop at that point because that's how the trial that got that combination of proof was run. But we're using this technology to shape future studies where the stopping usage is determined by the MRD status. So like I said, in the venetoclax-obinutuzumab CLL14 study, everyone just stopped at 12 months regardless of MRD status. But newer studies are stopping based on whether or not they're MRD undetectable. And when I say deep remission, I mean people come off therapy for years. So-

Dale Shepard, MD, PhD: That's a long time.

Allison Winter, MD: ... a long time. Yeah.

Dale Shepard, MD, PhD: And when you think about MRD testing, what are we using in CLL for MRD tests? Is it PCR or is it... What technology do we use in CLL?

Allison Winter, MD: Yeah, so there's two different strategies. So you can do it by NGS testing or by flow cytometry. I have in clinical practice, used the NGS technology with the clonoSEQ Assay. And a lot of the studies that I've participated in are using that assay as well.

Dale Shepard, MD, PhD: So tell us a little bit about the MAJIC trial.

Allison Winter, MD: The MAJIC trial is an international study. It's a frontline CLL study. And what's interesting about this is it's looking at two different combinations. One is with the BTK inhibitor acalabrutinib combined with venetoclax, and the other arm is what you may consider standard of care because it's venetoclax plus obinutuzumab. It's not exactly standard of care though, because again, standard of care, you just stop at 12 months regardless of MRD. So on this study, you have to have the combination of the two drugs for at least a year. So the length of time is a little bit different based on the lead-in times of the combination drug. But after a year, MRD is tested, and if a patient's MRD undetectable, they get to stop both drugs. But if MRD is still detectable, then they can go on to receive treatment for an additional amount of time up to an additional year.

So it's a pretty exciting combination and there are pros and cons to each arm, and I think it's going to be really exciting to see how it pans out. We have accrued a number of patients here at Cleveland Clinic, and we're getting to the point where many people are getting to that one year of therapy and starting to get their MRD testing. So it's currently closed. The entire study has reached the accrual.

Dale Shepard, MD, PhD: That's pretty good. You say pros and cons of the arms, what are the kinds of things that you think about?

Allison Winter, MD: Yeah, that's a good question. So for instance, the acalabrutinib plus venetoclax arm, one of the pros is the acalabrutinib is oral and the venetoclax is oral. So it's an all-oral regimen. One of the pros of the venetoclax plus obinutuzumab arm is, the obinutuzumab does a pretty effective job of debulking patients. So when I start the venetoclax, I almost always can do that as an outpatient. One of the things we worry about with venetoclax is tumor lysis syndrome, and the higher the disease bulk, the higher our worry is for tumor lysis. So in the past, and even sometimes still, we do have to bring patients into the hospital to do that. But again, with the VO arm, I'm usually able to debulk them enough with just a couple of doses of VO then I can do the venetoclax as an outpatient.

Dale Shepard, MD, PhD: You talked about how you get a year of therapy, you start looking for MRD. How do you know when someone needs to restart? Are you using MRD as a criteria to resume therapy?

Allison Winter, MD: We are not using MRD as a criteria to resume therapy in clinical practice or even on that study. So that can be a little challenging if you do have an MRD test that isn't undetectable even at the end of therapy. So you do VO and your MRD is still detectable at the end, there's some controversy about what we should do with it because that's not how the study was done. So I don't resume therapy or I don't not stop therapy based on that, it's really a clinical relapse that you would restart therapy.

Dale Shepard, MD, PhD: And not being a CLL guy, in a lot of diseases, earlier detection, earlier treatment, there's a lot of debate about is it really reasonable to expose people to toxic therapies and costly therapies and medicalize their life when you don't really know that it has to be treated. What are we using as a criteria to resume if we're not doing MRD?

Allison Winter, MD: So if we rewind and just think about CLL, there are many people who are on watch. I mean, that's the standard of care when you're diagnosed with CLL is to wait and initiate treatment when there is what we call a treatment-related indication. So if you come off of therapy, you might see the lymphocyte count going up, that signs that the CLL is progressing, but you might not necessarily need to start treatment if none of the treatment-related indications are there.

Dale Shepard, MD, PhD: And I guess on the backside of that, it begs the question of whether people have bulky disease and they're symptomatic because they have bulky disease. Do we necessarily think we need to treat them until you reach a certain MRD level or is simply debulking with these newer drugs may be enough and you can stop therapy earlier?

Allison Winter, MD: So if you have symptomatic disease-

Dale Shepard, MD, PhD: So I guess I'm thinking of a world where you have bulky symptomatic disease, you've started these newer drugs, you may have knocked the tumor down to where perhaps your scans look great, you still have detectable disease through a blood test. Do you really need to keep treating all the way down to a certain level of minimal residual disease? Are we treating too long?

Allison Winter, MD: Yeah. I don't think that's the case right now with CLL. There have been some different studies out there looking at the different MRD, like if you're saying 10 to the minus 5 versus 10 to the minus 6, and how they relate to outcomes like progression-free survival. And we do know that basically, the deeper you are, the longer your progression-free survival is going to be, which I think is important because patients want to get off therapy and stay off therapy for a decent amount of time after they've gone through a year of combination therapy.

Dale Shepard, MD, PhD: Other therapies coming around, where are the gaps, where are the exciting other new therapies?

Allison Winter, MD: So in CLL, there's an important term that most of us are using now called double-refractory. This is a group of patients who've seen both the BTK inhibitor as well as a BCL-2 inhibitor, usually venetoclax. So people who are double-refractory definitely need agents if they progress after these two. This is an unmet need in CLL. There are some future things coming. So for instance, pirtobrutinib was FDA approved just in December for CLL patients. And this is a BTK inhibitor, but what's different about this is it's a non-covalent BTK inhibitor. So even if you become resistant to a traditional covalent BTK inhibitor, including ibrutinib, acalabrutinib, zanubrutinib, you can still have activity again with this non-covalent BTK inhibitor pirtobrutinib. So that was very exciting to see that approval.

Most of us are looking forward to... There's a PDUFA date for CAR T-cell therapy with lysis cell coming up this month for CLL. And then there's newer agents, newer molecules that are already in clinical trials. For instance, we're involved with the company called Nurix, which is looking at targeting BTK but in a different mechanism. So this is a molecule that's a BTK degrader. So there's still exciting stuff out there that are going to fill the gaps for those patients who are what we call double-refractory.

Dale Shepard, MD, PhD: So just to, because it's not intuitively obvious to me, a non-covalent BTK inhibitor is better in what way? Because it seems like covalent sticking to something may be better. What's the attraction of a non-covalent inhibitor?

Allison Winter, MD: So a lot of people who progress on ibrutinib and acalabrutinib, or zanubrutinib will have certain mutations that we can pick up like a mutation in the BTK binding site. So this still has activity even with those mutations present. So this is reversible where the other ones are irreversible.

Dale Shepard, MD, PhD: All right, excellent. And of these new agents, we have trials going on here at the Cleveland Clinic?

Allison Winter, MD: We do. Like I said, there's the BTK degrader that we have available. We also have other CAR T therapy trials going on, which I think are still going to be useful even if lysis cell does get approved. And then there's some other strategies out there looking at the bispecifics in CLL, ROR1. There's some other exciting stuff to look forward to.

Dale Shepard, MD, PhD: So CLL has a fair amount of patients in terms of numbers of patients, who should seek a second opinion here at the Cleveland Clinic? Think about these novel therapies, there's so many things out there now. Who's best to be seen for a second opinion when in terms of the course of therapy?

Allison Winter, MD: A lot of patients with CLL will initially be managed with active surveillance, and I think that's... You don't necessarily need to have a second opinion, although I do find a lot of patients find it useful to come just to get a really thorough education about what to expect in the years to come. I would say if a patient is getting to the point where they need to start therapy, that's a good time to get a second opinion because there are changes in what we have to offer for the frontline setting and differences in opinions and pros and cons. And it's sometimes helpful to make sure you're getting the pros and cons and all the options because, unlike some cancers, there may not be a choice.

When I treat a diffuse large B-cell lymphoma, there may be just one option that I think is best. Whereas CLL, I lay out a couple options and I give the pros and cons. And then I think those patients who, especially if you're double-refractory, going around and seeing second opinions for various options. So sometimes a clinical trial might be opened at one location but not another, and getting the information to figure out which one makes the most sense, it would be helpful.

Dale Shepard, MD, PhD: Very good. Lots of exciting things happening. Very interesting approaches. Appreciate your insight.

Allison Winter, MD: Yeah, no problem. Glad to be here.

Dale Shepard, MD, PhD: To make a direct online referral to our Cancer Institute, complete our online cancer patient referral form by visiting clevelandclinic.org/cancerpatientreferrals. You will receive confirmation once the appointment is scheduled.

This concludes this episode of Cancer Advances. For more podcast episodes, visit our website, clevelandclinic.org/canceradvancespodcast. Subscribe on Apple Podcasts, Spotify, or wherever you listen to podcasts.

Thank you for listening. Please join us again soon.

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