Evolving Frontline Therapy for Chronic Lymphocytic Leukemia (CLL)

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, Director of International Programs for the Cancer Institute, and Co-Director of the Sarcoma Program at Cleveland Clinic. Today I'm happy to be joined by Dr. Brian Hill, Director of the Lymphoid Malignancies Program at Cleveland Clinic. He was here on this podcast previously to discuss biomarkers to predict outcomes of CAR-T therapies in patients with diffuse large B cell lymphoma, and to discuss advances in mantle cell lymphoma. Those episodes are still available for you to listen to.

He's here today to discuss first-line therapy for CLL. Welcome back, Brian.

Brian T. Hill, MD, PhD: Thank you for having me. Great to be here.

Dale Shepard, MD, PhD: So remind me a little bit again about what you do here at the Cleveland Clinic.

Brian T. Hill, MD, PhD: Yeah, so I see patients with lymphoid malignancies. We use that term to encompass lymphoma, which would be non-Hodgkin lymphoma subtypes, Hodgkin lymphoma, and chronic lymphocytic leukemia. A lot of people get confused by the term CLL because it sounds like a leukemia, but really from a biologic perspective, just to remind the audience, that really we think of it as a mature B cell malignancy, similar to the B cell, non-Hodgkin lymphomas. And so, we approach it very similarly and treat it with very similar agents and treatments.

Dale Shepard, MD, PhD: Okay. And so, we're going to be talking about CLL and maybe there's a lot of different people that might be listening in, different backgrounds, maybe not thought about CLL for a while as well. And so, give us a little bit of an idea about what the disease is, and really as we're going to talk about first line treatment, how we decide when someone's going to be treated. Because I remember back in my fellow days, there was a lot of incidental findings that we didn't really do anything.

Brian T. Hill, MD, PhD: That's right, yeah. So, still the case that it's often diagnosed incidentally. The disease is indolent, in the sense that it's a mature B cell clone that develops most commonly in people in their sixties and seventies. The median age is about early seventies, more common in males, more common in Caucasians than other races. Interestingly, very uncommon in East Asian populations, and that holds true despite migration. So, if you have Asian Americans, it's actually very uncommon to see CLL. Not impossible, but very uncommon.

So, in terms of what causes CLL, no real smoking gun. Maybe some associations with various exposures, benzene or Asian orange, that kind of thing. But most of the time we think of it as a sporadic incidental finding, just like many cancers that just are accumulation of new, novel acquired genetic abnormalities that happened during the patient's lifespan. The most common presentation of CLL is an incidental finding.

So it's the story of the person in their sixties or seventies who goes for perhaps, let's say, orthopedic surgery, pre-op clearance, or goes to the emergency department for some other unrelated cause, or is having elective surgery and then has a CBC which shows a high white blood cell count with lymphocytes. That's still what we see as being the most common presentation.

Patients are often alarmed when they're referred to a hematologist oncologist for their high white blood cell count, but we usually make the diagnosis just off the peripheral blood with flow cytometry, you don't need a bone marrow biopsy. Most patients are asymptomatic. You can do physical exam for lymph nodes and spleen size, but if they have no symptoms, and their other blood counts are normal, so no anemia, and their platelet count is normal, you don't need a bone marrow biopsy. You don't need a PET scan. In fact, the IWCLL recommendations are not to do imaging. That's the International Working Group for CLL.

So, we see a lot of PET scans done, a lot of full-body scans. And again, if someone just has a lymphocytosis and no symptoms, then usually what we're going to do is reassure the patient that we can appropriately and safely watch and wait. Some patients call it watch and worry. I prefer the term active surveillance, because it's not that we're doing nothing, it's that we're going to monitor for symptoms to develop or cytopenias, so anemia or thrombocytopenia.

And most of those patients will not have those at the time of diagnosis or presentation. Those symptoms like drenching night sweats, unintentional weight loss, bulky or compressive lymph nodes. But with time, those things may develop, and that's one of the first questions that we get from patients is, "If you're not going to treat me now, what would change, what would compel you to recommend treatment?" And those symptoms that I just mentioned, or anemia or thrombocytopenia, would be reasons to treat.

Dale Shepard, MD, PhD: And I guess that watch and worry part, if someone comes in, of course a lot of it would depend on when you incidentally found it.

Brian T. Hill, MD, PhD: That's right.

Dale Shepard, MD, PhD: How long on average do you follow patients before you have to pull the trigger and treat?

Brian T. Hill, MD, PhD: Yeah, so on average it's probably five to 10 years. And there are pretty simple prognostic tools that you can use to give someone a sense of how long it will be before they will need treatment. Some simple things, like their stage. So, if they have any lymph nodes go beyond rise stage zero, which is lymphocyte count elevation only, to rise stage one. And even if they just go from a zero to one, then that gives them a point on the prognostic scoring system that allows us to predict treatment.

The other thing would be their age, over 65 gets a point for that. And then increasingly over the past decade, we've really appreciated that there's two major flavors of CLL. Those that derive from a B cell clone, which is more immature, and those have an immunoglobulin heavy chain, which is unmutated, but then if you remember your biology and your immunology, that B cells, as they go through lymph nodes and go through germinal center, they shuffle their immunoglobulin heavy chains and they rearrange them in response to perhaps androgens presented in the germinal center, and then they arrive after that with mutated immunoglobulin heavy chains.

So, unmutated and mutated really is just a normal process of B cell maturation, and you can get a CLL that derives from the early cells that have unmutated IGVH, or you can get CLL on the other side of the germinal center that have undergone somatic hypermutation as a normal process, before becoming clones. And that test, IGVH test, is routinely available in the clinic and throughout the country and world, and it really tells you whether it's a unmutated IGVH, which is more unfavorable, more proliferative disease, versus the more mature B cells which have mutated IGVH, which is more favorable. Sounds backwards because everyone thinks of mutations as bad, but it does really refer to the two different groups.

So, if they have a mutated IGVH and they don't have a large lymph node, they may go 10 or 20 years, or never need to be treated.

Dale Shepard, MD, PhD: What has changed recently? So, historically how was this treated? Once a patient gets to the point where they needed treatment, what was the historic treatment, and how has the world changed recently?

Brian T. Hill, MD, PhD: So, the world has turned on its head in the last five to 10 years. For the last preceding 20 years, it was all about cytotoxic chemotherapy. So, chlorambucil was one of the oral alkaline agents that used to be used, then fludarabine, then cyclophosphamide, and then two drugs must be good, so one is good, so we put them together must be better. So then we put fludarabine and cyclophosphamide together, and then Rituxan came along, and three drugs must be better than two. So then we ultimately got to the regimen of FCR, which really was pretty toxic therapy, highly effective, but response rates of 98%, but also very immunosuppressive, and unfortunately can cause secondary malignancies.

For a period of time bendamustine was a safer, gentler alternative to FCR, and it's also very effective high response rates. But on average progression-free survival, with either six cycles of FCR, or six cycles of bendamustine, Rituxan, really maybe in the three to five-year range, there's some outliers and some of those low-risk patients can maybe be cured even. If you get 10, 20 years out, you can see some people who've had FCR 15 years ago, they probably had low-risk disease and they still are at some increased risk of secondary malignancies.

So, we don't really use those chemotherapy drugs anymore, because we're really, over the past decade, have moved into the targeted therapy, novel therapeutic era.

Dale Shepard, MD, PhD: Okay. So, what was the key within CLL? What kind of targets were identified, and how were utilizing those targets for treatment?

Brian T. Hill, MD, PhD: So, over the preceding 10 to 15 years it was really recognized that CLL proliferation of the B cell really relies on a ketonic aberrant signaling through the B cell receptor signaling apparatus, and the downstream mediator of the B cell receptor signal is a protein called Bruton's tyrosine kinase or BTK. And this, if you go way back to your medical school days, you may remember that Bruton's agammaglobulinemia is a general condition where kids don't have BTK, and they don't develop B cells. So, BTK was thought to be a good target to shut down the tonic signaling through the B cell receptor. It is downstream of the B cell receptor. And so, BTK inhibitors were developed which covalently bind to the active kinase domain of BTK, and shut down the signaling.

And so, the first of the BTK inhibitors was introduced over 10 years ago now was ibrutinib. And subsequent to ibrutinib, there've been others that are in the same class of covalent BTK inhibitors, such as acalabrutinib and zanubrutinib. Those three are all approved. And in the case of two of the three have been shown in head-to-head trials to be superior to chemotherapy, with either FCR or bendamustine-Rituxan. These are oral agents. They're taken daily, either once a day or twice a day depending, and they're very effective and very well tolerated.

Most of the side effects that we see are manageable. Sometimes we get some bruising and bleeding, some GI side effects, some headaches, rashes, but with dose reduction or modification, most people can tolerate them. And if they don't, you can switch from one to the other. And probably the biggest side effect of ibrutinib was atrial fibrillation, which can occur in five to 10% of people. And so, it's fallen out of favor for the newer BTK inhibitors. Acalabrutinib and zanubrutinib both have much lower rates of AFib, probably approaching what we see as a background rate for the patient population. So, these are very effective treatments, but you do have to stay on them. They're sort of like the current thinking is let's go on the treatment and stay on it as long as it's working. So you have people taking these sometimes for years and years and years, with excellent disease control.

Dale Shepard, MD, PhD: And then how do the BTK inhibitors compare to use of things like Venetoclax?

Brian T. Hill, MD, PhD: Yeah, so great question. Venetoclax is really a remarkable agent, is first in class. It's called a BCL2 inhibitor. BCL2 is anti-apoptotic protein, and it's very high not only in CLL but other hematologic malignancies. So it prevents cell death. And CLL in particular is exquisitely sensitive to BCL2 inhibitors, but BCL2 inhibitors, like Venetoclax, are really smart drugs. They mimic the BH3 domain of proteins which control or inhibit BCL2. So, it's basically by giving a BH3-mimetic, you're taking the breaks off the anti-apoptotic function of BCL2, which is at very high levels in CLL, and so what happens when you take a BCL2 inhibitor is you basically lead to very rapid cell death, through apoptosis. In fact, with Venetoclax, the cell death is so rapid that if you have a patient who needs treatment and has a high white blood cell count and big lymph nodes, you really can't give full-dose Venetoclax right out of the gate, because you'll develop tumor lysis syndrome within 12 to 24 hours.

In fact, the trial that led to the approval of Venetoclax really had to learn to give it slowly over a five-week ramp-up, where you start with 20 milligrams for a week, 50 for a week, 100 for a week, 200 for a week, 400 for a week. So it takes five weeks, it's a little bit of an inconvenience because you have to monitor for tumor lysis. But what I'll say is with adequate monitoring, we really don't see clinically significant tumor lysis with Venetoclax.

It is partnered with Obinutuzumab frequently in the front line. Obinutuzumab is basically a souped-up Rituxan. So Rituximab targets CD20, so does Obinutuzumab. And so, what you have as a frontline option for CLL is a doublet, basically, where you're giving intravenous Obinutuzumab, which is highly effective, and then adding in a five-week ramp up of Venetoclax. The advantage of this approach is that after 12 months of Venetoclax and only six months of Obinutuzumab monthly infusions, you're done. So, it's a time-limited therapy, which contrasts with the BTK inhibitors, which is basically continuous oral therapy.

So, we do have this dichotomy where we have patients coming in, let's say they need treatment, and you have two very good options, which is a continuous oral BTK inhibitor, or a little bit more work to do the doublet, but the light at the tunnel's after 12 months, you can stop all treatment and enjoy remissions, which probably last five to 10 years. So, it's pretty effective treatments. Not curative, but highly effective.

Dale Shepard, MD, PhD: What are some of the factors that go into deciding between the two? Because it seems like some people would definitely opt for more time-limited therapy and just be done.

Brian T. Hill, MD, PhD: Yeah.

Dale Shepard, MD, PhD: Are there particular patient characteristics that make one favorable over the other?

Brian T. Hill, MD, PhD: Yeah. I think that it's a little bit like car preference. I tell patients, "Do you like sports cars or minivans or SUVs?" There's no right answer. Everyone has different needs. They're all going to get you where you want to go. So, I don't think there's a survival difference. I think that survival of CLL with either of these treatments is really approaching the general population at this point, if not there already. And so, really what it depends on is individual patient factors.

So, if someone has a really busy work schedule and they live far away and they can't or won't travel back and forth for the infusions with the obinutuzumab and the ramp up with the Venetoclax tumor lysis syndrome monitoring, then it's just much easier to send a prescription for a BTK inhibitor that gets mailed to their house and they just start taking it at home, and maybe you check in a week later to make sure they're not having side effects.

But once they're up and running, if they don't have side effects over the first month or so, it's unlikely they're going to get side effects. So, one thing is cost. These aren't cheap drugs, and if they have a significant out-of-pocket expense every month, that could add up, year over year. And the other thing is if they're on other medications, so Coumadin, warfarin, Plavix, aspirin, Xareltos, and Eliquises of the world, so if they have reasons to be on anticoagulation or significant blood thinners, then a BTK inhibitor for life might not be the best option, because of the bleeding risk. So, that would maybe steer more towards the time-limited treatment, because Venetoclax doesn't have a bleeding risk.

Now, if they're willing to put in the time and effort to do time limited treatment, again, the advantage of the Venetoclax-obinutuzumab combo is they can get these, what we call deep remissions, with high rates of minimal residual disease, undetectable state. And if they have no MRD, or minimal residual disease, at the end of a 12-month treatment, they're likely to sail into remission for a very long time.

Dale Shepard, MD, PhD: So tell me a little bit about how minimal residual disease, how you utilize that to assess either response to treatment or starting another treatment?

Brian T. Hill, MD, PhD: Yeah. So, MRD has been used in different heme malignancies. I think it's most common in ALL, that's still sometimes used in AML. There are available tests for CLL, and one particular clonal seq allows, if you get a baseline sample you basically get a barcode, which allows you to track the CLL clone going forward. And where we use MRD testing is for time-limited therapy. At the end of 12 months, if the patient, again, has no detectable MRD, it's prognostic of outcomes, so the remission duration.

If they do have detectable MRD, but they're in clinical remission so their blood counts are normal, no lymph nodes feel fine, we're not extending treatment based on that, but it might make you less likely to re-challenge with Venetoclax if they have a short remission and they didn't clear their MRD at the end of frontline treatment. So, there are studies that are looking at response-adapted continuation of treatment based on MRD, but those are still a little bit not quite ready for primetime.

Dale Shepard, MD, PhD: I wonder where that was with a re-treatment standpoint because you have a disease where people come in, they have high white counts, and you know there's something there, but you may not start to treat them, but then after you've treated does minimal residual disease have any impact at all?

Brian T. Hill, MD, PhD: Yeah. So it's interesting to see patients who are, again, you look at them and at first pass they're in remission, and again, normal CBC, no lymphadenopathy, no symptoms, but you have detectable CLL base, with usually with a sensitive test like MRD. What I think that tells you is that they're going to probably recur a little sooner, but there's never been really proven that, again, just like at the beginning, early intervention, no clear advantage for MRD detectable state.

The final thing maybe we can just mention is that this whole notion of the watch and wait is something that historically was tested in big trials with early intervention, with really what we would now think of as antiquated therapy. So, it was actually chlorambucil that was tested, but we now have these tools, like the IGVH test that I mentioned, and fish panels that can show, for instance, people with 17p deletion or higher risk.

So, I am involved in a large cooperative group trial, which is challenging this whole notion of early intervention, being ready to go. We don't know the answer, but we do have a study open through SWOG in the cooperative groups, which is taking patients with high-risk features like 17p depletion, or certain combination of other biologic and clinical factors. And then it is a randomized trial of early intervention, versus delayed therapy, and the intervention is Venetoclax and obinutuzumab, because we believe that's the treatment that has the best likelihood of getting deep remission.

And so, it's an ongoing study. It's about halfway accrued. Once it's accrued, we'll have to wait many years to see the outcome, but the primary endpoint in the trial is overall survival. So, it could be practice changing if it shows early intervention for high risk actually improves survival, or if it's a, quote-unquote, negative trial. It could be practice affirming in the sense that we still in the current era don't believe that early intervention is needed, so it could affirm what our current practice is.

Dale Shepard, MD, PhD: Well, certainly a lot of activity here recently in this area and appreciate you coming by and giving us some insight.

Brian T. Hill, MD, PhD: Great. Thanks so much for having me.

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