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Michael J. Mauro, MD: Hello. I'm Dr Michael Mauro. Welcome to the Medscape InDiscussion podcast series on chronic myeloid leukemia (CML). Today we'll discuss the best developments and challenges ahead in the field of CML. We've seen a family of tyrosine kinase inhibitors (TKIs) developed. We now have one with a novel mechanism of action added to the list. We have very high response rates and excellent remission rates, and the ability to achieve treatment-free remission (TFR) in a proportion of patients. How do we finish the job? First let me introduce my guest, who probably needs no introduction: Jorge Cortes. Dr Cortes is director of the Georgia Cancer Center at Augusta University, an international leader in clinical research in leukemia, and a prolific clinical investigator. Dr Cortes is an author and coauthor of over a thousand journal articles. His current research emphasizes development of new therapies for leukemia, developing predictive models, reducing the toxicity of our therapies, and improving the quality of life for patients with leukemia. Welcome to InDiscussion.
By way of icebreaker, I usually throw one question out to everybody. What is the best thing that's happened, or the best thing that needs to happen, for CML patients? Not that we haven't had a lot already, but what do you think?
Jorge E. Cortes, MD: Thank you, Mike. Great to be with you. Of course, the introduction of the TKIs, as you mentioned at the beginning, is by itself probably the greatest thing that has happened to CML. After that, the best thing that has happened is our realization that we have the ability to stop therapy in some patients. That really has changed our approach to CML — not only the lives of the patients who have been able to stop therapy, but also the way we think about CML. We are not just looking at improving survival. We are aiming for different goals. That also brings us to the thing that has to happen because it is a reality, but it is a reality for only a minority of patients, which is stopping therapy. How do we get that to be something that applies to a majority of patients? Right now, we can play with the numbers, but grossly about 25% of patients, maybe 30%, successfully stop therapy. It's never going to be 100%. How do we get it to be at least two thirds or 70%, 75% successful? That's a big challenge.
Mauro: I love that answer. That's perfect. I couldn't agree more. When we see a new patient with CML, we talk to them about the option of a functional cure, but then in the end, we're not able to get there for the majority of cases, which is pretty frustrating. I'm so excited that you and I collaborate on research in trying to figure out how to make an attempt at stopping subsequent attempts down the road. I think that's really an area we need to work on.
Our job today is to figure out the future, which has not been written, but maybe we can talk about challenges that we've had. We have a lot of therapeutics. We have six drugs approved in the United States. We have some drugs approved ex-US. We have a number of drugs still in development, which is really encouraging, and not only in the US and EU but around the world. I think the whole CML community around the world has really banded together to try to come up with best therapeutics. Where do you think we've fallen short? Are there any specific gaps you can think of?
Cortes: I can think of a few. One of them is that although a lot of patients do very well — you and I have a lot of patients who we have started with one TKI at the time of diagnosis, and we've been following them for many, many years and they're doing great — but there are patients who just don't do well with any of the TKIs. I'm not only talking about being able to stop therapy, but they have resistance. They don't get to even a major molecular response or they have a lot of side effects. These chronic lingering side effects are a problem for many patients. We are still having those problems. Those multirefractory patients are a smaller population and getting smaller, but they are there and they are very challenging. Another big challenge that I see is those patients who transform to accelerated phase, who go to the blast phase. They're not many, but because they're not many, we haven't done much work on figuring out what to do with these patients and how to improve their outcomes. That has become an important challenge in the management of these patients. In referral institutions, we have more of these patients and they're hard to manage; we haven't really made that much progress, particularly in blast phase.
Mauro: I apologize, Jorge — I'm going to throw you a curveball. The World Health Organization is changing the way we define CML. What do you think of the difference between the way we used to think about it, as a spectrum of chronic, accelerated, and blastic phase, but now moving to this high-risk chronic phase, low-risk chronic phase, and blastic phase? I'm trying to settle that in my mind. I've actually had clinical cases already come across my desk in my practice where I'm trying to figure out what to do.
Cortes: I guess in the absence of figuring out their biology and how to approach these high-risk CML, chronic-phase, or accelerated-phase patients, we changed the name to think that we did something. There is this subset of patients in that intermediate category. They're not blast phase, but they're not that classic CML chronic phase, the patients I mentioned earlier in whom we give the first TKI or maybe a second TKI and they do well. These intermediate patients are not that. They are something in between. That intermediate category is very relevant. I think what's important is that we need to understand what is different biologically about these patients. Whatever we call these patients is probably irrelevant. We just need to understand why these patients don't do as well as those patients who have those beautiful responses where you give them their TKI and 3 months later, their grade response is already well below 10%. What is different between those two patients? To me, that's what matters and not what we call them. There's the International Consensus Classification which still recognizes the chronic phase. Now we have made it even more complicated.
Mauro: Your perspective is golden here because I know that you and your colleagues have really pioneered the way we look at this intermediate group. What is this accelerated-phase category really supposed to look like? I think that's a fair answer and I think time will tell. I guess I'm just worried that we're going to start thinking about chronic-phase patients needing treatment like in blastic phase. I think you're right; we haven't necessarily nailed down how to treat patients who progress to advanced phase. Thank goodness we don't see many patients presenting in advanced phase, although I think the global landscape in CML is a little different from what maybe you and I had the luxury of seeing through the US and the European Union. We both work with the International CML Foundation. You're a leader for us, and I think that's really one of our efforts. I applaud that. Where do you think the challenges are at the global level? What's the next most important thing we have to do to get this therapeutic advance up to speed everywhere?
Cortes: I think you're absolutely right. The way we see CML in this country and in countries where there's more access to healthcare, TKIs, and monitoring is very different. As you mentioned, the largest part of the world's patients present not only more frequently in more advanced stages, but even if they're in the chronic phase, the percentage of patients who present with a high-risk Sokal score is much greater. We know that those patients already have a worse outcome. They are going to have a lower probability of a successful TFR, for example. Even if there is no progression, their goals have changed completely. A lot of that has to do with the lack of access to care and even just having regular complete blood counts (CBCs). We diagnose patients during a regular annual physical or when a CBC is done for other purposes — a knee replacement or something like that. We diagnose patients very early. That's not what happens in other parts of the world. We cannot forget or ignore all those patients all over the world. That's why the work the International CML Foundation is trying to do is so critical.
Mauro: I definitely think we have the luxury of diagnosing CML relatively early because people are going in for other reasons. I think awareness has increased. I get the sense that globally things are getting better, and our partners in pharma have helped in regard to drug access. But even in the US, we struggle with cost and copay issues. That's a topic for a whole other podcast for us. I'll get other people to give me answers on that one. You mentioned advanced disease and bone marrow transplant. In your practice, how often do you see that and what do you think our best foot forward is? I know we have limited experience in this area, and trials with chemotherapy and transplant seem to be a bit of a forgotten issue in CML. When I lecture, I try to always include this in the discussion, but I think people tend to neglect discussion about it. What's your take on transplant in 2023 and beyond for CML?
Cortes: I agree. I think we've forgotten a little bit about transplant in settings where we should consider it, and we should consider it earlier. There is no question in my mind that a patient who has transformed to a blast phase or an accelerated phase — if you believe in that accelerated phase — that patient should be transplanted. Perhaps in the blast phase, it's more clear that we try to do that. We get patients into some sort of remission and then we transplant patients. In patients in whom we've already tried the six TKIs, I think we could probably move to transplant a little earlier, especially if these patients are young and they have donors. Rotating TKIs from the same class is not going to get us anywhere. Patients also feel less likely to accept the stem-cell transplant because of how we present things and give the impression that we have another TKI and that's going to help them. Yes, we have another TKI, but is it really going to help them? I'm not talking about a year or 2 years from now, but is it going to help this patient be alive and well 10 or 15 or 20 years from now, which is relevant for those younger patients? We do need to bring up those conversations about transplant much earlier, and in my view, use only three TKIs. If you started with the first generation, with imatinib, and then you went to a second generation and a third generation, that's it. You don't need to try all of the options that you have, especially if there is resistance. If there is intolerance, maybe rotation makes a bit more sense.
Mauro: I am going to call that the "three strikes and you're out" or "three strikes and you're transplantable." I know patients want to stay away from transplant discussions if they can, but I think the way we present the treatment landscape for a blood cancer like CML is that we're very hopeful that we can treat and bring on remissions and aim for functional cure, but it doesn't always happen. As you said in the beginning, it's actually a minority of patients who get to a TFR, not a majority. We clearly want to do better. One more thing to unpack in the list of challenges that I had is that we're starting to become a little smarter about what we do in the lab when it comes to sequencing. You were part of some research at a global level looking at mutations outside of BCR-ABL. It's funny; we focus so much on BCR-ABL kinase domain mutations as a relevant topic related to therapeutics. It is. My opinion is that BCR-ABL kinase domain mutations became a bit of a smaller concern than we thought they might be in the beginning. It's still a very relevant concern, particularly certain mutations and complex mutations. What do you think the role of other myeloid mutations is? You're an expert in leukemias, broadly. You're a master of multiple leukemias. I know that acute myeloid leukemia (AML) has a story written by the molecular signature. Acute lymphoblastic anemia (ALL) and Ph-like ALL are your bread and butter. What do you think about what we're stumbling upon in CML right now?
Cortes: It is amazing because we always thought about this as a very clean disease. Everybody has BCR-ABL so it's easy because you just give them a BCR-ABL inhibitor and they're all going to respond well. Now we've learned that it's not that simple. A sizable percentage of patients, maybe about a third of patients, according to some reports, will have additional molecular abnormalities or other BCR-ABL related events that make it much more complex. Those are probably patients who are not responding well, who are transforming earlier, who are not getting to the deep molecular responses. Clearly, we need to understand that complexity early on from the time of diagnosis. It's hard to promote doing next-generation sequencing (NGS) on all patients today because it has cost implications and other issues. Because of the significance of these findings, I think we're getting more toward that — looking at NGS — if not at diagnosis, then early on in those patients who have not done as well as we thought. Of course, it brings up the question of, what do we do now? If you have a patient who has an ASXL1 mutation, for example, changing to another TKI is unlikely to help. That has nothing to do with the tyrosine kinase that we are attacking with any of these drugs. How do we manage those patients? At least for today, perhaps those are the patients who we should be thinking about earlier regarding stem cell transplant, because we know that these patients are not going to be doing as well with just the TKI. Clearly, we need to start thinking about assessing those other events early on in the course of therapy — if not in everybody, then at least in those patients who start falling behind, but at an early stage.
Mauro: I think that's really sound. Some of these questions are not always answerable, just like you said. What do we do? We have probably both seen cases where things like that have really turned around. Some of the patients maybe had a high-risk profile or additional changes, and good BCR-ABL inhibitor therapy has really shut it down. Let's pivot a little bit. We've clearly both been working on, and are glad that we have, more therapeutic options. Can you give me some thoughts on probably the one drug that I would say is the most prominent, which is asciminib? I don't want to diminish the work and the effort to develop other drugs for later-line therapy, which I know you've been working hard on. Give me your thoughts on the newest of the TKIs.
Cortes: I think asciminib has been a great addition to our armamentarium of drugs, certainly because it has a different mechanism of action. It is a TKI but binding in a different place; the myristate pocket. It has to reflect that in a very high level of activity and is much less affected by these usual mutations that we see in patients. It also has a very clean safety profile. It is a very welcome addition. That's the good thing about this drug. It's not just another one of the TKIs. You're probably saturated with ATP-competitive inhibitors. There are other drugs being developed and they're good, but it is nice to have one that works completely differently, and it brings a whole lot of other possibilities — combinations with the traditional TKIs. I think we're just starting to scratch the surface as to the potential that a drug like asciminib can have in CML. Certainly the indication that we have now is that in patients who have received multiple TKIs, patients with T359 mutation, it works well. We know what we can do there, but I think it has a lot of potential earlier on in combination with other TKIs. There are a lot of attempts to combine pursuing TFR in patients who are doing well but not quite enough with their traditional TKIs.
Mauro: I'm going to put you on the spot again, Jorge. I apologize. What do you think myristate-pocket inhibitors like asciminib — or the ponatinib-like drugs, the better third-generation ATP inhibitors — where do you think we're going to get the most gain?
Cortes: I don't think there's one answer for everybody. In the equivalence, ponatinib and asciminib essentially have the same indications. I like them both and I use them both. I think that they have potential because they have different toxicity profiles and different schedules of administration and dosing. There are always roles for both of them and I'm glad that we have the two options because I always find myself trying to decide which therapy fits better for this patient vs another patient. I am glad that at this level we have more true variety than just another drug of the same class that just adds to the same thing. I am using both of them. We've improved a little bit on the weaknesses of ponatinib. One of the weaknesses that I don't like with asciminib is the number of pills that a patient with T359 mutation has to take. This is a formulation issue. I don't doubt that sooner or later we're going to have a better formulation that will allow for patients to take one or two pills instead of the pills that they take now. I like having both. I don't think that I'm going to just be a physician who only prescribes one of these two drugs.
Mauro: I think the patients would echo us 100%: The more the merrier. It's really a treat to be in the clinic and to be able to say that we have a new drug that was approved a year or two ago that really is different and doesn't have the same adverse-event profile. It really may work. I couldn't agree with you more. We've talked about the tough stuff. Let's talk about the good stuff, which is TFR. It's going pretty well. The numbers are ticking up quite robustly in the US, and across the world, we hope. Each of the things we've talked about probably is mirrored in the TFR and its development. How pervasive is it globally? What about pediatrics? What about other areas? What do you think we're missing there? What's the future of TFR?
Cortes: I think that we're missing at least two important elements. One is, how do we improve the number of patients who are going to be eligible? Of course, one of the possibilities is to make the eligibility more relaxed. Instead of going for molecular response (MR)4.5, go for an MR4. Instead of going for 2 years, do it for 1 year. I'm not a big fan of that because we've done some work. It's just that the more durable the remission, the better the probability of when you stop being successful. How do we get more patients to have the deepest molecular response to MR4.5 and more durable response for 5 or 6 years? I think that asciminib front line could lead us that way. Some years ago we did a study with ponatinib front line and the results were impressive. We had to stop because of the toxicity, but the results were impressive. I'm hopeful that now we'll get that with asciminib. How do we keep the patient there once you stop? One is more durable remissions, but we are probably thinking about adding other things, combining two TKIs, some immune approach. We've toyed with that idea. There are many things in the laboratory and starting in clinical trials; I don't think we have quite the grasp on what is going to work. Perhaps the complexity here is that you may need two different approaches for different individuals. We may need to understand better what is going to work for a given individual. That's a big challenge. I think we're getting there because at least we have a solid starting point.
Mauro: I get the sense from that answer that we're not done yet. We have a little more work to do. Today I talked to Dr Jorge Cortes about the challenges remaining in CML, how the therapeutic landscape looks, what our studies in the laboratory are showing us about complexities of resistance, where the gaps are in different areas of CML, and what the future looks like for TFR. As I said, I think we have more work to do. I thank him immensely for his time today to share some brilliant thoughts on a field that I know he's devoted a good part of his career to. Thank you for tuning in. Please take a moment to download the Medscape app, and listen and subscribe to this podcast series on CML. This is Dr Michael Mauro for Medscape InDiscussion.
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Cite this: Developments and Challenges in the Therapeutic Landscape of Chronic Myeloid Leukemia - Medscape - Jul 27, 2023.