Chronic Myeloid Leukemia Podcast

Targeted Therapy and Evolving Research: Where Are We Winning and Losing in Chronic Myeloid Leukemia?

Michael J. Mauro, MD; Ehab Atallah, MD


June 29, 2023

This transcript has been edited for clarity. For more episodes, download the Medscape app or subscribe to the podcast on Apple Podcasts, Spotify, or your preferred podcast provider.

Michael J. Mauro, MD: Hello. I'm Dr Michael Mauro and welcome to the Medscape InDiscussion podcast series on chronic myeloid leukemia (CML). Today we'll discuss the state of CML research in 2023. The advent of targeted therapy occurred with the development of small molecule inhibitors for the BCR-ABL oncogene, which is the driver of CML. Research into this pathway — the concept that we can have targeted therapy and the proof of concept and the validation — has really led to a revolution in cancer therapy. I think it's set an example for what can be done in cancer medicine, in general. If we think back, targeted therapy really didn't exist before we had therapy for CML. Back then, we had trastuzumab and hormonal therapy. Research in the field of CML has evolved, and I think my guest and I will both convey to you that we still have many questions to answer. Organizing that research is really crucial. We have a fast pace, limited funding, and a complex regulatory environment we're working in. It's tough, so how do we do it? Where are we winning, and where are we losing? First, let me introduce my guest, Dr Ehab Atallah. Dr Atallah is a professor of medicine and section head of hematologic malignancies at the Medical College of Wisconsin Division of Hematology and Oncology. He specializes in leukemia, myelodysplastic syndrome, myeloproliferative neoplasms, and other bone marrow failure disorders at Froedtert Hospital. Ehab is also the administrative director of the H. Jean Khoury Cure CML Consortium, affectionately known as the HJKC3. This consortium was established in 2016, and it is a collaborative effort of physicians and researchers at 21 academic medical centers committed to CML research and improving patient care and quality of life. Welcome to InDiscussion, Ehab.

Ehab Atallah, MD Thank you so much, Mike.

Mauro: I have been opening episodes with a teaser or an icebreaker, but it's also an important question: What do you think is the best thing that's happened for patients or needs to happen, if it hasn't already, in the space of CML?

Atallah: Obviously, finding the Philadelphia chromosome (Ph) and developing drugs that specifically affect the Ph are definitely the best things that have happened for patients with CML. Going forward, I'm really encouraged. I think the best thing that's happening now is all the enthusiasm for research to improve the care for patients with CML, whether to manage side effects, manage long-term toxicity, or trying to get more patients off drugs. Looking at patients with advanced disease and resistant disease with all the collaborations that are happening here in the US and around the world is really the best thing going forward that would be happening to patients with CML.

Mauro: Fantastic. There's a great analogy of ducks on a pond. They may be smooth sailing on the surface, but their feet are paddling furiously under the water. I think we're making nice progress, and we've come a long way, but we are working pretty hard, too, to answer a lot of questions, particularly the cure question. I love that focus. I know that's what we're working toward in our collaborative research. CML research in 2023 is a little different if you look at where we are in the US vs the rest of the world. I know we both have a little insight into this. With what you do with the Cure CML Consortium and as a prominent leukemia researcher, what do you think are some of the strengths, weaknesses, and opportunities? I definitely see some of the differences.

Atallah: I think we're very different when we go to the meetings, and we talk about research here in the US and research in the rest of the world, especially the developing world. Maybe we'll start with that. The developing world still has a lot of issues in terms of drug cost and testing. There's a lot that needs to be done to improve the testing, improve accessibility to drugs, and manage the side effects. These are really important in the developing world. For us in the US, our focus is that we still have some accessibility issues to get the drugs. We have some adherence issues with patients unable to keep their drug or stay on their drug. We also have the challenge for the patients who need to take their drug forever of how we can get them to a cure. What are the tests, the studies that we could do that, in terms of toxicity, are acceptable to both the patient and physician to investigate more and get patients off their drug and to achieve a cure?

Mauro: I think that's a great point. In the developing parts of the world, we have this real gap because I don't think we're as close to a cure, treatment cessation, and defining treatment as much as we are in the US or in other parts of the world. The need is almost vastly greater there based on the number of people affected and the cost of therapy. I think this is a great point. I always think of the United States as 50 little countries stuck together, and we're all trying to cobble our research together. Whereas you look at centers in Europe, where they have a lot of centers of excellence, and they're able to funnel a lot of their patients and their efforts together. They definitely have shown some advantages. I think we all struggle with the issues with funding and logistics. Have you had any challenges with the US and Europe in regard to logistics and data? We ought to be putting these struggles on the table.

Atallah: Yes. There are differences between the US and Europe. With Europe, they've been able to develop studies and registries that are more cohesive. Having said that, though, Mike, with the consortium, I think we're really making excellent progress there. We have 21 centers in the consortium, and the number is increasing. We're developing registries. We're developing a way to look at the real-world outcome. I think we may be overcoming that. In terms of funding, yes, it is a challenge. You and I know that. The problem is with CML, a lot of people think, Just take the drug every day. Why do you need more research? This is enough. Survival, at least in the data from Europe, seems to be similar to the general population. However, when we look at the SEER data here in the US, survival is still lower than the general population, and we don't really know why. Is it related to CML? Is it not related to CML? We really need more done. We need to figure out why is there a survival difference? Is it the toxicities, the co-morbidities, or access to drugs? Regardless of the survival, when we think or tell patients who are on drugs, "You are cured," the patients don't think so. We conducted a survey where we asked patients, "What do you consider cured?" It was a very clear message from patients. Cure means I'm off drug and I'm not taking this medication. From a physician's standpoint, taking a pill every day is considered great. From a patient's standpoint, it's great, but no one wants to take a pill every day.

Mauro: No, and we're going to touch on that more later because I think the patient in the equation of our research is huge. You very appropriately are weaving in the Cure CML Consortium, which is phenomenal, and I'm honored to be part of it. Tell me a little about that and the story about how it was born, because I think it is a nod to certain individuals. I think you tell the story quite well.

Atallah: The consortium officially started in 2016-2017. Prior to that, we were working together. When I say "we," it's all the CML community and multiple CML specialists in the United States. We were working together on a study to try to get patients off their drug and see who's eligible and who can stay off the drug. It was a really awesome collaboration. I can say that because we worked with everyone, and it was a very productive collaboration with multiple CML investigators. We realized that in the US, we don't have a consortium. We don't have a group of CML scientists and physicians who are working together to get to a cure. The person who really started this was Dr Jean Khoury, who passed a few years ago from another cancer. He was the one who brought us together and said, "We've worked well together on the study, let's keep working together." That's why we named the consortium after him. Since then, this collaboration has increased to 21 centers and more. We have multiple studies going on. We also have a registry. It's not just a registry for data collection, but it's looking at patients' outcomes in the real world and how they're doing. It's been a very fruitful collaboration, and I hope it continues.

Mauro: Yes. Let's cover the projects because I think it's important for people to know about them. People might not be aware of the registry and some of the research projects that we have ongoing. The first study that triggered everything has a terrific name, the LAST study, although it was really the first, if you think about it. It was the first study of the consortium. Give me a thumbnail sketch on where we were at. I know we have a couple of different active trials, and I know we had some plans and some exciting projects that are unfolding.

Atallah: We'll start with the active studies right now. Our focus at the consortium is to cure patients and get them off their drug. We're really focused on treatment-free remission (TFR), which is getting off drug. We have two studies ongoing where patients who have attempted stopping drug fit certain criteria. The patients have been on drug for at least 3 years and in a deep remission for 2 years. Those patients would be eligible to stop with very close monitoring. In patients who fit those criteria and stopped drug, about half of them will recur and the other half won't. We are looking into half the patients whose disease came back and went back on drug. We have two different studies we're calling it second TFR attempt. One of them is to add asciminib and the other is to add ruxolitinib for a limited period of time and then going off drug again. There's pretty good basic science data that suggests that adding those to the current tyrosine kinase inhibitor (TKI) may lead to deeper responses and get more patients to a successful TFR. Those are the two second TFR studies.

Mauro: Then we have some registry and some data dives that we're looking at because we have some unanswered questions about deciding which therapies are best really in later lines, right?

Atallah: Yes. All the data that you and I talk about have really been from clinical trials. As we all know, clinical trials just include a very controlled group of patients. What happens in the real world when we have four different TKIs available, and it's not really clear which one would be the best to choose? We're looking at the real-world data and seeing how the choice of the drug really affects getting to TFR or achieving treatment-free remission. We're looking into that. Another way we're looking into research of getting more people to TFR is we also have a frontline asciminib trial. If we put patients who are just newly diagnosed on asciminib and use it as frontline (it is currently FDA approved as third line), will we get more patients to a deeper remission and end up being able to get patients to a TFR? Obviously, we don't know the answer. That's why we're doing the study to see if that would.

Mauro: Fantastic. As you know, I'm not only a big fan, but I formulate some of these studies. Asciminib seems to be prominently figuring into our equation. Share some thoughts on that. What do you think? How good do you think that that drug is going to be for us in CML? How is it going to figure into our research in the future?

Atallah: It's really hard to tell. It's interesting because in terms of the way it works, it binds to a different spot on ABL. All the TKIs bind to the ATP pocket. Asciminib binds to a different pocket. It's called a Specifically Targeting the ABL Myristoyl Pocket (STAMP) inhibitor. If you imagine asciminib binding to ABL in two different spots and blocking ABL, would that lead to a deeper remission? Maybe. It seems promising. It seems really promising in third line. I think most research in cancer, you test something in third line and then you bring it to the front and see if it works better. Maybe it will, and we're waiting for the results.

Mauro: The bar was set a bit higher for front line with ponatinib when it was studied, but we really fell on our sword. There was some side effect questions, and I think we're hoping that asciminib will be the better choice. The Cure CML Consortium sounds like it's well established and humming along. That's fantastic. In a perfect world where we didn't have so many limitations or we could organize a little better, what's the vision? What kind of things do you think we can achieve there? You and I've tried to tackle some of the issues about getting people familiar with trials and drug trial access, getting the word out, and again, there are some limitations. Where could we go? Any ideas? It's a tough question.

Atallah: I do have ideas. I'm just wondering how much time we have.

Mauro: That's a good problem.

Atallah: CML is a rare disease by definition, and there are a lot of patients who are managed not by specialists. CML seems to be pretty easy: "Here's a pill. You'll handle it well." There are a number of patients — maybe almost 30% of patients or even more — who don't stay on the first drug. The drug they start with first is switched, which means that there are ongoing side effects and resistance. I think we could give access to physicians who are not specialists and patients who are followed by general oncologists to be able to just ask a question about their treatment. We don't necessarily have to see the patient or have the patient drive 3 hours to the academic center. One area we would love to develop is how to consult remotely with patients. That is a concept we're working on, and I think it's going to be very hard to achieve. The idea is almost similar to Europe, where all the decisions for cancer go through a centralized process. The patient doesn't have to travel. There is a centralized tumor board that makes the decision. I'm not saying we can get to that, or we have to do that, but something similar, like a remote consultation. We can also improve the care with the drugs that we currently have. The second area of development is despite the TKIs being great, there's still 10% of patients who develop accelerated phase or blast crisis. This is a huge need in research, and it's such a small number of patients. How can we develop studies for 10% of a rare disease? That's just one of the biggest challenges we have.

Mauro: I'm intrigued that we're thinking about accelerated phase differently. Do people have mutations like patients with acute myeloid leukemia (AML) have? Maybe low volumes of immature cells and the bone marrow might be a real flag. I feel like we need to step up our game when we see patients for the first time. I loved your first idea. I hope pharma, academia, and philanthropy are all listening to this podcast because we need some help. We want to do it as good as we can with the 50 different fiefdoms we have in the US and work together to lace everything together where CML patients can be managed better, more efficiently at a higher level, flowing through people who are thinking about it all the time and formulating research so we don't miss any opportunities. That brings it home for one of the last points, which is the patient. It's an interesting world in 2023. It's very tech savvy. Everything's instant. People have access. They'll have access to this [podcast], and I hope patients will be listening. Where are the patients in this equation? I think they are sometimes not part of the discussion, and they should be. They are sometimes needing more support and more follow-through.

Atallah: Truly, the patients are the center of all this. We've done this for a long time, and we're so interested in it. We actually had a patient survey with more than 400 patients responding. The message was clear: More research is needed. Patients are taking a pill every day, and their quality of life is affected. More needs to be done. This is not enough. We published on that. The patients are really the center of all this. The consortium and in all our grants, we always have a patient advisory panel because I truly believe my view and the patient's view are very different. Hearing from the patients on what is really needed and how we can advance things is really the center of this whole consortium and our goal.

Mauro: I couldn't agree more. It's like a marathon. I always say that I'm a sucker for runner analogies because I am one, but this is not an intense and defined amount of time. It's long term. It's a marriage of treatment. People can be on treatment for maybe 3 to 5 years or some number of years. They might be on treatment indefinitely. It's a great problem to have, but it is something we have to tackle. I think that's an excellent point.

Atallah: I have to follow up on the marathon, Mike, and tell everyone that we climbed Mount Kilimanjaro 3 years ago to support the International Chronic Myeloid Leukemia Foundation (iCMLf), and Mike Mauro ran a mile at 14,000 feet. For whoever has attempted that, you understand how difficult that is. I could hardly walk 10 feet.

Mauro: I thought it was 15,000 feet, for the record. I was misbehaving. We were supposed to be acclimating, meaning just breathing and walking around. I thought I would go for a run to really test the waters. Philanthropy is a huge part of the equation, too. I think we need the support from others besides the government and pharma to help us. We've been so grateful for all the support for the iCMLf. Maybe the Cure CML Consortium could benefit at some point. Today, we've talked with Dr Ehab Atallah about CML research in 2023, including where we've been, where we are, and where we're going — especially in the US and comparing and contrasting to other places where some things are being done better. We're going to strive to perfect this work. I am delighted to be along for the ride, working with the Cure CML Consortium and Dr Atallah. Thank you for tuning in. Please take a moment to download the Medscape app and listen and subscribe to this podcast series on chronic myeloid leukemia. This is Dr Michael Mauro for Medscape InDiscussion.


Chronic Myelogenous Leukemia (CML)

Tyrosine Kinase Inhibitors

BCR-ABL Fusion Gene

Trastuzumab/Hyaluronidase (Rx)

H. Jean Khoury Cure CML Consortium

Genetics, Philadelphia Chromosome

National Cancer Institute Surveillance, Epidemiology, and End Results Program (SEER). Cancer Stat Facts: Leukemia — Chronic Myeloid Leukemia (CML)

Assessment of Outcomes After Stopping Tyrosine Kinase Inhibitors Among Patients With Chronic Myeloid Leukemia: A Nonrandomized Clinical Trial

Treatment-free Remission: The New Goal in CML Therapy

Monitoring Molecular Response in Chronic Myeloid Leukemia

Protocol Number: HJKC3-0003. Treatment Free Remission After Combination Therapy With Asciminib (ABL001) Plus Imatinib in Chronic Phase Chronic Myeloid Leukemia (CP-CML) Patients Who Relapsed After a Prior Attempt at TKI Discontinuation


Treatment Free Remission After Combination Therapy With Ruxolitinib Plus Tyrosine Kinase Inhibitors

Ruxolitinib (Rx)

Asciminib as Initial Therapy for Patients With Chronic Myeloid Leukemia in Chronic Phase

ATP-competitive Inhibitors Modulate the Substrate Binding Cooperativity of a Kinase by Altering Its Conformational Entropy

The Specificity of Asciminib, a Potential Treatment for Chronic Myeloid Leukemia, as a Myristate-pocket Binding ABL Inhibitor and Analysis of Its Interactions With Mutant Forms of BCR-ABL1 Kinase

Ponatinib (Rx)

Accelerated Phase Chronic Myelogenous Leukemia

Acute Myeloid Leukemia

Patients' Perspectives on the Definition of Cure in Chronic Myeloid Leukemia

International Chronic Myeloid Leukemia Foundation

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