How Targeted Therapies Are Transforming Chronic Myeloid Leukemia Care

Dr. Jorge E. Cortes sat down with CURE to discuss the evolution of chronic myeloid leukemia (CML) treatment, advances in targeted therapies, and emerging strategies aimed at improving patient outcomes and quality of life.

In this interview, Cortes shares insights on the transformative impact of tyrosine kinase inhibitors (TKIs), the significance of second- and third-generation therapies, and ongoing research focused on the ultimate goal: curing CML.

Cortes, director for the Georgia Cancer Center and Cecil F. Whitaker Jr., GRA Eminent Scholar Chair in Cancer, also sat down with CURE earlier this year for a conversation on myelodysplastic syndromes.

CURE: What has been the most important milestone in the evolution of CML treatment?

Cortes: The introduction of TKIs has left room for improvement in terms of responses, tolerability, and other outcomes. When I started my career, we were treating patients with only chemotherapy, [and a few other options], which did not work at all. A significant change occurred when we began using interferon and transplants. However, those treatments were highly toxic.

Interferon had a response rate far lower than what we see with TKIs, and transplants were limited to only a few patients and carried high risks. When the tyrosine kinase inhibitors (the first one being Gleevec [imatinib]) became available, they completely changed the history of CML and, in many ways, the history of cancer. They ushered in the era of targeted therapies that are more effective, better tolerated, and transformative in altering the natural course of the disease.

How have second- and third-generation TKIs improved patient outcomes and quality of life compared with the pre-TKI era?

The outcomes have continued to improve. There was a dramatic change with the introduction of imatinib, but not everyone had the response we wanted. Some responded and then lost that response, and some could not tolerate the medication. Even though it was much better tolerated than interferon, some patients still could not tolerate it. With the introduction of the second-generation TKIs, we were able to overcome resistance in many patients, and individuals who did not respond to imatinib were now responding to one of the newer drugs, Tasigna (nilotinib) or Sprycel (dasatinib). Other patients who may not have tolerated imatinib could now tolerate these other drugs because they have different safety profiles. That improved outcomes further.

With the newer generation, we filled a few additional gaps. Iclusig (ponatinib) was the first drug that worked in the T315I mutation, for which we previously had no options. It also introduced awareness of other side effects, such as cardiac problems, that we had not fully recognized until then. Now, with the new drug Scemblix (asciminib), which is the first with a very unique mechanism of action, we have seen even further improvements in responses and tolerability, which so far appears to be the best of all the drugs. That does not mean there are no side effects, but generally, we see fewer side effects and far fewer patients who have to discontinue therapy.

We continue advancing and improving these outcomes, and we are also paying much more attention to quality of life, which is important since most patients live a very long time but may need to continue taking the medication.

How does the recent approval of Scemblix as a frontline therapy impact CML treatment decisions and patient management strategies?

Well, you know, in cancer in general, the more options you have, the better, because there are always needs to improve something. Although we have reached essentially normal life expectancy for patients who can get access to good treatment and good monitoring and good management, more and more we want to focus on having the option to eventually stop therapy and be free of treatment. Right now, before assuming this was a reality only probably in approximately 25 or 30% of the patients, considering where we were 10 to 15 years ago, that is huge. We never thought we would be able to stop therapy when we started doing the TKIs.

But of course, it is a minority, so we want to make it much more available for us. With the data that we have in the frontline setting with a simile, we think we are going to get to much higher numbers of patients who, number one, are eligible to consider stopping therapy, and number two, can remain off therapy once they stop.

In addition, it brings another advantage, that if everything continues with the tolerability benefit that we have seen so far, then for those who do not have the option to discontinue therapy, they will at least have less impact on the quality of life. It gives us another option that provides additional benefits, which we still need to improve on in patients with CML. Now, the advantage in CML, as I like to tell patients and my colleagues also, is that we have good drugs and better drugs. You know, all these drugs are good. There is no good and bad. They are good and better.

That gives us the option to tailor the treatment to the needs of the patient, to the patient characteristics, very importantly to the patient goals, and then select the best option for them.

What are the key considerations for clinicians in balancing long-term efficacy and daily quality of life for patients living with chronic myeloid leukemia?

We need to make sure that we, first of all, from the very start of treatment, understand the goals the patient has in the treatment. Make sure that we provide all the information about the efficacy goals, the safety goals, what we know about the different treatment strategies, which ones provide what, the benefits, and the potential disadvantages, and continue evaluating that, because the goals and how the patient feels about a certain aspect of the disease, or the treatment may change over time.

We need to keep paying attention to these things. I think that focusing a lot more on the quality-of-life elements is critical, because I think that when we perceived the disease as highly lethal, the main emphasis was to let the patients live. And that is very important, and we have achieved that largely, but I think that more and more patients are not only interested in living more but living better.

We need to make sure that we understand how the patient feels, what other elements may matter, as well as managing other comorbidities. Patients may have other diseases, may take other medications, and we need to balance all of that when we are selecting the treatment and managing them long term.

What emerging therapies or ongoing research in CML are most promising for improving treatment outcomes and patient care?

There are some new drugs that are being developed, and it is always good to have better drugs, because if they can improve something in our efficacy and our safety, or provide alternatives to patients who have problems with one drug or another, that is always good. I think that the main goal right now is to focus on the ultimate cure. You know, how can we eliminate and eradicate the disease completely in patients so that most of them can stop treatment and have no recurrence of the disease. That is our main goal.

We are making progress, although we are not quite where we want to be. We are putting together a large proposal for a big study with colleagues from all over the world through the International CML Foundation to focus on that, because that is where we want to be. We want to really aim for the final stroke, to get rid of the disease in any patient who is diagnosed with it.

Transcript has been edited for clarity and conciseness.

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