Recapping A Quarter Decade of Chronic Myeloid Leukemia Therapy

Jorge Cortes, MD, believes that, despite the rapid improvements made in CML treatment, there is always more to be done to help patients.

Chronic myeloid leukemia (CML) was once known as a deadly disease, renowned for its difficulty to treat. Now, therapies exist such that, following initial therapy, patients can live for years without treatment. Rapid strides in treating CML have been made over the past quarter century, and at the beginning of that turn was the advent and approval of imatinib (Gleevac), the first tyrosine kinase inhibitor (TKI).¹

Several generations of improvements to TKIs have followed, and oncologists/hematologists continue to seek out ways to best enhance outcomes for patients. To explore the pathway and transformation of the CML landscape, CancerNetwork® spoke with Jorge Cortes, MD, the director and the Cecil F. Whitaker Jr., GRA Eminent Scholar Chair in Cancer of the Georgia Cancer Center.

What did treatment for patients with newly diagnosed CML look like before the development of imatinib in 2000?

In the standard of care prior to TKI development, there were 2 options: 1 was interferon, usually combined with low doses of cytarabine, and the other was transplant. Neither one was great. Interferon was [quite] toxic, and it had low response rates. The significant responses, which are what we call the complete cytogenetic responses, happened in 20% to 25% of patients with a lot of toxicity.

The other option was transplant, which is [better]. Transplant is curative, but particularly in those days, it was still limited [due to] age, availability of donors, and the toxicity and even the mortality rate, which has improved since then. In those days, we were facing difficult choices for patients, and many did not have great options. The outcomes were not good, overall.

How did TKIs and imatinib change CML treatment?

The impact of imatinib was [quite] noticeable from the beginning, even in [a] phase 1 study. It was early in my career that I was working with my mentor, [Moshe Talpaz, MD], and I remember we were seeing those patients in the clinic and having patients start to respond even in the beginning of these early trials. Many of them had gone through transplant and relapsed, and [interferon-alfa] and so on. It was remarkable.

That led to the approval of imatinib to be used for patients who had received interferon-alfa and had not responded or tolerated the treatment. Then it came to the initial therapy study, which was called the [phase 3] IRIS trial, where [imatinib] was compared to interferon-alfa—it was randomized head-to-head. By then, it was obvious that imatinib was a completely different gain and was better tolerated with a much better response. It was a difficult study from the point of view that we all wanted our patients to get on imatinib, and patients wanted to get on imatinib—they would cry if they were randomized to interferon-alfa. Sure enough, the study clearly demonstrated the benefit of imatinib. That's when it came to the approval.

Since 2000, we have had imatinib available as part of our standard therapy. The initial approval was for patients [who progressed with] interferon-alfa—of course, that category does not exist anymore, because we do not use interferon initially, but it became the standard of care for frontline therapy.

How have TKIs evolved since then?

Imatinib, of course, was the groundbreaker; it was the starting point. It changed, not only CML, but cancer in general. As you can imagine, we started seeing patients who did not respond—it's great, but not everybody responds. Some patients lost their responses. We started learning about the mechanisms of resistance, and that created the need for other drugs that could overcome those failures, either because of poor tolerance, lack of response, or loss of response.

That brought the second generation—dasatinib [Sprycel], nilotinib [Tasigna], and a bit later, bosutinib [Bosulif]—and they worked [quite] well. We had drugs that would give us responses in patients for whom imatinib had not worked well. Then they were compared to imatinib in the frontline setting, and they gave us further improvements. Imatinib performed well, but these drugs were even better in many aspects. That's what constituted the second generation, but even then, we still had a few gaps.

For example, there were still patients who, after 2 or 3 of these drugs, did not have a good response, did not tolerate [the agent], and then there was 1 mutation that started emerging. We started recognizing it in the lab, and more and more, we started seeing it in the clinic, which is that mutation, T315I. None of these drugs worked [for it], and that created the need to develop new drugs.

The one that emerged was ponatinib [Iclusig], which was in the third generation of [TKIs]. It was potent and effective. That was remarkable because, for the first time, we recognized that some patients would have arterial occlusive events, [like] heart attacks, strokes, and things like that. It had never been reported with the other drugs—now we know it happens with most of these drugs, but at that time, we had not recognized that.

It created a commotion because, on the one hand, you had an effective drug, but you also had these adverse [effects] that were life-threatening. It's not like having diarrhea, nausea, or things like that. Heart attack and stroke are serious things. The drug was removed from the market. The whole strategy was reenvisioned, and it eventually came back. We use it [often], and we've learned how to use it better, but it taught us about that.

More recently, we had, [beyond the] third generation, a new mechanism of action, which is this blocking what's called the myristoyl pocket. In that sense, it’s a new generation because it works in the same settings as ponatinib, but through a completely different mechanism of action. [It’s] another step in the development to try to overcome resistance and [achieve] better tolerability. That is also valuable.

We continue improving and innovating, and we still want to get patients to be able to have a normal, not only life expectancy—which we already have—but quality of life, and to stop therapy at some point. Hopefully, everybody can get to that point.

How has CML treatment become a more multidisciplinary field?

Going back in history, interferon and transplants were only done in big academic centers. Not everybody could [receive] a transplant, and not everybody could use interferon. It was too complex, too difficult, too toxic, et cetera. It was [quite] specialized. Now, because these therapies have democratized the treatment availability, but also, because these patients live longer lives, we must focus on other elements, [like] drug-drug interactions—our patients end up taking other drugs for other conditions. They live longer and they develop other diseases, [and have] other needs. They need visits between visits, so [they need] someone to call for advice for things like that. That's created that need for a good pharmacist who knows about these interactions, and the nurse practitioner who can advise about [adverse] effects and can call them in between visits.

[We need] a pathologist because we had to develop new techniques to monitor patients—now we have better responses, so we needed to be able to monitor that, and developing and perfecting these techniques was a path that took years. We still need to rely on them, and we continue finding new abnormalities, so we must work closely with them. [We also use] the cardio-oncologist because, with these cardiac issues, we need to make sure that we can manage our patients. Many of them will have cardiac issues, but we must be able to give them their leukemia treatment. We need to do those things safely. [Increasingly], we rely on that multidisciplinary team that can work together and look at these patients and give them the best options long term.

How do you choose a TKI for newly diagnosed patients with CML?

What’s most important to me is an open discussion with my patients. I want to understand more than the medical characteristics of my patient: Do they have comorbidities or diabetes, and have they had a heart attack? But also, what are their goals? Do they want to live longer? Do they want to aim for a better chance of stopping therapy at some point? Do they want to have the least risk of [adverse] effects? What are the financial considerations for them, depending on insurance coverage and things like that? I must understand all of that, holistically, to be able to select what may be best to fit those goals that the patient has. That's the advantage of having options.

[What’s important for] 1 patient, I could probably achieve with drug A, whereas for other patients, I need to use drug B because that gets me closer to their goals or gives me the best probability of getting closer to that goal. [If there’s a] patient who wants to stop therapy and have a better quality of life, I want to go with the drug that gives me the best chance for that. This takes a deep conversation with the patient. My job is to explain what I know about the disease, the pros and cons of each drug and the possibilities that exist in terms of outcomes and guide them through that decision.

What factors help you choose which TKI to give?

Increasingly, patients want to have an opportunity to stop therapy. Right now, the drug that gives us the best chance of that is asciminib [Scemblix] because it gives us a higher rate of responses and deeper responses early on. It also has the best tolerability so far. [It’s usable] in terms of somebody who wants [good] quality-of-life and so on.

There are patients who may have a high risk of arterial occlusive events, and the drug that has the lowest risk for that is imatinib—in those instances, that may be a special consideration. We hate to think about financial considerations driving decisions, but sometimes that is a consideration, and imatinib, because it's generic and is the lower cost, would be the choice. Fortunately, imatinib is a good drug. We are fortunate in CML that we do not have good drugs and bad drugs…. If I have to treat somebody with imatinib, I am comfortable with that. It can give good outcomes. In many instances, I prefer to use other drugs, but even when I must use imatinib for some of these considerations, I feel comfortable.

What do you envision as the next breakthrough in CML care? Are we getting closer to a curative approach?

The 2 main break points that will come, we are most intensively looking for in research. Number 1 [is that] we can stop therapy effectively in some patients, but it's only in a subset. Grossly, about 25% to 30% of patients can effectively stop therapy and never have to resume therapy. Some years ago, we thought that was not a possibility. Twenty years ago, we did not think that was even a choice, so 25% to 30% compared with that is great, but we would like to have that for the majority of patients. Whatever gives us [the best chance] of at least doubling that is the next breakthrough. The other breakthrough that we need is that there are some patients who have other genetic abnormalities that we didn't know about 5 or 6 years ago. Now, 20% of patients have other genetic abnormalities, and those patients do not do as well. Finding what works in that subset of patients, which are the most complex right now, would be a breakthrough that we need, and it will come.

In terms of whether we are getting closer to a cure, I think we are. We can stop therapy effectively in some patients, which is equivalent to a cure. If [a patient has] done well, and you can stop therapy and the disease doesn't come back, that's essentially what we think about as a cure. We are there, just not on as many patients as we want.

References

Center for Drug Evaluation and Research: Application Number: NDA 21-335. FDA. May 10, 2001. Accessed August 27, 2025. https://tinyurl.com/44xh2u9j