CML Paradigm Transforms With New Treatments, Potential for TKI Discontinuation

Jorge E. Cortes, MD, associate professor of oncology and urology at Johns Hopkins Medicine

Jorge E. Cortes, MD

The second-generation TKIs dasatinib (Sprycel), nilotinib (Tasigna), and bosutinib (Bosulif), along with the emerging potential for TKI discontinuation, have transformed the treatment paradigm for chronic myeloid leukemia (CML), said Jorge Cortes, MD.

Researchers are now seeking to enhance patient responses through combinations, such as a regimen combining the BCL-2 inhibitor venetoclax (Venclexta) with a second-generation TKI.

In an interview with OncLive, Cortes, deputy chair of the Department of Leukemia in the Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center, discussed frontline advances, discontinuation, and remaining challenges in the CML paradigm.

OncLive: What new frontline therapies have come out recently and how are they improving?

Cortes: The most recent change was the approval of bosutinib, another second-generation [TKI], as frontline therapy. Now we have 3 second-generation TKIs for frontline and imatinib. So, 4 approved [TKIs] for frontline therapy. I think the bulk of the data, if you put all the second-generation data together, they all look consistent with that benefit compared to imatinib. There are some differences which are difficult to reconcile considering that these are similar but not identical studies from one drug to the other, but I do think that it is fair to say that these have become standard.

One of the important things that is emerging now is, for dasatinib in particular, the use of lower doses. It's no surprise that the initial results that have emerged from our institution are positive when we consider that with both nilotinib and bosutinib, the dose that we use for frontline is lower than the dose that we use for salvage, so sure enough, that's proving to be the same with dasatinib.

I think that a lot of the focus now is to see if we should do some interventions early on to try to optimize the number of patients who get to the deepest molecular responses and that would, at some point, be eligible for treatment discontinuation. There are studies adding ruxolitinib [Jakafi] and adding interferon and other agents. Perhaps one of the most exciting ones is adding venetoclax [Venclexta] with some good preclinical data, but there's not enough data yet clinically to assess, but they will come soon.

What are the benefits of using second-generation TKIs over first-generation?

There are randomized studies, there's several of them now, and then some sequencing studies independent from the initial studies. They all have confirmed that we have a faster response [with second-generation TKIs]. We get a deeper response. We have fewer transformations and it is more and more important that over time we get more patients with the deepest molecular responses, the MR^4.5 and sustained MR^4.5.

These events, or the frequency of these responses, is not inconsequential. For example, from the ENESTnd study, which has some of the longest follow-up. We know that, for example, 5 years you get to over 50% of patients with an MR^4.5, whereas with imatinib only about 30% of patients. It's a 20 percentage point difference, which is important. The sustained MR^4.5 goes from 40% to 45% versus 20% with imatinib, so I think that those are the things you need to keep in mind. It doesn't improve survival, or it hasn't so far. I think that if we had enough patients and enough follow-up, we would probably see a small benefit, significant but small. But I think we're beyond that now. We've established that other endpoints are important and I think that’s the type of consideration that you, at the very least, have to discuss with the patient—what you're getting with one drug versus the other.

What are some challenges that are still unmet in the CML space?

I think that I mentioned briefly the challenge of these 2 or 3 occlusive events and these are events that happen with all these drugs, particularly the second- and the third-generation drugs. More with ponatinib [Iclusig] perhaps, but it also happens with nilotinib and dasatinib. Maybe a little bit less with bosutinib and certainly much less with imatinib. It's a challenge because it has to do with the comorbidities that patients have, but a lot of our patients have comorbidities. Some are diabetic, some have hypertension, some smoke. We need to learn more about how to manage these patients so that we give them the benefit of the drugs to try to minimize the risks, because we don't understand the mechanism and we cannot prevent it. I think that's still a big challenge.

The other one that's big is the treatment discontinuation. It's become a reality, no question, and it's a big thing for the patients, but unfortunately today it benefits only about 20% to 25% of the patients because not everybody gets to have the criteria of sustained deep molecular responses, which in my opinion has to be a sustained MR^4.5 for at least 2 years, and ideally 5. And then, of those patients who meet the criteria, about half of them will relapse. So, it is great, but it is not a reality for most patients, so how can we improve [that rate]? How can we make more patients eligible and how can we decrease the relapse rate? Either one of those 2 would help us improve the overall impact of this approach, but ideally, we would like to address both. Some combination studies may help us with that hopefully, but we'll have to wait for some data because right now we do have some leads pre-clinically, some early data in the clinic, but nothing definitive yet. I think that's an important challenge for the future.

What do you see coming in the future for CML treatment?

I think that the future is still bright for CML. I think that there are some interesting new drugs coming along. Asciminib seems to be a very potent, active drug that'll be very helpful. I think it is important that we haven't addressed much in more advanced stages, blast phase, etc. I think it is important that we continue treating our patients in the best possible way, meaning good monitoring, good management, and that we can continue addressing those unmet needs with clinical trials.