Emerging Developments in CML

Kendra Sweet, MD

Appropriate and effective first-line therapies for patients with newly diagnosed chronic myeloid leukemia (CML) are currently under investigation. Groundbreaking clinical trials involving tyrosine kinase inhibitors (TKIs), such as imatinib (Gleevec), dasatinib (Sprycel), and nilotinib (Tasigna), show promising results in the treatment of patients with CML, explains Kendra Sweet, MD.

The common practice has been to keep a patient on TKI therapy indefinitely, but according to Sweet, an assistant member in the Department of Malignant Hematology at Moffitt Cancer Center, TKI discontinuation has been achieved and continues to be studied. In order to increase the potential for treatment discontinuation, a new combination therapy approach might need to be taken—something that Sweet says is currently being explored.

Once therapy is administered, it becomes necessary to monitor the patient on a continual basis to ensure long-term favorable outcomes. “Now that discontinuation is a real possibility for patients, [continual] monitoring becomes even more important because we want to maximize the chance that someone can actually get to that point and have that opportunity,” Sweet said in an interview with OncLive^®.

OncLive: Can you give an overview of the main points discussed in your presentation?

During the 2017 OncLive^® State of the Science Summit^TM on Hematologic Malignancies, Sweet discussed the various factors that must be taken into account when prescribing first-line therapies to patients with CML, the novel studies that are paving the way for improved outcomes in patients, and the increasing likelihood for TKI discontinuation on the horizon.Sweet: One of the main points I brought up in my presentation was selection of firstline therapy for a newly diagnosed patient with CML. What are the factors that need to be considered when making the decision on how to appropriately treat someone in the upfront setting? We’re looking at things like risks scores, comorbidities, and longterm goals, and then analyzing the data from all frontline studies to make a decision about how to best treat those patients.

Another key point was the need for frequent monitoring in CML—not just starting someone on therapy and hoping for the best. Monitoring according to the guidelines is necessary because there are certain milestones that need to happen or be achieved in order to ensure long-term outcomes are favorable for these patients.

What pivotal studies have led to the basis for what you use for frontline treatment?

Finally, the new term, “TKI discontinuation,” suggests that there is a subset of patients who are likely to do very well when they have achieved a deep molecular response and we stop therapy.The 3 studies, which I showed today, were the IRIS trial, the DASISION trial, and the ENESTnd trial. IRIS was a phase III study of imatinib versus the prior standard of care, which was interferon and cytarabine. We now have long-term data from that study, that was published a couple of months ago with 10-year follow-up, which shows remarkable improvements in long-term survival in chronic-case patients with CML compared with the pre-imatinib era looking at toxicities and things along those lines.

Overall, what are some really exciting things on the horizon in CML?

The DASISION trial was a study looking at dasatinib, which is a second-generation TKI, compared with imatinib in the frontline setting. The ENESTnd trial was the phase III study of nilotinib versus imatinib upfront. The data I showed compared cytogenetic and molecular responses early on and then, over a 5 year follow- up period, and looked at rates of progression to advanced phase CML and all of those studies.TKI discontinuation becoming more of a mainstream option is extremely exciting because we’ve had a wealth of discontinuation studies that have been published over the past 5 to 8 years with data that are all very similar. Regardless of the TKI being looked at, or if it’s all TKIs that are being looked at, it all looks pretty similar; about 50% of people can stop treatment and stay off treatment long term. Even if there is some reemergence of molecular disease, a lot of the time it just stays at a very low level and the leukemia lies dormant. It’s really exciting that that’s now become part of the mainstream guidelines for management of CML.

What are some of those novel therapies? Also, could immunotherapy ever be studied in CML?

A lot of people are interested in trying to understand the difference between patients who successfully discontinue TKIs and those who relapse. There are lot of people looking into that information and trying to get an answer to that question. Some of us are trying to design trials with additional treatment or other types of therapies added to a TKI—particularly in people who have attempted discontinuation and relapsed. We would add in a second therapy for a set period of time and then try to discontinue again to see if that can increase the chances of success.There are some studies looking at PD-1 inhibitors and PD-L1 inhibitors in CML. They are on the horizon. Again, there are some studies looking at people who have discontinued and relapsed, added in a PD-1 inhibitor for a specified period of time, and then tried again.

What points do you hope community oncologists took away from your presentation?

Another drug that is being looked at seriously in CML is ruxolitinib (Jakafi), which is a JAK2 inhibitor. The study is looking at altering that JAK/STAT pathway, which has some effect on the bone marrow microenvironment. There are a lot of preclinical data suggesting that by inhibiting the JAK/STAT pathway, we are able to sensitize the leukemic stem cells to TKIs and, hopefully eradicate minimal residual disease. Those are 2 key areas that are being studied right now.You need to look at all of these factors—age, long-term goals, risk of progression, and comorbidities—together to make a good decision about how best to start your patient on therapy when they are newly diagnosed. I want to drive home the point that frequent monitoring to ensure that patients are meeting those early milestones is absolutely essential to ensuring good outcomes for these patients.

Now that discontinuation is a real possibility for patients, the monitoring becomes even more important because we want to maximize the chance that someone can actually have that opportunity. We need to be watching them closely to make sure we are heading in that direction if that’s something we want to consider down the line.