Exciting Advances Are Coming for First-line CML Treatment

Kendra Sweet, MD

Promising treatment options are in the pipeline for patients with newly diagnosed chronic myeloid leukemia (CML), as groundbreaking trials are highlighting the potential of tyrosine kinase inhibitors (TKIs), such as Gleevec (imatinib), Sprycel (dasatinib) and Tasigna (nilotinib), explains Kendra Sweet, M.D.

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 CURE.

Can you give an overview of some of the main points in CML advances?

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.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 long-term 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 mile stones 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 three studies, which I showed today, were the IRIS trial, the DASISION trial and the ENESTnd trial. IRIS was a phase 3 study of Gleevec 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-Gleevec era looking at toxicities and things along those lines.

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

The DASISION trial was a study looking at Sprycel, which is a second-generation TKI, compared with Gleevec in the frontline setting. The ENESTnd trial was the phase 3 study of Tasigna versus Gleevec upfront. The data I showed compared cytogenetic and molecular responses early on and then, over a five-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 five to eight 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 percent 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.

Another drug that is being looked at seriously in CML is Jakafi (ruxolitinib), 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 two key areas that are being studied right now.