Cessation of TKI Treatment in Patients with CML May be Beneficial, Says Expert

Johan Richter, MD, PhD

Johan Richter, MD, PhD

Two-thirds of patients with chronic myeloid leukemia (CML) who ceased to receive the TKI treatment imatinib (Gleevec) did not relapse after six months.

In an interview withTargeted Oncology, Johan Richter, MD, PhD, physician, Skåne University Hospital, discusses the results of the multicenter, open label, uncontrolled EURO-SKI trial, which examined over 800 patients with CML who ceased to receive a TKI therapy after a certain amount of time.

TARGETED ONCOLOGY:Can you give an overview of the EURO-SKI trial?

Richter:

It's a trial about stopping tyrosine kinase inhibitors in patients with CML who have been on treatment for at least 3 years and who reached a certain depth of molecular response to that treatment. That depth of response should be MR4. In reality, we see a heterogeneous group of patents in here. Some have been treated for almost 15 or 20 years, and then there's a range down to the inclusion criteria of 3 years.

Also, we see different responses, and this is one of the good things about the trial. It's the largest trial ever performed, and I don't think there will be any bigger cessation trial in CML with more than 800 patients included. This gives us the possibility to do separate analyses and maybe identify prognostic factors that can help to identify what patients can stop therapy and which ones should continue.

TARGETED ONCOLOGY:What are some of the key takeaways from this study?

Richter:

I think if we are considering moving this concept to the clinical everyday situations, there are certain prerequisites that need to be filled. It’s important to know the transcript type and to have a good lab that can monitor this and express it on an international scale. It’s also important to keep a close rapport with patients, to talk to them continuously, and to inform them and monitor them in a proper way.

These are key components, and what we know here is that we have identified a cutoff. So, if a patient is treated with imatinib (almost 94% of patients on this trial were on first-line imatinib), we identified a cutoff of about 6 years. If, after 6 years of treatment, patients are taken off of therapy, about two-thirds of them can do that successfully and, in our analysis, they did not relapse by the sixth month time point after stopping. That was the primary analysis time point.

TARGETED ONCOLOGY:You mentioned identifying prognosis factors. Where are we at right now in terms of doing that?

Richter:

We looked at a number of factors that have been examined in other trials as well. It doesn't seem that the so-called "risk score" matters in our trial, nor do age and gender. Also, when we looked at the depth of response, whether a patient was an MR4 or MR4.5, it didn't seem to matter. That's two factors so far that have come out, and then there’s duration of therapy of 6 years that I mentioned, and also the duration of MR4 prior to stopping. This refers to how long a patient has had a deep response.

The problematic thing here in terms of analysis is that there's a co-variation that these two are linked—the time that patients have been treated and the time they have been an MR4. We need further analysis in order to also identify an optimal cutoff for MR4, so we have not been able to go out with that yet.

Then there are further analyses that are trying to identify the factors, and there are sub-studies being performed. I would like to mention that one is looking at the natural killer (NK) cell count, which seems to be of some influence in terms of when it can be successfully stopped or not. That's being done in a sub-study to EURO-SKI.

TARGETED ONCOLOGY:How long were these patients followed, and how long do you think they would need to be followed to get a clear picture?

Richter:

So far, there is a variation of follow-up. This trial is still ongoing. Patients were included from mid-2012 to December 2014, so that's a good variation. Some patients have left the study after 3 years. We plan to follow these patients further on, and I think that's very important. In this context, I would like to mention that the original sub-study, the French STIM study, is now being updated on their cohort, which had many patients stop in 2007 and 2008. So they have a longer follow-up. Of course, it will be important for any type of trial like this to have a long follow-up to see if there are late relapses or not.

We saw relapses as late as 33 or 34 months. That means that if one does stop TKI therapy in a patient, that patient should be continuously followed for any relapse. The interval of monitoring also needs to be stricter. First, monitoring should happen every month, then every six weeks in the second half of that year. In the EURO-SKI trial, we followed them every 3 months. That might need to be a bit tighter, if they seem to have some sort of detectable disease. This needs to be adjusted on a patient-to-patient basis.

TARGETED ONCOLOGY:If they do relapse, are they to be put back on a TKI inhibitor?

Richter:

So far in EURO-SKI and in all the other trials, relapsing patients have been put back on TKI therapy. In most of the cases, it's been the same therapy that they were on prior to stopping. In some cases, there has been a shift to another therapy, but I think all patients so far, more or less, have responded to therapy again. That's an important and reassuring piece of information. What we haven't seen in the EURO-SKI trial is any progression to more advanced disease, or any CML-related deaths on trial.

TARGETED ONCOLOGY:What is the biggest advantage of stopping TKI therapy?

Richter:

Stopping therapy means that it does not need to be life-long. If a patient had side effects throughout therapy, they may be able to be eliminated, hopefully. There's also the health economy issue, where these have been costly drugs. Even now, if we move into generic imatinib in the next year or so, that will reduce the price, but it's still a costly medication. So it will have an impact on health economy.