TFR With Nilotinib in CML: ENESTfreedom and ENESTop

Transcript:

Harry P. Erba, MD: So, I would like to spend some time talking about nilotinib and the treatment-free remission studies that are now incorporated in the nilotinib label, and that’s the ENESTfreedom and ENESTop because there were very specific requirements in those studies for getting on and how you monitor those patients. I’ll just start by saying these patients were monitored, as we talked about, on an assay that could detect down to MR4.5. It happened to be the MolecularMD assay, but that’s very important. And patients had to be in a definite response—which I’ll define in a second—before and had to be followed afterwards on the same assay. So, making sure patients are being monitored on one assay that’s that sensitive is very important.

ENESTfreedom was a study looking at stopping patients who initially started on nilotinib, and ENESTop was a study looking at patients who were on second-line nilotinib, either because of intolerance or even resistance. About a third of patients were resistant to imatinib. What they did for both of these studies is patients had to be in chronic phase, they had to be on an ABL TKI for at least 2 years, and then they went on the study. So, we’ll talk about ENESTfreedom. They had to have BCR-ABL transcripts that were amplifiable and can be measured, quantitated, and they needed to demonstrate that they were in a deep response for 1 year prior to stopping. So, basically, when they went into the treatment-free remission, they had been on therapy for 3 years and in the last year during what was called the consolidation phase, they were monitored every 12 weeks; very strict criteria. The last assessment had to be an MR4.5. They could not have more than 2 assessments between 4.0 and 4.5.

Now, with those strict criteria, only 88% of the patients who were interested actually got to the treatment-free remission. And what was found was—and I like to round numbers—roughly 50% of patients at the endpoint of the study, 48 weeks, and then 96 weeks, and most recently, 144 weeks, have remained in a treatment-free remission, meaning that they have not lost MMR. That was the definition. I agree with your point. The longer that we’ve waited, that curve came down very quickly to just above 50%, but with each assessment, just a few more patients are falling off. And with Jerry Radich’s publication of the 144-week data, it was shown that there are some predictors. The patient who blipped up more than once above 4.5, less likely to maintain a response. The high-risk patients, less likely to maintain a response. But the important part of this is that of the 50% of patients who relapsed, about 88 patients in 1 analysis, all of them got back in an MMR. The median time to that was 7 weeks, and most of them got back into an MR4.5, and none of them progressed.

In the ENESTop study, very similar that they had to be on an ABL TKI for 3 years and at least 1 year of that imatinib and then they switched because of intolerance or resistance. Same criteria to get in the study, but much more stringent consolidation phase where during that nilotinib period, they had to, for 1 year, maintain an MR4.5 every single quarter, every single assessment every 12 weeks or else they couldn’t go on. And so, with those stricter criteria, only 77% patients went into the treatment-free remission but remarkably similar results with a little bit over 50% of patients maintaining a treatment-free remission. And I believe Dr. Mahon updated the 2-year update of that now at this ASCO meeting.

So, I think the package insert at least gives a practicing clinician one place to go that will have very clear criteria on how you identify the patient who may be eligible for a treatment-free remission and how you closely monitor these patients. Once they go off daily oral therapy and monitoring, they are monitored every 4 weeks by CBC and PCR in the first year, every 6 weeks in the second year, and every 12 weeks 3 years and after. And that’s the same in the NCCN guidelines for monitoring. So, both studies show that we could do it without losing patients, at least so far to accelerated phase or blast crisis. The one toxicity that I think we need to talk about, and maybe Jorge, I’ll turn to you, is one thing that’s come from all these discontinuation studies, which is the signal of increased musculoskeletal adverse events with that. Do we understand why and what’s that all about?

Jorge E. Cortes, MD: Yes, that’s an interesting phenomenon. We’ve termed this withdrawal syndrome, and patients do get some symptoms, most frequently, as you mentioned, musculoskeletal aches and pains. Other things, fatigue and sometimes fevers, have been reported and other symptoms, usually constitutional symptoms, of that nature. We don’t understand how this works, but I think it is important that we discuss this with patients, so that they understand that this may happen. Importantly, it happens probably in about a third of the patients, maybe a little bit less than that. But, importantly, it’s usually mild. It’s something that many times doesn’t even need an intervention but occasionally does, and a nonsteroidal anti-inflammatory agent, that kind of intervention is enough for the majority of patients.

There are a few that are grade 3 or 4, and there are the few extreme instances. I have 2 patients of mine who just had to resume therapy again because of that. But those are by far the exception. I think with proper monitoring and again, educating the patient before they stop so they know that these things happen, to call you so that you can manage them, then we can manage these symptoms. We still need to do a lot of work on knowing why because it’s interesting. Why? You were not born with the TKI, yet when you stop it, your body kind of misses it in some ways.

Harry P. Erba, MD: And it does tend to get better though with time.

Jorge E. Cortes, MD: It gets better over time. That’s why some patients don’t need treatment because there are little aches and pains and then it goes away.

Transcript Edited for Clarity