Harry P. Erba, MD: So, in terms of very specific guidelines on what to do when the patient is in a treatment-free remission and relapses, the first important thing is, as I said, they’re being monitored with an assay that has a level of sensitivity down to MR4.5. For those of you who don’t talk log anymore, we haven’t said it yet, that’s a BCR-ABL to ABL ratio of 0.0032% or lower. And what the patient should have done is… I said how often they’re monitored. If they lose an MMR at any point—1 determination—you start them right back on nilotinib at their prior dose and you monitor them closely. And, if they’re not achieving an MMR again, I would say within 3 months, definitely do mutational analysis. If they’re on second-line nilotinib or an ABL TKI, maybe being a little bit more careful, and if they lose an MR4.0—2 determinations confirmed—you should start them back on an ABL TKI and, again, monitor them very closely. But as long as a patient remains on an MMR, you can continue them in a treatment-free remission because that’s the level at which we feel people are prevented from progressing to blast crisis. Mike, do you want to talk then about what are our unmet challenges and needs in treating CML and maybe this issue?

Michael Mauro, MD: I think you just hit one, which is the re-treatment success. Prompt re-treatment with the same TKIs tends to work, which is a real boon because I think many people were concerned that we would have to change things up on the advent of a failed TFR. But probably the biggest issue is that across all these studies, it’s a 50/50 shot basically. We love to say it’s 70%, 80%, 90%. So, with the increased prevalence of CML we talked about a while ago and this journey, the fact that this is our goal but still 50% of people miss, what can we do to try again? Now, there are some data out there, just simply restarting the TKI, waiting an appropriate amount of time. Maybe we’re just a bit premature. I think there’s mixed feelings on how successful that is, it’s probably lower, of course, than the first trial. It may be quite a bit lower, maybe just a bit lower.

But I think there’s a lot of ideas out there. What’s going on? Maybe we need to change the quality of the remission. Most ideas are thinking about adding something to the backbone of that stable patient again who’s back on their TKI, probably back in deep remission, to deepen it a bit more, hit another pathway. Examples include ruxolitinib. Maybe ABL001 can be incorporated into this picture, I think, with the promise of that drug and a number of other ideas. So, second TFR is probably the next horizon, I think, because we’ve got to help that unmet 50% who can’t hit it the first time.

Harry P. Erba, MD: Yes. In fact, in both the ENESTfreedom and the ENESTop studies during that consolidation phase, as I mentioned, some patients were not eligible for TFR and so they had to continue on. But when they were still followed and later on when they achieved those things, they then stopped the nilotinib in that study. It was a very small number, but it was a similar number of patients who were able to maintain that treatment-free remission and not lose a major molecular response. Well, this has been a great discussion. Before we conclude, I’d like to ask each of our panelists to provide a takeaway from this program. So, I’m going to start with you, Jorge.

Jorge E. Cortes, MD: My takeaway is going to be about TFR because I think it is something that has become very real. I think we never thought we would be at this point, and some of us may have been actually skeptical even when we started hearing about these points. But it is real. It is here and I think we need to help our patients get to that point. We talked about the fact of the education to the patient from the beginning, their responsibilities, but our responsibilities as well to try to optimize the chances of the patient getting to that point. And one thing that I wanted to emphasize—we frequently talk about—that’s the clinical trials, but what about the real world? This is the real world.

The 2 studies, the ENESTfreedom and the ENESTop, these patients started on treatment before they got into those studies. They were already on treatment. They were part of the real world. The key difference here is that when they got to the trial, they were monitored very closely, and they were managed very properly. So, I think this can be done and can be done safely, but we have to manage them as if they were in clinical trials, which is essentially what the NCCN guidelines and the ELN guidelines tell you: do it this way.

Now, if we’re not going to do it, sure, we’re going to lose some responses, we’re going to miss them. And then we’re going to say, “Oh no, they do transform to blast phase and whatever.” Well, yes, if we’re not looking, that’s going to happen. So, this is the real world. These studies have been done in the real world. Many of them have been observational. We just need to make sure that we do it safely for our patients. We don’t want to transform something that was very, very good, a good response into a very bad situation for our patients because we’re not looking, we’re not doing our job.

Harry P. Erba, MD: Yes, I agree with you. I think this TFR data, all of these multiple studies, the length of follow-up we have, sure, it’s not decades, but it’s long enough for us to say, “I think it’s reasonable under certain conditions, close monitoring, to attempt this after you discuss it with patients.” And they may consider it because of conception issues, short-term, low-grade toxicities, the concern of long-term toxicities and financial issues, which, by the way, that would be my point about TFR. And you mentioned this earlier at the beginning. The prevalence of this disease is going up. And, of course, we all know that imatinib is generic and some day that will translate into a lower cost for society and maybe even our patients. But if you think at a global level, and I am not a healthcare economist, but maybe we should start thinking about starting with second-generation drugs, not just because of preventing progression, not just because of those early MMRs, but really because of getting patients to a point where they may attempt a treatment-free remission. And if we could get patients off of these drugs with the prevalence of the disease going up, would that be more of a cost savings for the entire population than thinking about which ABL TKI we can get the best deal for? Mike?

Michael Mauro, MD: I’ll take Jorge’s ball downfield a little bit and say that we have to pay attention to how we treat our patients. This is such a good story, such good success that missing small things, having the monitoring trail off a little bit, not really being engaged with adherence. The cardiovascular risk stratification, these are not hard things to do and it probably can make a real difference for patients. So, as a community, we owe ourselves to watch programs like ours, like this here, work with our sponsors that can sometimes help get molecular assays, can really provide good education materials, and just make sure we do the best for our patients because it fortunately is a very good story and a disease we could treat really well. We just have to be meticulous.

Harry P. Erba, MD: I agree. Well, thank you all for your contributions to this discussion. On behalf of our panel, we thank you for joining us and we hope you found this Peer Exchange^® discussion to be useful and informative. Thank you.

Transcript Edited for Clarity