David Snyder, MD, FACP: Thank you. Obviously, CML is the major diagnosis for transplant in the pre-TKI era, and that has changed dramatically. What I would say is, I would encourage physicians to make the referral to the transplant center with that first failure, first breakthrough in resistance. Not that you’re going to go to the transplant, but I think it’s a time to: number 1, look at donor options available for the patient. Number 2, to talk to that patient about the alternative options that are available. And I said it doesn’t mean they’re necessarily going to need the transplant. Even with the T315I, if you switch to ponatinib and they’re doing very well and they’ve gotten a good response, they may have a very good survival.

Javier Pinilla-Ibarz, MD, PhD: Another very important point for when you visit a transplanter is to really increase the adherence because they now have to consider the toxicity of the transplant. So I’m sure they are really encouraged to take the drug for the rest of their life.

Jorge Cortes, MD: I think David was trying to make a different point.

David Snyder, MD, FACP: No, no, but it’s very important. I won’t argue with that.

Javier Pinilla-Ibarz, MD, PhD: I was kidding.

David Snyder, MD, FACP: Clearly, the elephant in the room, the risk of transplant, is graft versus host disease (GVHD), and we haven’t yet gotten to the point where we can accurately predict which patient is destined to get severe GVHD. And when that time comes, it will make our lives much easier.

Javier Pinilla-Ibarz, MD, PhD: No, no. The joke I was making is if you want some patients to really take the drugs, bring them to an allogeneic stem cell transplant doctor.

David Snyder, MD, FACP: I have. I would just say I’ve had patients come to me in the clinic. They’ve requested, they say, ‘Why do I have to keep taking these drugs? Why don’t I just go to transplant?’ I say, ‘I have a patient I’d like you to meet, a patient who’s gotten severe GVHD,’ so it can be sobering.

Harry Erba, MD, PhD: It’s an important part of education because we also talk about our younger physicians who never managed patients in the era of busulfan and interferon, and the toxicities of those therapies. And the same applies obviously to our patients: they’re not aware of the therapies that have been there and the toxicities associated with them, including transplant. So, it is an important part of the education process. The other point I would make that a transplanter could help us with is that poor adherence to therapy is a key reason why patients lose responses or progress. If they aren’t adhering to their ABL TKI, are they going to adhere to tacrolimus, mycophenolate, steroids, all of the antibiotics, and all of the visits? I mean, it’s an important part of the education that we do.

Jorge Cortes, MD: I’m glad David brought up this issue because I think I always remind the patients that transplant has not gone away. The order on how we choose therapies changes based on the data we have. But I also want to remind them because many times they say, ‘I thought a transplant was a treatment of last resort,’ and I want to remind them that if I leave it as a treatment as last resort, then transplant doesn’t work. I want to bring it at the right time. And I agree with you: once a patient starts having particular resistance, intolerance is a different business. But [in the case of] resistance to one TKI and definitely two TKIs, it’s time to at least talk to the transplant doctor, at least see what options do we have for donors, etc. You may or may not decide to do it at that point, but at least let them understand what it means—see what options you have for a donor—and help you decide when is the right time for that particular patient to bring that to actual practice.

Javier, in this topic about changing therapies, of course we have many drugs available now, several approved; it’s a wealth of treatment options. But there are some new ones under development. Can you just give us briefly the discussion of what’s coming that you see interesting?

Javier Pinilla-Ibarz, MD, PhD: I’m always really greatly surprised to see how drug development doesn’t stop in the United States where we have really, really great choices. So, I was very glad to really see the data that I already was aware of, of this new drug, ABL001. It seems like it’s working in a different mechanism from the ones that we are used to. It’s a known APT mimetic, so it is not really working in the classical area where the other TKIs are working. They’re very, very exciting results. However, I’m also interested to really see that mutation may arise in another area of the kinase domain, in this case in the APT binding pocket; so, quite interesting. So, this maybe a drug that in the future may be seen in combination. That is something that seems like will be one of the future uses of these drugs. Just lastly, in Korea, another drug is being developed that we may not really see in the United States. But it seems it’s kind of imatinib-like that has been developed with very, very interesting results; very, very comparable with imatinib.

Jorge Cortes, MD: It’s radotinib, right?

Javier Pinilla-Ibarz, MD, PhD: Radotinib? Sorry, that’s exactly correct. Well, if it is what I see, it’s amazing that we still see these new drugs. We keep discussing about combination therapies in TKIs just to completely eradicate or cure this condition. [It] is kind of a controversial issue because we say that maybe we don’t need that. However, I mean, there is an initiative to combining the JAK2 inhibitor, ruxolitinib, and many other drugs have been tested already; Interferon has had some news in the past. The Germans have presented some other data. So we may see these, but I have to really admit that it’s going to be quite challenging because our patients are doing relatively very well. And to really enroll them in trials where they have another drug on top of the one is going to be a tough, tough future.

Jorge Cortes, MD: Yeah. I see two areas where perhaps combinations may have a role, although there are the challenges that you describe. One is in the advanced stages of the disease, particularly in the last phase where we know TKIs work—but by themselves, very short remission durations—so we combine them with chemotherapy and hypomethylating agents and other things. I don’t think we still quite have the best combination, but that’s one area combinations is really actually what we do, even sometimes just ad hoc. The other one is to pursue these sustained durable remissions because we talked about the treatment discontinuation. But the reality is that the percentage of patients that reach these sustained MR 4.5s, even with second-generation TKIs, is at best 40%, 50%. So, there’s still a significant number of patients who don’t quite make it to those criteria for treatment discontinuation, and that’s where there’s an interest in can we do something else to push them to that level. Now, there are the challenges that you describe that adding another drug increases the toxicity, even if it’s just for administration for a few years. So, not easy, but an area of research.

Javier Pinilla-Ibarz, MD, PhD: I just will add this group of patients who have been in this discontinuation trial in the last years who failed [the] discontinuation trial. Maybe it’s another area, because in the past, every time that we used to combine drugs, we never knew what will be the outcome after discontinuation that happened without any additional drug. And now we may really answer this question in patients who fail this discontinuation trial.

Jorge Cortes, MD: One interesting approach that’s happening there and perhaps many of you are working on this in some of these clinical trials, is with these checkpoint inhibitors, ipilimumab and the like, which is very attractive.

Javier Pinilla-Ibarz, MD, PhD: Very attractive and has good data.

Jorge Cortes, MD: But very early.

David Snyder, MD, FACP: I think there’s a signal. I’m trying to understand why and when people are successful at discontinuation. Interferon certainly has immune modulatory effects. And, to me, frankly, if I can express my belief, that the depth of response and talking about digital PCR, MR 5, MR 5.5, I don’t think that’s the key. To me, it’s what is the host immune response doing, and I think that’s going to be the success. And if we have a strategy to boost that immune response, whether it’s the checkpoint inhibitors, interferon, whatever, to me, that’s the direction to go, recognizing that you’re adding toxicity potentially with a second drug.

Transcript Edited for Clarity