Management of Primary Refractory AML

Transcript:Ruben A. Mesa, MD, FACP: We’ve talked about induction. We’re talking about consolidation. But clearly we know many patients can have a more difficult course and have more difficult disease. First, let’s tackle those with primary refractory AML, a particularly challenging group, but in terms of a nonclinical trial setting. Of course, if there’s any group that really needs a clinical trial, I would argue it’s certainly this very refractory group. It’s very stubborn. I know sometimes we’ve struggled, as well. Even people who failed studies: do we transplant them in aplasia? What have been some of the approaches that your centers have taken with this most difficult group?

Elias Jabbour, MD: You know, Ruben, as you mentioned, the refractory patients have very poor prognosis. In fact, we published a couple of years ago that patients who fail high-dose ara-C induction, their median survival is only three months. So, it’s really horrible.

That being said, if you have a clinical trial, that would be great. What we do at my institution is we look for a donor immediately. So, whenever somebody is coming in with AML, before we induce them, we have a donor. If they have a sibling, we have a donor. If not, now with the new techniques of transplant, haplo transplant seems to be really good and gaining momentum. So, if you have somebody with refractory AML, we think the only way to save them is transplantation. It can give you a survival at two years of 25% instead of three months.

Therefore, I have somebody who is young, well, fit, gets high-dose ara-C, and failed. My plan is to give them very suppressive chemotherapy. Like at Anderson, we use clofarabine/idarubicin/ara-C plus decitabine priming, and then we do not wait until they recover. I get day-21 bone marrow. If they are plus or low, which hopefully most will be, I will go for transplant. If they have a sibling, it’s a sibling; if not, a haplo. Any donor available, go for transplant and hope for the best because if you leave them otherwise, they’re going to die. If you have good trials, by all means do that.

Ruben A. Mesa, MD, FACP: That’s very helpful. Now, what about the relapse patient, a slightly different scenario. The patient had achieved their CR; they had their consolidation. They were happy that the disease was in remission, but now it’s relapsed. So, what are your different thoughts around that relapsed patient, both in terms of time from the prior therapy as well as other factors in terms of determining what to do next? Rami?

Rami S. Komrokji, MD: I think you mentioned the key point, Ruben, that basically the time of relapse is one of the most important points. Like some would include that a relapse within the first six months is really refractory AML. And what the studies have shown is that the most predictable factor for a second remission is really the duration of first remission. So for those patients that their disease relapses after a year or two years, I think we have a really decent chance to get the patients back into remission.

Sometimes if somebody relapses after a year or two, you could go back to the 3+7 regimen itself. The patients that relapse earlier are really the challenging ones, and they almost could be like a refractory group. So it depends, obviously, even in that setting at the time of the relapse. The idea in those patients is to try to achieve a second remission, if possible, and take them to allogeneic stem cell transplant. And I think that’s challenging, and that’s always back and forth between us and our colleagues and transplant. They want patients to be in complete response, whereas Eli mentioned, sometimes an approach is, maybe you can take those patients at their nadir.

I think you published nicely in patients that transform from MPN to AML, those patients are almost impossible to get to complete remission. I think you showed that the best outcome for those patients was to go at that time—but that’s always a challenge. So, when they relapse early, obviously if there’s a clinical trial, we try to go for that. If not, I don’t think there is a standard relapse regimen for AML. I think every institution uses a combination, whether it’s MAC [standard dose ara-c + mitoxantrone], FLAG [fludarabine + high-dose ara-c + G-CSF], or CLAG [cladaribine + ara-c + G-CSF]. They’ve never been compared head-to-head, but the idea is to try to get patients into second remission and take them to transplant. In the early relapses, the chances of that are really small. So there is definitely an unmet need to improve that.

Ruben A. Mesa, MD, FACP: Now, Rafael, one scenario in this mix is the patient who is relapsing. Let’s say they have that potential donor. That is an option for them, but now they have 8% blasts, so they’re moving in that direction. And the question always comes up: do we re-induce them? Do we give them some sort of lower-intensity cytoreduction? Or do we take them straight to transplant? Obviously, the concern is, if we undertreat them, then they’ll have a higher risk of relapse on the back-end of the transplant. What are your thoughts trying to decide between those options?

Rafael Bejar MD, PhD: Well, Rami mentioned it earlier. I think the amount of time that you predict the transplant will take to get in place may determine your choice of therapy at that point. If you’re ready to go, and you’ve planned things ahead of time, it may be best to just go—if you think your chance of actually cytoreducing the patient isn’t great. If you know it’s going to be a while before that transplant is in place, I think it does make sense to try to cytoreduce them. Now, whether that actually helps, I don’t know that it’s entirely proven. We know that if patients can achieve a deeper remission or clear their blasts, they’re likely to do better. But that just may be identifying those patients that are likely to do better regardless. So, I’m not sure that you’re obligated to treat right at that moment if you’re ready to go to transplant.

Ruben A. Mesa, MD, FACP: Elias, what would be the approach, particularly with that delicate piece? You guys clearly must see a bunch of these folks back in that sort of same scenario? Cytoreduction before transplant, or not? What do you think?

Elias Jabbour, MD: You know, as Rafael mentioned, if I have donor, really I may go for transplant and use my maintenance program afterward. But most of the time, we don’t have transplant happening. As Rami mentioned, in my institution where we do a lot of transplants, it won’t happen before six weeks, sometimes three months. And that will be an opportunity to treat somebody. I may not go for intensive chemotherapy. I like to go for something like what I discussed—maybe some innovative approaches, like ABT-199 [venetoclax], cytoreduce them, and go for transplantation whenever they’re ready.

Transcript Edited for Clarity