Select Topic:
Browse by Series:

Maintenance Therapy for AML

Panelists: Naval G. Daver, MD, The University of Texas MD Anderson Cancer Center; Harry Erba, MD, PhD, Duke University; Mark J. Levis, MD, PhD, Sidney Kimmel Comprehensive Cancer Center; Alexander Perl, MD, Abramson Cancer Center, University of Pennsylvania; Raajit K. Rampal, MD, PhD Memorial Sloan Kettering Cancer Center
Published: Monday, Feb 04, 2019



Transcript: 

Harry Erba, MD, PhD: So we’re really running out of time on this section, but I do want to discuss 1 important abstract: maintenance therapy in AML [acute myeloid leukemia]. Basically, in no area of AML have we shown definitively that a maintenance therapy has improved outcomes. Even with the RATIFY trial, the FDA said, “You know, patients weren’t rerandomized, so we don’t really know the impact of maintenance midostaurin in that setting.” Hypomethylating agents. A lot of people do that, but I’m not sure that does anything except make your patient come back month after month for treatment without a real benefit in survival. But there was a very important German study presented, the SORMAIN study, looking at sorafenib for the prevention of relapse after allogeneic transplant for patients with AML with a FLT3 ITD [internal tandem duplication mutation] in remission. Naval, do you want to tell us more about that?

Naval G. Daver, MD: Yes, I think this is very important. As you said, of course, we were initially struggling to keep people alive—elderly patients—and doing new things. And now that we have a lot of tools, how are we going to use maintenance? And FLT3, I think, has been the area that has been the most intense in research. With sorafenib, there have been phase II studies published by a number of groups—Dana-Farber [Cancer Institute]; the Lebanese group. Others show that if you do FLT3 inhibitor, induction, consolidation, and transplant, followed by maintenance—so a total-therapy approach—75%, 80%, 85%, even 3-year survivals. Of course 10 years ago, when we first found out about FLT3, it was 20%. So this was very nice. But there was no randomized experience.

So now the German group, which has done a lot of work with sorafenib, did a study in which they took people who received induction consolidation and had transplant, and then post-transplant the question was maintenance with sorafenib versus just observation, which is what we do traditionally as a surveillance approach. And what they showed was that there was feasibility, because I think there’s a lot of concern and question about whether you can use sorafenib post-maintenance toxicities. And indeed, in most patients, at least in our experience at [The University of Texas] MD Anderson [Cancer Center], we have to reduce the doses. So we have to go to 200, or whatever it may be. But in the end, they said it was feasible for the majority. There were not a lot of discontinuations, and, of course, the most important punch was that they had a very clear survival benefit with that maintenance approach.

So based on that, at least in my opinion, we’ve been doing maintenance anyway, but I think it will continue to be used. And there was another study, the RADIUS study with midostaurin. Smaller numbers, phase II randomized, weren’t as clear. There were trends, and they suggested that it may be beneficial, but I think we need more time. And then there’s a third large study ongoing which I think will be very, very important with gilteritinib as maintenance in the post-transplant setting. And I think all these data will hopefully be consolidated, but, at this time, we routinely do maintenance for these patients.

Harry Erba, MD, PhD: So someone said the gilteritinib and placebo study should be closed based on this SORMAIN data showing a benefit of sorafenib. But I have a feeling that the gentleman to my left may have a strong opinion on this.

Mark J. Levis, MD, PhD: I was fascinated to watch the SORMAIN data, and the feasibility issue comes up. The trial took 6 years to accrue. You and I have given sorafenib. It makes your hands fall off and your feet fall off.

Naval G. Daver, MD: No, no.

Mark J. Levis, MD, PhD: Chronic diarrhea. No, no, of course not. But nonetheless, 6 years to accrue a trial of only 80 patients. This is something feasible? So while I have used sorafenib for many years—and in fact, it was the impetus for investigating post-transplant FLT3 inhibitor therapy—that also was done in a population that has not received induction with midostaurin going into transplant with a deep remission, where you saw the much better outcomes in that patient population. The RADIUS trial, again, was kind of frustrating because really it did not reach statistical significance and didn’t even try.

Alexander Perl, MD: It wasn’t placebo controlled either.

Mark J. Levis, MD, PhD: It wasn’t placebo controlled. It was open to all manner of shenanigans, shall we say, and manipulation. So that’s my objection. In the modern era with the current treatments, what is the best approach post-transplant? And a good randomized trial incorporating MRD [minimal residual disease] to decide who actually needs it. So my patients say to me, “When can I go off my sorafenib? I can’t walk. I’m on oxycodone from pain.” Well, you can’t. I don’t actually have any study that tells me that. But the BMT CTN 1506 study, which is actually half-accrued and will have that information, will tell us who needs it and for how long, using what I think is a vastly better tolerated, superior FLT3 inhibitor compared with sorafenib.

Alexander Perl, MD: So I agree you can also look at things like MRD going into transplant, MRD coming out of transplant, serial monitoring—to answer important questions, like what’s the natural history of that? Because there is actually a placebo arm where we’ll figure that out on an appropriately powered study.

Naval G. Daver, MD: I think this is the same problem that’s going to happen with induction with our FLT3 inhibitors, and we’re going to talk about quizartinib, gilteritinib studies, right? Once you have a drug approved, it is harder, and I actually think in terms of efficacy, in fact, our Fellow presented this more as if there’s no question about it. As a single agent, quizartinib or gilteritinib is 10 times more potent to induce response than sorafenib or midostaurin. We don’t have that data. Our experience is very different. We’ve treated 200-plus people. Sorafenib is tolerable. We haven’t had that severe hand-foot syndrome. But in the end, I don’t think it’s the one that’s going to be used for efficacy reasons. Quizartinib and gilteritinib are more important, we think.

Harry Erba, MD, PhD: So we’re really going to have to move on. But as moderator, I’m going to take the prerogative of having maybe the last comment on this session. First of all, we don’t even know what conveys the benefit of sorafenib or midostaurin, since they target so many kinases. And they target FLT3, and all of this may have more to do with a graft-versus-leukemia effect than anything else. And so just substituting a more potent FLT3 inhibitor actually might miss the target in that population. I agree with your points that it’s going to be a different population of patients coming in. But remember what the German speaker said about the difficulty in enrolling in that trial. Some doctors already felt they knew the answer and didn’t want to put their patient on a placebo-controlled trial. So the challenge the BMT CTN will have is now we have even more evidence that sorafenib is there. Can you put your patient on a placebo-controlled trial? So I agree that the effort needs to be there, but you might be challenged to get the patients now.

Mark J. Levis, MD, PhD: It’s going to be more.

Transcript Edited for Clarity

SELECTED
LANGUAGE
Slider Left
Slider Right


Transcript: 

Harry Erba, MD, PhD: So we’re really running out of time on this section, but I do want to discuss 1 important abstract: maintenance therapy in AML [acute myeloid leukemia]. Basically, in no area of AML have we shown definitively that a maintenance therapy has improved outcomes. Even with the RATIFY trial, the FDA said, “You know, patients weren’t rerandomized, so we don’t really know the impact of maintenance midostaurin in that setting.” Hypomethylating agents. A lot of people do that, but I’m not sure that does anything except make your patient come back month after month for treatment without a real benefit in survival. But there was a very important German study presented, the SORMAIN study, looking at sorafenib for the prevention of relapse after allogeneic transplant for patients with AML with a FLT3 ITD [internal tandem duplication mutation] in remission. Naval, do you want to tell us more about that?

Naval G. Daver, MD: Yes, I think this is very important. As you said, of course, we were initially struggling to keep people alive—elderly patients—and doing new things. And now that we have a lot of tools, how are we going to use maintenance? And FLT3, I think, has been the area that has been the most intense in research. With sorafenib, there have been phase II studies published by a number of groups—Dana-Farber [Cancer Institute]; the Lebanese group. Others show that if you do FLT3 inhibitor, induction, consolidation, and transplant, followed by maintenance—so a total-therapy approach—75%, 80%, 85%, even 3-year survivals. Of course 10 years ago, when we first found out about FLT3, it was 20%. So this was very nice. But there was no randomized experience.

So now the German group, which has done a lot of work with sorafenib, did a study in which they took people who received induction consolidation and had transplant, and then post-transplant the question was maintenance with sorafenib versus just observation, which is what we do traditionally as a surveillance approach. And what they showed was that there was feasibility, because I think there’s a lot of concern and question about whether you can use sorafenib post-maintenance toxicities. And indeed, in most patients, at least in our experience at [The University of Texas] MD Anderson [Cancer Center], we have to reduce the doses. So we have to go to 200, or whatever it may be. But in the end, they said it was feasible for the majority. There were not a lot of discontinuations, and, of course, the most important punch was that they had a very clear survival benefit with that maintenance approach.

So based on that, at least in my opinion, we’ve been doing maintenance anyway, but I think it will continue to be used. And there was another study, the RADIUS study with midostaurin. Smaller numbers, phase II randomized, weren’t as clear. There were trends, and they suggested that it may be beneficial, but I think we need more time. And then there’s a third large study ongoing which I think will be very, very important with gilteritinib as maintenance in the post-transplant setting. And I think all these data will hopefully be consolidated, but, at this time, we routinely do maintenance for these patients.

Harry Erba, MD, PhD: So someone said the gilteritinib and placebo study should be closed based on this SORMAIN data showing a benefit of sorafenib. But I have a feeling that the gentleman to my left may have a strong opinion on this.

Mark J. Levis, MD, PhD: I was fascinated to watch the SORMAIN data, and the feasibility issue comes up. The trial took 6 years to accrue. You and I have given sorafenib. It makes your hands fall off and your feet fall off.

Naval G. Daver, MD: No, no.

Mark J. Levis, MD, PhD: Chronic diarrhea. No, no, of course not. But nonetheless, 6 years to accrue a trial of only 80 patients. This is something feasible? So while I have used sorafenib for many years—and in fact, it was the impetus for investigating post-transplant FLT3 inhibitor therapy—that also was done in a population that has not received induction with midostaurin going into transplant with a deep remission, where you saw the much better outcomes in that patient population. The RADIUS trial, again, was kind of frustrating because really it did not reach statistical significance and didn’t even try.

Alexander Perl, MD: It wasn’t placebo controlled either.

Mark J. Levis, MD, PhD: It wasn’t placebo controlled. It was open to all manner of shenanigans, shall we say, and manipulation. So that’s my objection. In the modern era with the current treatments, what is the best approach post-transplant? And a good randomized trial incorporating MRD [minimal residual disease] to decide who actually needs it. So my patients say to me, “When can I go off my sorafenib? I can’t walk. I’m on oxycodone from pain.” Well, you can’t. I don’t actually have any study that tells me that. But the BMT CTN 1506 study, which is actually half-accrued and will have that information, will tell us who needs it and for how long, using what I think is a vastly better tolerated, superior FLT3 inhibitor compared with sorafenib.

Alexander Perl, MD: So I agree you can also look at things like MRD going into transplant, MRD coming out of transplant, serial monitoring—to answer important questions, like what’s the natural history of that? Because there is actually a placebo arm where we’ll figure that out on an appropriately powered study.

Naval G. Daver, MD: I think this is the same problem that’s going to happen with induction with our FLT3 inhibitors, and we’re going to talk about quizartinib, gilteritinib studies, right? Once you have a drug approved, it is harder, and I actually think in terms of efficacy, in fact, our Fellow presented this more as if there’s no question about it. As a single agent, quizartinib or gilteritinib is 10 times more potent to induce response than sorafenib or midostaurin. We don’t have that data. Our experience is very different. We’ve treated 200-plus people. Sorafenib is tolerable. We haven’t had that severe hand-foot syndrome. But in the end, I don’t think it’s the one that’s going to be used for efficacy reasons. Quizartinib and gilteritinib are more important, we think.

Harry Erba, MD, PhD: So we’re really going to have to move on. But as moderator, I’m going to take the prerogative of having maybe the last comment on this session. First of all, we don’t even know what conveys the benefit of sorafenib or midostaurin, since they target so many kinases. And they target FLT3, and all of this may have more to do with a graft-versus-leukemia effect than anything else. And so just substituting a more potent FLT3 inhibitor actually might miss the target in that population. I agree with your points that it’s going to be a different population of patients coming in. But remember what the German speaker said about the difficulty in enrolling in that trial. Some doctors already felt they knew the answer and didn’t want to put their patient on a placebo-controlled trial. So the challenge the BMT CTN will have is now we have even more evidence that sorafenib is there. Can you put your patient on a placebo-controlled trial? So I agree that the effort needs to be there, but you might be challenged to get the patients now.

Mark J. Levis, MD, PhD: It’s going to be more.

Transcript Edited for Clarity
View Conference Coverage
Online CME Activities
TitleExpiration DateCME Credits
Community Practice Connections™: New Directions in Advanced Cutaneous Squamous Cell Carcinoma: Emerging Evidence of ImmunotherapyAug 13, 20191.5
Advances in™ Multiple Myeloma: Changing Treatment Paradigms and the Emerging Potential of CAR T-Cell TherapyAug 30, 20191.5
Publication Bottom Border
Border Publication
x