Strategies for Treating Patients With Relapsed/Refractory Acute Myeloid Leukemia

Expert Roundtable Part 3

In this expert roundtable series, Jorge Cortes, MD, Augusta University, Augusta, Georgia leads a panel discussion on the latest updates in acute myeloid leukemia treatment and management with Justin M Watts, MD, University of Miami, Miami, Florida and Rami S Komrokji, MD, Moffitt Cancer Center, Tampa, Florida. 

In part 3 of the roundtable discussion, the experts provide insight into strategies for treating patients with relapsed/refractory acute myeloid leukemia.

Transcript:
 

Jorge Cortes, MD: Let's move now to the relapse/refractory setting and first, what do you do? What do do in this setting in general, Rami, what's your go-to therapy approach and both for the fit and the unfit patients, what do you do?

Rami S Komrokji, MD: Right, so that's changing as well, I think. And even now, the relapse/refractory setting, we could be even talking about molecular relapses and what we do in the molecular relapse setting. But I think in general for patients that are fit for chemotherapy, the general principles in the path, at least it depends on the duration of the first remission. So if a patient got classical intensive chemotherapy and they relapse 2 years later, historically and traditionally we said that those patients could probably benefit still from salvage chemotherapy and it could have a role to come back into somebody that had 2 years benefit of a CPX-351 or 3+7 to go to some other salvage chemotherapy. So that group is maybe easier to manage the patients that relapse early on within the first year.

I think those patient chances of achieving a remission with another round of intensive chemotherapy is really low.We've seen a lot of the control arms and studies compared to other things where really the performance of just salvage chemotherapy, the classical [inaudible] is really very low in patients that have early relapse. In those cases, if there are targeted mutations that we can go after with targeted therapy, I think that's the way we go to. In the non-fit for intensive chemotherapy and the patients that are getting HMA-VEN upfront, that's really becoming a challenging field because we really don't have good data on how they do even with salvage chemotherapy. Then in general, the responses have been poor to most of the treatments.

Again, if we have targeted mutation, I think that's the best way to go forward. Obviously there are selected things that maybe patients can benefit from some of the clinical trials, like if patient have MPM1, now there are the menin inhibitor trials and stuff like that. But in general, my approach, if there is targeted mutations, especially in the early relapse, is to go after that HMA-VEN failure is really challenging and I don't know if we have a good answer for those patients.

Dr Cortes: Yeah, well certainly when there's targets you, we have good options. So let me ask you, Justin, let start with the FLT3 to different scenarios. One is the fit patient that probably took either quizartinib or midostaurin. What do you do? We do have gilteritinib approved in that context, but there's been prior FLT3 inhibitor exposure. Do you use it alone? Do you use it in combination? How do you use it in that setting? And then for the unfit patient, you talked earlier about mostly using [VEN-AZA], if you use let's say gilteritinib, which is one that's approved as a salvage, again, do you use it by itself? Do you use it in combination?

Justin M Watts, MD: Yeah. Great questions. The first 1, for a fit patient who presumably has failed chemotherapy plus a FLT3 inhibitor, I think that's actually evolving now that we're using more and more quizartinib frontline, right? We don't have a lot of experience or as much with gilteritinib post quizartinib, probably more post midostaurin because it's been around for a while and we've been using it in practice. For TKD, we'll still induce midostaurin. But for ITT now we've moved to quizartinib and I think it depends on do they relapse with FLT3, right? I guess question of 1, you need to know that they might not. Do they also have a RAS mutation?

There's a lot of things to consider, but if the FLT3 is still present, that is the population where gilteritinib driven to monotherapy was studied, right? It was versus intensive salvage. So these weren't like [inaudible] patients presumably, right? And it beat it, but using a monotherapy in a patient with a FLT3 that maybe some clonal, maybe it's further up the tree, but there's other things there.

To me when we have so many other options that I feel like I could be doing more, I mean that's the approved setting, but there is on guidelines and based on published data combination regimens like VEN-GILT right? I don't think do triplet at that point, I'm not sure how much the HMA adds and that would, again, not unless it was on a study, but there are some other combinations options because there's not really a salvage option either. plus FLT3 that is proved right? Then you're still combining things and it's a wide open space.

I've had success with using the VEN-GILT combination particularly in bridging younger patients to transplantation and then that's been published by [inaudible] and the JCO, but phase 1b study. There's options. I try to incorporate a FLT3 inhibitor of course if I can, if I think that's what is driving their disease, if it's shifted towards RAS or so on, there may be other salvage options that include cladribine, include agents that may be more active and monocytic leukemias.

For unfit patients, fif they failed VEN-AZA, which is the standard of care, then you also have options including gilteritinib because it's not approved based on what they failed, this was approved for refractory AML as a monotherapy there. As Rami mentioned, if prior HMA is bad prior VNH, even worse in terms of resistance, including the most targeted therapies. There's other considerations there. Monotherapy may not work, but you could again consider combinations with your reason.

Dr Cortes: Let me ask now, Rami, the other area where we have good targeted therapies is IDH and in particular in the IDH1, we have 2 good therapies. We have ivosidenib and we have a olutasidenib more recently, how do you see these drugs? Evidently they're standard and we use them in that context. How do you see the data with these two drugs? Do you think they're the same? How do you view that data?

Dr Komrokji: Yeah, no, that's an excellent question. And both of you led the development of those drugs, so you probably know this better than me, but obviously we have 2 IDH1 inhibitors, the ivosidenib and olutasidenib. There are some slight differences. I think the ETA is more mutant specific, maybe potent. I think we have more data on the EVO in the upfront based on the AGILE study.

So if patients are getting upfront HMA plus an IDH1 inhibitor, we are still tending to do more AZA-ivosidenib. We have a randomized clinical trial there. As I mentioned, if we have the say on what to start patients, we favor starting HMA-IDH1 inhibitor first line and do the venetoclax in the salvage setting. However, many times we see the patients were treated out in the community, they come with HMA-VEN and the question is what to do with that.

Upfront, if I had a patient with an IDH1 mutation, I probably favor HMA-ivosidenib based on the phase 3 data. When they had HMA-VEN and they had failure, we really don't have much data on ivosidenib. I think we have a little bit more data on olutasidenib that you recently published that in that setting. It seems, again, not head to head comparison with IVO, but there were responses similar to what we're seeing in the relapsed/refractory setting after chemo. So for HMA-VEN failure, if patients had an IDH1 inhibitor, we do tend to favor a little bit olutasidenib, whether done in combination or single agent, most of the time single agent, and obviously the hope it's a bridge to transplant.

Again, the 2 drugs have never been compared head to head. The appeal with the all olutasidenib was the durability of the response. I think Justin published on that extensively as well, that they seem to have similar response rates but the durability was more. I've seen few cases, as I mentioned earlier, that we have this flip in the mutations. We have patients IDH1, they are relapsing, we check back, they have IDH2, so actually add an IDH2 inhibitor, they do well, then we see another IDH1 mutation. So I think it's important to reevaluate and make sure that the clones that we are targeting are still there.

Dr Cortes: Justin, let me ask you, as Rami mentioned, you've been the leader here on olutasidenib, so I'd love to hear your take now that it's in the clinic and you have different options and different scenarios. The patient that took VEN-AZA initially and relapses and has an IDH1 mutation, the patient that chemotherapy and has an IDH1 mutation relapse, how do you use them and what is your take between these olutasidenib, ivosidenib? No question. Both good drugs, but how do you select them? How do you choose?

Dr Watts: Yeah, thanks. Thank you guys. Hard question, but I think in some ways it's nice to have different options. We don't always have that. We were just talking about FLT3 where other than gilteritinib in the relapse setting, what are you going to do? We have different options here and different sequencing options. The question of VEN-AZA versus IVO-AZA frontline is really interesting and hard to answer, and it's kind of hard to be wrong.

It is hard to compare the 30 or so patients with IDH1 pulled from VIALE-A subgroup combined with the phase 1 pool population to compare those data to a randomized phase 3 trial of a pure IDH1 population. But the response rates with VEN-AZA and IDH1 are quite high. Their durability may be less if they're a transplant candidate, that may play in there for a real truly unfair patient.

I think IVO-AZ clearly the way to go, but it might limit your options later a little bit, right? Because our second line option here that stood out from your data, Jorge, looking at olutasidenib, in the 20 or so patients who had VEN-HMA in the pivotal trial, is it performed surprisingly well because usually when we look at targeted therapies, including ivosidenib, including INA and including gilteritinib, post VEN in the case reports and so on out there, they do terribly. They just don't respond. The response rates with olutasidenib that setting, and these were then HMA failures, a couple may have had VEN, but they were real VEN failures, was about the same as the overall population, right?

About 50% response rate and the median overall survival in those 20 patients, was like 16 months. That's really long in all patients responders, non-responders combined but that's long for VEN-HMA and a failure. Whether that was a fluke, I mean at least those data are there, right? And they had to be acknowledged. So, but then you're arguing for saving therapies for later, but we don't know, I think in an unfit patient sequencing makes sense. Are we going to move the triplets eventually, maybe in another patients, we don't know yet, right? Those studies are probably going to be done.

If a younger patient, is the other side of the question, has failed chemotherapy and relapses with an IDH1 mutation, you also have lots of options. You could use a olutasidenib or ivosidenib as a single agent. The duration of response data favors all olutasidenib, but again, those aren't head-to-head trials—it's hard to compare, but it is quite impressive the duration of response data to all olutasidenib or you can consider combination therapies with HMA, for example, and an IDH1 inhibitor in that setting, trying to get that patient to a transplant.

The last thing I would say is that we're talking about responders, right? If you have an IDH1 mutation and you don't respond, right? If you're one of the half of patients who just doesn't respond at all, or maybe it's more with ivosidenib, you don't do well, right? We're talking about these patients who respond can do very well with IDH1 inhibitors, particularly olutasidenib, even as single agent.