Amir Fathi:
Hello, everyone. Welcome to The AML Sessions on VJHemOnc. Today, we are joined by my good colleagues Stephane De Botton, who is the Head of the Hematology Department at the Institute Gustave Roussy in Paris, France, and Dr. Daniel Pollyea, the Associate Professor of Medicine at the University of Colorado in Denver and the Clinical Director of the Leukemia Program there. My name is Amir Fathi. I’m the Director of the Leukemia Program at Massachusetts General Hospital and Associate Professor of Medicine at Harvard Medical School. Thank you so much for joining us.

Amir Fathi:
Today we’re going to be doing a deep dive into the latest research and development in the field of IDH inhibition in myeloid malignancies and acute myeloid leukemia, and I’m lucky to be joined by these two experts here today to go through some of the more recent data. I would like to start actually with some of the background in IDH mutated AML just to sort of place this in the proper context.

Amir Fathi:
So approximately 10 years ago, IDH mutations were first discovered in myeloid malignancies. Initially IDH1 and then a short while thereafter, IDH2 mutations. And not long after that there was a sort of a very frenzied attempt at drug development, which was very successful. First, the IDH2 inhibitor enasidenib, and thereafter the IDH1 inhibitor ivosidenib, were studied in Phase I dose-escalation and expansion. And thereafter, a Phase II study leading to the approval of enasidineb, the IDH2 inhibitor, in relapsed/refractory IDH2 mutated AML. And then shortly thereafter, the approval of ivosidenib, the IDH1 inhibitor, in relapsed/refractory IDH1 mutated AML. And then afterwards, ivosidenib was also approved for frontline use.

Amir Fathi:
In recent years, there has been a development in trying to see if these drugs can be used in other settings and in combination with conventional therapies, which I think somewhat brings us to where we are today, which is the development and study of these drugs in combination with conventional therapies, and in other myeloid malignancies. The field of AML has been further crowded by other therapies that may be effective in IDH mutated AML as well. So I’m happy to have Dr. De Botton and Dr. Pollyea here with me today to discuss some of that.

Amir Fathi:
So with that, I’d like to sort of open up the panel and speak to my colleagues here. Let’s start with relapsed/refractory IDH mutated AML. So let me start with Dr. Pollyea. What is your general approach now when you have a relapsed or refractory IDH mutated AML patient who has progressed beyond initial line of therapy? I assume the answer is probably relatively straightforward, but in some patients it may not be.

Daniel Pollyea:
Yeah, thanks Amir. I think we have a labeled indication for that setting and specifically use of the IDH2 inhibitor enasidenib. And as you well know, and Stephane too, so much depends on the goals of the patient and the setting. If this is a patient who has a path to a cure via a transplant, then that could be our goal, whether that’s a first transplant in the relapse setting or a second transplant. Getting a patient back into remission for that purpose is a very reasonable endeavor, and I think an IDH inhibitor is a reasonable attempt to try to do that.

Daniel Pollyea:
And then alternatively, if we’re more in a palliative situation, then again getting a patient back into a remission or some degree of disease control is the goal. And again an IDH inhibitor can do that successfully. Or even sometimes, even if you aren’t able to get an objective response with an IDH inhibitor and your goal is palliation, you can still get closer to that goal through what we’ve seen, and you’ve published some of the improvement with respect to the transfusion needs and secondary sort of quality of life end points as a result.

Amir Fathi:
So that’s actually an interesting point you brought up Dan. So, some of these patients actually go into a remission and get transplants, depending on their goals of care. When do you decide to move toward a transplant? This is something that I struggle with a little bit in my practice. Do you wait until you have cleared the IDH mutational burden? Do you attempt to do that before you go to transplant? There’s not much data guiding us. Do you go at first remission? Immediately when you get a remission, then go to transplant? Do you wait a little bit to deepen that remission? What is your approach?

Daniel Pollyea:
I think our transplant colleagues mostly are looking for a morphologic remission. Yeah, they would like as deep a remission as possible, but I’m fortunate to work with some pretty realistic people who know that I can only do so much. And so yes, I think in an ideal world, deep remissions, but we’ll take a morphologic remission to a transplant.

Amir Fathi:
Stephane, some of the recent data emerging from the IDHENTIFY study, which I think you’re very familiar with, Bristol Myers Squibb recently had a press release that announced that it did not meet its primary endpoint of overall survival. I would say, and I suspect Dan would probably agree with me, that that probably won’t change our general approach to the management of relapsed/refractory IDH mutated patients in this country. How about in Europe? What are your thoughts about that?

Stephane De Botton:
Thank you. I fully agree with Dan already said. But in Europe, the drug is not approved yet in that indication, so it’s easier. And we have the compassionate use program in France and in other countries, but it’s very limited outside France at first sight. So what we are doing, it’s exactly the same as Dan already said. The thing we take into account, if we intend to administer an IDH inhibitor, is trying to decide, because there are new treatments you both developed, especially with venetoclax, that could be interesting in that situation. We try to select those who won’t respond, and we have molecular ideas about those who won’t respond due to primary resistance, meaning for instance, if they had more than six associated mutation, huge co-mutation burden is something that is important to take into account. But also the type of mutations. For instance, if you have RTK mutations, especially FLT3, the response rate is rather low.

Stephane De Botton:
Because the drug is safe, you can use it, but expectation are not so high as what we have had in other circumstances. So it’s something to take into account. So in Europe, I can tell you for IDHENTIFY the key question is about how do you realize a randomized Phase III trial when you know it by heart, because some promising drug may have difficulties in the setting of randomized Phase III trial in center which has not train. Because it’s quite difficult to continue in treatment without seeing any improvements after two months, for instance. But you must be really very patient with these drugs. It’s not so easy to use.

Amir Fathi:
So you think that the results of the IDHENTIFY trial may be particularly challenging to interpret because of that, because of the potential lack of experience?

Stephane De Botton:
I don’t have all this data, but I suspect that the response rate would be very low, which is very unusual. And in the US country where you are the most trained, I’m probably sure that if you take into account what has been done the last two years, your resources are by far much better.

Amir Fathi:
Yeah. But it wouldn’t necessarily change your personal approach to managing these patients, the Phase III data from IDHENTIFY trial?

Stephane De Botton:
Probably not, because I’m very confident what we have seen together in the field, it’s really promising. We all know that it’s not a monogenic disease. And for the first time we know the precise role of the mutation, co-mutation conundrum. And is it a true mutation that may block the differentiation or not? We have the answer because the drug is always on the target, or almost, for most mutations. So it’s something really promising, but the combo is really promising because most of the patient relapsed, we need to combine it. And you’ve seen these results in the US, with the combination with intensive chemo, but also with ven-aza. It’s really impressive.

Amir Fathi:
Right. So let’s move on. Actually, we’re going to talk about that shortly. But I also wanted to bring up some of the results that were presented at SOHO in Houston, or at least virtually this year. I think that Stephane you were there. Courtney presented some data, not on AML, but on MDS. So let me go back to Dan and get his thoughts regarding his general approach and if there is any variance in how he approaches the treatment of IDH mutated MDS. Courtney presented some data that, in combination with azacitidine, IDH inhibition leads to a fairly impressive overall response rate, but the range of responses are different than what you generally see with AML. Much more marrow CRs is much less full CRs, although the benchmark, as we all know, of CR for MDS is a bit higher. But nevertheless, promising data. So what is your general approach to an MDS patient who has an IDH mutation? What type of MDS patient do you sort of generally choose to use IDH inhibitors either in combination or as monotherapy?

Daniel Pollyea:
Yeah, well as you know Amir, the incidence of IDH mutations in MDS is lower than in AML. So it’s not as common a finding as the 20-ish percent incidence in AML. But because we’re so desperate for treatments for MDS, and because we’re so bad at treating MDS, we all welcome this type of opportunity when we see the presence of an IDH mutation in an MDS patient, and we should all view that as an opportunity. So for a high risk or high grade MDS patient with an IDH mutation, it would be an off-label effort to try to get an IDH targeted therapy. But I think that that would be a reasonable effort. And as you said, Courtney’s data show a pretty promising morphologic response rate, at least compared to what the expectations would be with a hypomethylating agent alone.

Daniel Pollyea:
So I definitely think that that is something that we need to consider and to refer patients for clinical trials to further understand this, because I do think that the difference between AML and many patients with MDS that’s on its way to AML, is almost nothing biologically. So there’s no reason to assume that the responses that we’ve seen an AML couldn’t be applied to MDS. I myself outside of a clinical trial am not giving upfront IDH inhibitors to MDS patients with IDH mutations. But absolutely in the hypomethylator failure setting, or in the relapse setting, or an intolerance situation, I think it’s definitely a reasonable thing to try to do despite the restrictions that we have from the label.

Amir Fathi:
Stephane, do you use IDH inhibitors in MDS?

Stephane De Botton:
Again, the same way it’s not approved, but it’s something that can be, as Dan said, very interesting. Besides clinical trial, it’s very difficult. I think it’s the best way to judge efficacy of the treatment and you need to refer these patients to trained centers with clinical trials. I think it’s the best way to do it. The other thing is, it’s critical to have synergistic effects with 5-aza or other HMA. That’s really very interesting. And lastly, the mutations again are really very important. In MDS it’s a little bit different than in AML, but the general approach should be the same.

Amir Fathi:
I agree. I mean, I think the only scenarios where I’ve generally used IDH inhibitors in MDS have been predominantly in the relapsed/refractory setting where I’m desperate and I can’t get responses. And I think in those settings, just like Dan was describing with his AML patients, on occasion you’ll get a nice response and you can actually bridge a patient to transplant.

Amir Fathi:
Let’s move on to what Stephane was mentioning earlier, the promise of adding IDH inhibitors to hypomethylating agents. This data has been recently presented at several meetings. Stephane summarized this at SOHO as well. The overall response rates associated with ivosidenib and enasidenib in combination with azacitidine is promising. A small number of patients in a Phase I, large Phase I studies with ivosidenib and a randomized phase two study with enasidenib, revealed a composite remission rate, meaning CR plus CRI in the sort of mid 60 percentage range, which is what you see also with hypomethylating therapy plus venetoclax. And the overall response rate was also quite impressive, sort of in that 70 to 80% range, which is quite interesting.

Amir Fathi:
So, as someone who is an expert in the field of treating patients with HMA venetoclax, I want to ask Dan what his general.. This is a sort of a perennial question now. What to do with an IDH mutated patient in the upfront setting? I think everybody has their own thoughts about this, but there was recent data that had emerged showing that HMA venetoclax, at least recent Phase III data, confirming prior speculation that this regimen is quite impactful and efficacious in IDH mutated patients. So Dan, what is your approach?

Daniel Pollyea:
Yeah, I think you nailed it. I mean, I don’t think you can be faulted for considering targeting the IDH in the upfront setting. I think any therapy, including a targeted therapy, is viable to work better in the upfront setting. The issues are a little more… And with ivosidenib, you’re on label, so at least in this country. I mean, the issues get a little more complicated when you take into account the fact that a venetoclax based regimen is sort of agnostic to these different mutations. And one can, with confidence, start a therapy with a venetoclax based regimen without the extra time that is necessary to wait to get back your IDH results, which in some places could be a considerable amount of time. And then also take into consideration… the comparison that one needs to make, it’s like you said, it’s not just an IDH inhibitor plus aza, versus all ven-aza patients. You really would want to look at how the IDH positive patients do.

Daniel Pollyea:
And like you suggested, the New England Journal of Medicine paper is out, randomized Phase III data there with a fair number of patients. And the propensity for IDH positive patients to have an even better response than expected, with a IDH wild-type patient with venetoclax based regimen, really well into the 80, mid 80 and higher percentage is clear. So I think it’s impossible at this time to compare these two treatments, but my bias, for all those reasons, is to continue using the venetoclax. And then having the IDH inhibitor in your back pocket for an on-label relapse situation is really reassuring. Venetoclax in the relapse situation, you’re off label, not much data, real unclear expectations. So that’s another reason that’s how I prefer to sequence it.

Amir Fathi:
How about you, Stephane? New patient, not induction eligible, hypomethylating therapy. You want to use a combination. IDH mutated. Do you do HMA venetoclax? Or do you use an IDH inhibitor in combination?

Stephane De Botton:
We need to test this hypothesis in a randomized trial yet. What will be approved in Europe will be ven-aza. With the combo with IDH, especially the randomized phase two presented by Courtney, should be positive because for the first time, aza alone had very good results. It’s a big surprise. Why?

Stephane De Botton:
That’s crazy. We’ve never seen that. And in the ven-aza trial, it’s completely different. So it’s very difficult to determine which is better or not.

Amir Fathi:
And that was a small study also, relatively, so it’s difficult.

Stephane De Botton:
Yes. With ivo, you have a huge proportion of mutational clearance associated in the combo. So obviously we would like to combine these three drugs.

Amir Fathi:
That’s very interesting.

Stephane De Botton:
If your intention is to compare both, the safety and tolerability, will be something very important. And maybe you have to change the way of administration with ven-aza.

Amir Fathi:
That’s a big consideration. As we all know, the combination of HMA and venetoclax is quite marrow suppressive. It is somewhat challenging in some patients. The combination of IDH inhibition and HMA is probably not as marrow suppressive, so that is a consideration. But the last topic I wanted to cover is actually related to tolerability, which is differentiation syndrome. And I wanted to ask Stephane, since he is an expert in the field of differentiation, whether in the studies of IDH inhibitors in combination, versus IDH inhibitors as monotherapy, has he seen a difference in terms of the incidence and severity of differentiation syndrome? Or the timing of it?

Stephane De Botton:
At first sight, yes, because with the combination with chemo, as the differentiation syndrome is related also to the leukemic burden, at least in APL. If you had chemo, you have less DS syndrome in APL. And at first sight it’s also true with the US series; the US and German series combining IDH inhibitors with intensive chemo. So I think it’s roughly the same, except the incidence, because it’s not completely super plausible. APL is a monogenic disease. You always have a differentiation, which is not the case because we have… Most of the patients do not respond to IDH inhibitors in the relapsed-refractory setting. So if you do see something that could be it, yes. And if he’s not responding, by definition it’s not a DS.

Amir Fathi:
Yes. This is something that you and I have worked on a lot, to try and figure out what is DS and what is not DS, it is challenging. I mean these patients, as we all know, have multiple… So differentiation syndrome is a vague syndrome of pleural effusions, fevers, respiratory distress, rash, renal issues, lymphadenopathy, all of which can be seen in leukemia by itself and all sorts of infections that arise during the treatment of AML. So it’s hard to tease out sometimes.

Amir Fathi:
But to our viewers, I always advise that if you’re suspicious of differentiation syndrome, around two to six to eight weeks, maybe even longer, following the initiation of IDH inhibitor therapy. You should treat everything else that you’re suspicious of, but also treat the differentiation syndrome presumptively because it can get out of hand quickly. And the treatment of that is dexamethasone typically 10 milligrams twice a day. Stopping the drug by itself will not achieve your aims because of the long half-life of the drug, so that is generally what I recommend. If there is ongoing leukocytosis, you can manage that with hydrea. If there’s tumor lysis syndrome, you can manage that using the typical recommended pathways, but that is the general approach.

Amir Fathi:
So I wanted to, with the remaining time left, to leave the viewers with some final thoughts regarding the field of IDH inhibitors, what the current status is and what the future may hold. So let me just turn over to Dan and see what his thoughts are about where we are and what he thinks is perhaps most exciting in the future.

Daniel Pollyea:
Yeah. IDH, like you said, it’s a super exciting confluence of our sophisticated understanding of the biology of this disease, and that merging into targeted therapies. And so, there’s a lot of appropriate enthusiasm around this as a strategy. But I think we would all agree that where we are now is not where we want to be. I think we all would agree we want to do better. And like Stephane already said, whether that’s through combinations, whether that’s through finding a better setting, there are other strategies in very early phase clinical development targeting IDH in a variety of very novel ways. And so I’m excited about the future of this, but I think it’s really important for us to not be complacent and to continue to stretch our boundaries, refer patients to clinical trials, think of new and better ways to do this, and better settings for the patient for the drugs that we already have.

Amir Fathi:
Stephane?

Stephane De Botton:
Nothing more to say, except that maybe we’ve seen the secondary resistance could be also due to selection of the opposite mutation, and that’s very interesting. Also, second site mutation hampering the binding of the drug. So there’s a clear need for combination, and always in the field of clinical trials.

Amir Fathi:
Thank you so much, Stephane. I’ll just leave with a few words. I agree with everything that Dan and Stephane said, they’re obviously experts in this field and know a lot. It’s an exciting time. We’re lucky, I think, as a leukemia specialists to sort of be working during this era. There were probably decades of leukemia docs who didn’t have much to work with, we have a little bit more to work with. So I think this is an exciting time of drug development.

Amir Fathi:
Dan is right, there is lots of exciting approaches being developed, combinations being studied. I will bring up that there is also trials looking at IDH inhibitors, just as with FLT3 inhibitors, as maintenance therapy in the post-transplant setting. And probably they’re going to be studied in other settings as well, so that might be another way to potentially study these drugs and assess their promise going forward.

Amir Fathi:
So with that, I’d like to thank you so much for helping me discuss and delve deeper into the field of IDH inhibition and myeloid malignancies on AML. And I wish everybody a good day.

Stephane De Botton:
Thank you very much.

Daniel Pollyea:
Thanks guys.