Jessica K. Altman, MD: Hi, everyone. My name is Jessica Altman. I am at Northwestern University in Chicago, Illinois. I am very happy to be here with my colleagues who have become very close friends of mine, Dr. Tapan Kadia and Dr. Amer Zeidan.
We are excited to talk to you and spend some time talking amongst ourselves about really challenging forms of acute myeloid leukemia. In particular, we're going to try to address the approaches to relapsed and refractory acute myeloid leukemia. I will start with relapsed FLT3-mutated acute myeloid leukemia. Tapan, can you discuss your approach to a patient with relapsed and refractory FLT3-mutated AML
Tapan Kadia, MD: Yeah, thanks Jessica. I'm really happy to be here with you guys. So, I think the approach to relapsed leukemia in general, we make sure, like you said, to characterize that relapse. Are there any potential mutations that I can address? If not, then I go with agnostic treatments, but, in patients with FLT3-mutated AML which has relapsed, the current standard of care, according to the ADMIRAL Trial, is gilteritinib single agent. The trial, which in a Phase 3 randomized study, showed a significant improvement in overall survival. It’s a drug that's very well tolerated as a single agent, improved overall survival, was able to get people to allogeneic stem cell transplant, and then, in some cases, was able to be continued post-transplant to maintain that remission and extend that overall survival. So that is the standard of care.
On clinical trials, of course, we are doing many different things, many investigational agents. The biggest data set in terms of chemotherapy, we would use intensive chemotherapy backbone, using [inaudible 00:01:43], such as FLAG-IDA (fludarabine, cytarabine, idarubicin, and granulocyte colony-stimulating factor) or CLIA (cladribine, idarubicin, and cytarabine) in combination with gilteritinib. There is some data with 7 and 3 gilteritinib in the frontline, but also, in the relapse refractory study, we've had nice success, with response rates in the 60-70% range, and again, able to get these patients to allogeneic stem cell transplantation.
So those are my initial approaches to a person who is younger and fit with relapsed disease with intensive chemotherapy. Again, older, we may consider single agent gilteritinib. Beyond that, again, clinical trials potentially with some combinations.
Dr. Altman: Okay, thank you. And at Yale, Amer, what are you doing for your relapse refractory FLT3-mutated patients?
Amer Zeidan, MBBS: Yeah. I think very similar thoughts to what Tapan has mentioned. I think I usually start the conversation is, what are we trying to achieve? I think that's a very important discussion to have with the patient. In general, if a cure is a potential, that's usually, in someone who did not have a transplant, and happens to be someone who potentially could tolerate a transplant, usually what I would do is to try to get the patient to a remission, and then go to a transplant, if we can identify a donor and the setting for that is present.
If the patient is not a candidate for curative intent, I tend to choose therapies that generally will maximize quality of life, trying to keep the patient outside of the hospital, generally minimize the use of intensive treatments and this kind of paradigm, clearly clinical trials whenever available. I generally tend to stay away from intensive chemo, I would say as much as I could in the refractory relapse setting, because, especially if the relapse is very quick after the initial treatment, and for those who relapse relatively quickly after bone marrow transplant.
I think the main treatments, like Tapan outlined, the IDH inhibitors, FLT3 inhibitors, those are clearly standard of care as monotherapies. We are using more and more Aza-Ven (venetoclax) in the refractory relapse setting after intensive chemo. In my experience, actually, probably as good as getting, or even probably better than, some of the non-venetoclax-based intensive treatments, like FLAG-IDA or those type of regimens.
But ultimately, I think you really want to have that clear goal in terms of what you're trying to achieve with the patient, because the survival, unfortunately, except in rare situations – I think, I'm sure some of you might have, but I have patients who are on an IDH inhibitor for 2, 3 years out in a relapse refractory setting in an older patient. That's unusual. I would say the average survival is generally 6 to 12 months.
Dr. Altman: Yeah. I agree with you. I think the continued conversation, just like we talked about in the prior segments, of understanding what patients' goals are, and hearing those goals, and then being able to develop a plan, whether that plan involves stem cell transplant, or not, and then the utilization of best supportive care in the management of our patients, I think is critical. Thank you for sharing those thoughts, and thank you also for touching on the use of the IDH inhibitors.
Because you mentioned them, I'm going to turn then to some exciting data that came out of ASH. We've had some updates on the use of menin inhibitors. Tapan, can you maybe start us off by updating us on those abstracts. And then I'm going to ask a little bit about the potential toxicities of these agents too.
Dr. Kadia: Sure. So menin inhibitors, right? Really exciting new molecules. I think potentially the next big thing in treatment of acute myeloid leukemia. MLL-rearranged leukemia, those patients who have translocations of 9;11, 11;14, 11;Q23 as a partner, we know that, initially, in the frontline, they tend to respond well to chemotherapy. The problem is, even in patients who get transplant in CR1, there is a really high rate of relapse. Right? That's why they're high-risk disease.
So, in the relapse setting, we've thrown everything at it over the years. Not much has worked. But recently, because of the biology of how menin associates with the histone methyltransferase that's involved in KMT2A, inhibiting that interaction with a menin inhibitor may be potentially active. Right? So theoretically, biology, and then biology's translated into clinic, and now we have at least 2 menin inhibitors, if not more, but at least 2 were presented as oral presentations at the ASH meeting.
The first is a drug made by Kura as a single agent. And they treated patients with relapse and refractory AML. Those patients who had MLL-rearranged AML, as well as those patients who have NPM1-mutated AML. Turns out that NPM1 and menin and also have an association. There may be some benefit there too. And overall, as a single agent, what they found is that there was a response rate probably around 33% CR/CRh. But if you add things like MLFS, PR, CR, CRI, altogether, it was just around 40-45% overall response rate in with Kura.
The second agent, a drug called SNDX-5613, is made by Syndax. They treated patients with relapse refractory MLL-rearranged or NPM1-mutated AML and saw a similar response rate around 40-50%. If you then went back and looked at the true CR rate overall was 20%. So true CR rate of 20% with a single agent inhibitor without chemotherapy in the relapse refractory setting. So, 20% doesn't sound like a lot, but to get a complete remission of count recovery, I think, is pretty cool with just a single agent drug. And then if you looked at the subset of patients who had MLL-rearranged, the overall response rate was over 50%, I think 55%, again, including the MLFS and so on.
So the drugs are very exciting. There are some side effects, which I think you'll get to just in a minute, but very encouraging data. And I think the next step over the next few years is going to be combinations.
Dr. Altman: Yeah. So, I think this is really cool. Right? We're hearing a similar story to what we've seen with FLT3 inhibitors and IDH inhibitors, and now we're where we are with menin inhibitors. So, right, these agents by themselves, for some patients, the disease goes away completely and they have restoration of the blood counts, but not for all patients. And so, the tracks are more combinations in relapse patients, and also adding them to the upfront setting. So that's the paradigm that we're seeing with the addition of these targeted agents.
Some of these targeted agents, though, have some side effects. Amer, can you talk about the differentiation syndrome that we're seeing across these targeted therapies?
Dr. Zeidan: Yeah. And I think this is very important, especially with the evolution of oral agents. I think one of my concerns historically have been about the use of oral agents in AML is that some people might end up underestimating that the toxicity of the drug, just because it's an oral pill and, especially, in a setting where the patient might not be monitored as carefully. So those drugs certainly are active and effective, but certainly have some toxicities that could be lethal if not detected and managed appropriately.
So, a differentiation syndrome is typically associated with IDH inhibitors, but we certainly see it with FLT3 inhibitors. It has been described with menin inhibitors. So, it certainly happens across a number of what I would call differentiating agents. The good news is that, I think most oncologists have a sense of the ATRA differentiation syndrome in APL, so it's really very similar in terms of the clinical syndrome itself.
So usually, it involves symptoms of increase in the white cell count, which tend to be generally more differentiated neutrophil left shift, along with fevers, pleurisy, hypoxia, pneumonia, infiltrates, sometimes skin rashes. Sometimes it can be subtle. And I have to say one of the challenging aspects, sometimes, is differentiating progression from differentiation syndrome. A rule of thumb that I have used is that if it's mostly blasts that are increasing, it could be progression, but I have to say this is not always the case.
I think the management generally involves some use of steroids, in addition to supportive measures. Some of those patients could need diuresis, could need additional oxygen support. They have to be admitted to the ICU in some situations, and clearly, holding the agent. But most important is recognizing it, thinking about it, monitoring the white cell count, and managing the patient appropriately.
And on that front, Jessica, maybe I can ask you, you have worked on very cool studies combining FLT3 inhibitors with venetoclax as well in the refractory lab setting. So, is that issue also something that you see? Or is, generally, I thought about adding any kind of intensive chemo to those agents as a mitigation strategy. So, do you think that combinations with these agents not only can help the efficacy, but potentially lower the risks of differentiation?
Dr. Altman: Yeah, thanks Amer. I agree. I think a lot of us hope that when these agents are combined, that we're going to see less of a differentiation syndrome, and less differentiation effect in general. And with the Aza-based studies, I think that that's been the case. I think the numbers are still too small with our Gilt-Ven experience, but there's still the risk with venetoclax of tumor lysis syndrome, and there's still the risk of a differentiation effect or differentiation syndrome, though it was not reported in our trial at a very high rate.
What was reported though, and what still concerns many of us with the use of gilteritinib and venetoclax, is the significant myelosuppression that occurs. So just like with the triplet agents, in anytime we're using venetoclax in combination with another agent, really understanding, trying to make sure that we have enough of a basis to understand the appropriate dosing of these regimens to minimize the significant myelosuppression that occurs.
So I wanted to give a summary statement, and then pick your brains a little bit more. We have seen an incredible growth of these targeted therapies, and it's been a really exciting and a very rewarding time to be a leukemia physician and take care of patients, and we have a lot more that we can offer patients. But there are still some subsets of individuals who have not had benefit from the potential of targeted treatments. And so, I'd like to ask your approaches for those individuals with relapsed and refractory acute myeloid leukemia whose disease does not have a targetable mutation. Tapan, I'll start with you. What are you guys doing at MD Anderson?
Dr. Kadia: Sure, sure. Yeah. I think you bring up a great point, right? There are people who we can target with IDH1, 2 inhibitors, FLT inhibitors, menin inhibitors maybe, but they're still probably the majority of patients who we are unable to target. The way I approach them, I think similar to what Amer pointed out earlier, what is our goal? Are we going to do palliation and prolong life, and optimize supportive care time outside the hospital, time with family until you progress? Or are we going to swing for the fences? Are we going to be able to get you in remission, get you to either your first transplant, if you've never had one, or even potentially a second transplant? And so, that's where we start baseline, right? I think, and it's part of what I'm going to tell you. And I want to talk about a growing subset of patients that I'm seeing.
These are patients who are treated in the frontline with HMA-Ven, who respond, and then they progress. So, these HMA event failures tend to be one of the most difficult subsets of patients that we have, median survival anywhere from 3-4 months. And I think it's a really challenging subset biologically. Clinically, they tend to be cytopenic. They tend to be transfusion-requirement. They tend to have prolonged neutropenia, existing infections, fungal infections. They tend to be deconditioned. Biologically, there's some suggestion that, well BCL2 has been inhibited beyond belief, and so now, there are other anti-apoptotic mechanisms, such as MCL1 and things that are arising. Can we potentially target those?
In those patients, our first priority is get them to a clinical trial. What works? Well, we have tried MCL1 inhibitors, right? Because if MCL1 is upregulated, so we're looking at those. We've seen some promising activity there. Is there another way to inhibit MCL1? Sure. CDK9 inhibitors can downregulate MCL1 and MYC, and so we're using CDK9 inhibitors alone, or in combination with venetoclax in the second line.
We have a series of immunotherapies, antibodies specific to CD33, or CD123, which are bispecific, which are antibody drug conjugates. We're considering CAR T-cell therapy. So a whole basket of clinical trials trying to match biology with what we're seeing.
In the other patients who, let's say have not had venetoclax in the frontline, or who have had minimal exposure of venetoclax but who are fit, and, as I say, we want to swing for the fences and try to get them to transplant, we're using intensive chemotherapy with venetoclax. Our primary regimen is something like FLAG-IDA venetoclax, sort of agnostic of the mutations, with very high response rates, particularly in this first salvage setting with CR rates of about 60-70%, and are able to get to transplant in most of those cases. Another approach, CPX plus venetoclax, also in a clinical trial, or other options. So that's sort of our basket. Swing for fences, try to get there. If not, can we figure out different ways on clinical trials to exploit different pathways?
Dr. Altman: Amer, anything to add?
Dr. Zeidan: I follow a very similar approach. I have to say one of the most intriguing abstracts to me from ASH 2022 in this particular area was a randomized European study in which patients were randomized to go directly to transplant in the refractory lab setting after primary refractory disease, versus getting a chemotherapy regimen they use in Europe called HAM. And what was interesting is that the overall survival out of this study was somewhat similar, but also importantly, that the rate of survival among the entire cohort was actually unexpectedly high. And this is somewhat of challenge to the dogma that we generally have been approaching refractory disease and trying to cure some patients is that we generally try to control not only morphologic remission, but, ideally, try to get to MRD negativity if possible. So, this trial has certainly given me a pause. I actually been presenting in a number of ASH highlights meetings, and this question keeps coming up. We certainly are discussing it internally.
So, I look forward to seeing the manuscript, because, as I keep pointing out to the community docs and my colleagues that, in this trial, they used a type of transplant, what it's called, it's a reduced intensity. They used something called FLAMSA (fludarabine/amsacrine/cytarabine), and this, actually, almost like giving FLAD-IDA in some ways, and then transplanting the patient in aplasia. So those were not patients technically just going directly to transplant. And I think this is very important when people talk about this as an option to patients, but also when they talk to their transplanters. I don't think this study, in my view, is actionable, until we see the manuscript, and the breakdown, and all these details. But I'm also interested in your thoughts on this.
Dr. Altman: Thank you for bringing that up. I was hoping we might be able to sidestep that study, because I think there's so much that we still need to learn from that presentation. I was really excited to hear the presentation at ASH – it was an ASH plenary session, which is amazing that there's a transplant conversation at the plenary session at ASH. But, like you, I am really eager to see that manuscript. I want to dig a little bit more into who these patients were, and how they're doing this, because there are things, just like you mentioned, Amer, that were surprising in terms of the response rate and the survival. So, I'm very excited about that.
Since we're talking about transplant, I think it might be worth mentioning that there is a one post-transplant study that I'm particularly eager to see the readout on. The MORPHO Study looked at either gilteritinib or placebo in patients post-transplant with a FLT3 mutation. We're eager to know that, right? We've had this conversation throughout our meetings, our conversations today, about FLT3-mutated AML, and the use of midostaurin upfront and gilteritinib or other agent in the relapse setting. We and others...and there was another abstract at ASH this year having shown that, it appears that gilteritinib retains its activity in individuals who've had midostaurin in the upfront setting. So those very few patients were included in Chrysalis and in the ADMIRAL Study, who had had prior midostaurin.
So that was a question, does gilteritinib even active in the current era? And there was a publication, or a presentation, at ASH, and some recent publications that have demonstrated that. And now, the potential of gilteritinib as maintenance, I think many of us are using some maintenance approach in our FLT3-mutated patients post-transplant.
I'll also mention that many people are really interested in the menin inhibitors, in particular, in relapsed FLT3-mutated disease, with a concurrent NPM1 mutation – individuals who've been treated with potent FLT3 inhibitors in the relapse setting. It's not really clear that, when their disease relapses after that FLT3 inhibitor, that their disease is still going to be sensitive to continued FLT3 inhibition. So looking at something like a menin inhibitor, and other agents, and that are novel, is really exciting.
So, I'll just summarize what my colleagues have said. Dr. Tapan Kadia, from MD Anderson, has really done a nice job of spending some time looking towards the future of what agents exist, particularly in patients without a targetable mutation, and really has outlined the potential use of immunotherapy, MCL1 inhibition, and then the option of intensive chemotherapy with venetoclax, particularly in those patients who have not had prior venetoclax. Tapan, it's been an absolute pleasure to spend time with you.
And the same, Dr. Amer Zeidan, from Yale University, has shared his thoughts on the uses of targeted therapies, particularly FLT3, IDH, MLL, and really the conversation he has with his patients in understanding their goals, and would not allow us to sidestep the ASAP plenary session from ASH.
Thank you guys very much. It's always a pleasure to spend time with you.
