iwAL 2023 | Novel targets, combinations & treatments

Hello, my name is Dr Eunice Wang from the Roswell Park Comprehensive Cancer Center in Buffalo, New York. I am here at the iwAL Leukemia 2023 meeting, and I’m joined by my colleagues Dr Thomas Cluzeau, from the University Hospital in Nice, as well as Marina Konopleva from Montefiore Einstein in New York, New York.

And so we’re here to talk about our talks that we gave at the meeting. The topic of my talk was intensive chemotherapy versus HMA venetoclax for younger intermediate risk patients with AML. And this topic is one of the controversies in AML because we know very well that venetoclax-azacitidine represents the standard of care for older and or unfit AML patients, but for over 40 years, the standard of care for our younger fit patients has been cytarabine and anthracycline based therapy, i.e. seven plus three. However, given the excellent tolerability and now emerging data that patients can tolerate venetoclax azacitidine and potentially go to successful allogeneic stem cell transplantation, the question is whether younger fit patients should also be offered this less toxic regimen and whether it represents a potential new standard of care for these individuals.

So in my talk, I reviewed some of the literature. There’s retrospective data, and currently there doesn’t necessarily seem to be a clear consensus whether intensive chemotherapy versus HMA-ven it is possibly going to be what we would use for these patients in addition to just standard HMA-ven. We now have triplet therapies where a targeted therapy is being incorporated into upfront therapy. For example, FLT3 inhibitors in combination with HMA ven and comparing the results of, for example, FLT3 inhibition plus seven plus three, suggests that there actually might be an advantage to a less intensive regimen in combination with the targeted therapy. Importantly, we also need to understand that most patients treated with HMA ven are not going to be cured of their disease, and therefore, if we are going to use this regimen in younger patients, allogeneic stem cell transplantation has to be part of that equation moving forward.

There are many randomized trials that we’ll be investigating this question in the next coming years, and we look forward to those results to determine which backbone regimen and targeted therapy should be used for our patients moving forward. So I’d like to introduce my colleagues, Thomas, who gave us an excellent talk on P53 mutant disease, and he’s going to give us a summary of what his conclusions were for treatment going forward for this disease.

So, thank you. Yes, yesterday I talked about the TP53, therapeutic strategy in acute myeloid leukemia. As you know, TP53 is a very poor disease and today the usual treatment failed to improve the outcome of this disease for patients eligible to intensive chemo, but also for patients not eligible for intensive chemo. The complete remission rate, CR/CRI rate, is around 30 to 40% and the median overall survival is around 5 to 6 months for patients eligible for intensive chemo using three plus seven or CPX-351, or also for patients not eligible for intensive chemo using HMA and HMA plus azacitidine and independently, if you use azacitidine or decitabine.

We observe an increase of CR rates, with the HMA plus venetoclax, but it failed to improve the median overall survival. So, I discussed during my talk, what could be, maybe the next step, in this setting in patients TP53 mutated, and we discuss about the magrolimab of course. So as you know, the magrolimab is a CD47 antibody, inhibits the ‘do not eat’ signal, and today there is two Phase III clinical trials in this setting. So the ENHANCE-2 study evaluating in TP53 AML, azacitidine plus magrolimab versus intensive chemo in patients eligible to intensive chemo and versus Azacitidine plus Venetoclax in patients not eligible to intensive chemo. This clinical trial is ongoing. there is a partial hold now, but we hope we could continue this clinical trial until the end and we hope to obtain  good results based on the results of the Phase I. And there is also another clinical trial. It was the ENHANCE-3, clinical trial evaluating a triplet azacitidine venetoclax plus magrolimab, versus azacitidine venetoclax plus placebo. It was more for patients not eligible for intensive chemo. But this clinical trial is also in partial hold, and we hope we could go to the end, maybe to improve, of course the outcome of these patients.

And in the second part of my talk, I discussed about if this disease could be cured, because today we have a good, we have discussion about if the treatment is just to prolong the survival or if it’s possible to cure, and using the data we presented, David Sallman and me, about azacitidine plus eprenetapopt, we could identify a subgroup of patients obtaining deep CR after this combination, and could undergo to allo-stem cell transplantation. And we observe a plateau around 50% in this patient, So maybe, if with the new drug, magrolimab or other drug, if we could obtain a deep CR and if we could undergo to allo stem cell transplantation, maybe we could cure these patients. It was my conclusion, it’s a hypothesis of course, but there is a lot of drugs, a lot of reconforming agent for TP53 and maybe we could find the, the good strategy for these patients.

Well, that’s great. That’s very helpful for us moving forward.

And Marina Konopleva gave us an excellent talk on one of the hottest issues in the current clinical practice of patients with AML, how to overcome or potentially address venetoclax resistance.

Thank you, Eunice. So I presented the laboratory data trying to understand the mechanism of venetoclax resistance in acute myeloid leukemia and potential novel ways to overcome that. So we all know that, HMA venetoclax has been a changing paradigm regimen for all the unfit for chemotherapy patients with acute myeloid leukemia. But the long-term results now show that perhaps the cure rate is somewhere in the range of 20% only long-term results. So majority of the patients are relapsing, and then there’s a fraction that are primary refractory. So, our lab and also other labs have been working for years now trying to understand the mechanism of resistance to venetoclax.

So I presented several potential mechanisms of resistance. One of them was newly discovered role of mitochondria as resistance, with a novel process called mitophagy of clearance of mitochondria, and also change in the mitochondria structure. Unfortunately, we don’t have yet clinical drugs that can affect these processes, but they’re being developed.

Then I discussed two known mechanisms of resistance. One is emergence of signaling mutations, and second is TP53 mutation. So as far as signaling mutation, I presented our laboratory data, which correlate with the clinical findings that the RAS mutations are representing one of the several signaling mutations that confer resistance to venetoclax.  and, how to overcome that. We currently do not know, but at least combination with MCL1 inhibitors in the lab are promising. Unfortunately, these agents have difficult clinical paths because of cardiotoxicity that was encountered. So the novel NRAS inhibitors are needed, or other ways to inhibit downstream NRAS, such as perhaps PLK1 inhibitors, which was also presented at this meeting.

And then finally, we discussed the TP53 mutation as a major mechanism of resistance and how that mechanistically it’s mediated through pro-aptoptic Bax deficiency because p53 controls Bax activation. We also discussed that there is a potential of developing Bad activators that perhaps could overcome this resistance when used in combination with Venetoclax.

And finally, in the last part of my talk, I discussed the role of BCL XL inhibitors. This is a new development, we think some of the BCL XL overexpression can confer resistance to venetoclax also in the setting of P53 mutation, particularly in a subset of acute leukemia called acute erythroleukemia and we have used in the laboratory, the novel degrader of BCL XL and shown that it works in this subset of leukemia, which has really poor outcomes.

So I think a lot more needs to be learned from the studies. But we are hoping that in the next few years we’ll have a novel combination that canimprove the outcomes of patients treated with venetoclax among, like among us.

So I just wanted to thank you very much for your wonderful talks and for your summaries of your talks. I just wanted to know for you, what were the highlights of the meeting, sort of the take home points that you think we should be looking at, or you’ll be thinking about when we return from the meeting? Thomas what are, what are your thoughts about things on the meeting that were, you think are next unmet needs or things that we should be looking at moving forward with acute leukemia?

So, thank you for the question. I think TP53 stays an unmet need for the moment. So we have clinical trials, we have to wait of course, the, clinical trial, as you know, there is a lot of clinical trials in acute myeloid leukemia fail to improve the outcome for the TP53. So, yeah of course the TP53 mutated patient is an unmet need today. And of course the resistance to AZA-ven is a big challenge. But you find some way to bypass the resistance.  So it’s good to know that maybe we will find something to bypass the azacitidine venetoclax.

Maybe one question for you. Do you think we could be able to maybe to have a BH3 profiling, maybe before azacitidine plus venetoclax, and maybe at relapse to decide when we will have BCL XL inhibitor, vaccine, inhibitor, maybe to define which inhibitor we have to use in the future?

Yeah, I think that’s a great question. So the biomarkers of resistance and response have been challenging in the clinical setting. So there are two potential assays. One is to do BH3 profiling, which is a functional assay. And it is challenging because of the combination that we are using. So it’s a perfect predictor of dependency, but then in the setting of frontline therapy, when you combine the two drugs is difficult. But then I think at the time of progression, it’s actually feasible to understand if, what is the switch and the dependency, as you said, to BCL XL or MCL1, so we collected samples in the lab and hopefully we can do it in the next year or so. Actually, it’s on my list to do. The other essay is to do the BCL2 family expression. And there was a very nice paper came out from Andreas Trumpp Group in the Cancer Discovery that showed that expression of BCL XL and MCL1 like in a ratio of, of fashion on the stem cells, specifically correlates very well with the responses in the HMA-ven in two different clinical trials that they performed in Germany. So we are collaborating with Andreas and getting this assay in our lab and hoping to reproduce that in our work as well.

So I think these two assays hopefully will help us to figure out the dependency. And then we need drugs, of course, which is a separate discussion.

Now, there was a case presentation on a patient that had a Bad mutation and have some of these other mechanisms. So do you recommend that we should be looking for anything other than P53 in terms of predicting response? Because as we know, when patients become resistant or they’re resistant upfront to Venetoclax azacitidine, we already know that they have a poor prognosis and the treatment options are limited. Do you recommend any mutation testing prior to starting Venetoclax therapy as a, to try to anticipate who’s not going to respond?

Yeah, I think, I personally think that the mutations and signaling pathways and P53 are much more common mechanisms of resistance to venetoclax, but certainly Bax mutations exist. And we’re looking at that in our own studies. I think we have to confirm. And, so large series that Bax mutations and which ones of them really confer resistance, I think there is one specific mutation that can in fact be selected for. And I think we have to be probably test for that mutation going forward. But I assume the mutation pretreatment is at very low levels, so it unlikely that we are able to detect that at the time of diagnosis. But again, the time of progression, I think it’s worth looking into that.

And then the question is, what are we gonna do about that if we define that mutation? Because, but at at least based on Andrew Wei’s data, these mutants were remaining sensitive to chemotherapy. So I think if we detect the mutation, we probably should not be using venetoclax based regimens, but some sort of chemotherapy perhaps could be useful in the salvage setting. Yeah. So, and then, the recent unpublished at work suggests that BCL2 mutation can actually happen in AML, although very rare. Again, they have been described in CLL as mechanisms of resistance, there’s some data from Sasha Perl and Andrew Wei who identify a patient who actually developed BCL2 mutation as well. Yes. So, I think that’s also, you know, we should probably include to our panel, this mutation so that we at least understand at the time of progression that this drug should not be used.

And then, Thomas, you talked about a lot of treatment options for P53. So looking towards the future, what are you most optimistic about? Do you think we should continue to pursue immunotherapy for P53 mutant disease? Because obviously venetoclax doesn’t work. I know you talked about magrolimab, which we’re kind of waiting with bated breath. I mean, what do you think is going to be sort of the most promising or possibly potential therapies in clinical development for p53 mutant disease?

So I, I guess the the reconforming agent could be really interesting for TP53. So we try with eprenetapopt, unfortunately the Phase III in MDS was negative, so we can’t continue for the moment the development in the acute myeloid leukemia. But there is a lot of reconforming agent, so for the moment, it’s not in development, but it’s our job to do that. So, but we identified a big list of drugs, could reconform TP53 to change the mutated TP53 in the wildtype TP53, and reactivate the function of the TP53 pathway. So if I want to do a hypothesis, I would like to go on the maybe a little bit more in a reconfirming agent and to find the good one, to improve the outcome of this setting.

Now, in the discussion part of your talk, there is some controversy because some people believe that patients with P53 mutant disease should not undergo allogeneic stem cell transplantation because the outcomes are so poor. Now, you presented data that patients can actually get upfront therapy and successfully, I think the cure rate or the survival rate was up to like 45%. Can you discuss that controversy, because I think we’re a little torn in the field. We wanna do something for P53 mutant patients, but is transplant the right way to go? Or maybe just, you know, clinical trial? What, what are your thoughts?

I totally agree about the two parts because, today the allo stem cell transplantation do not work in TP53. There are some patients alive after allo stem cell transplantation, but it’s not too much. We stay around 10 to 15%. It’s not good, but it’s not good maybe because  before stem cell transplantation, we have not the good strategy, today, azacitidine alone, maybe azacitidine venetoclax, is a little bit better because we could, we could put more patients to allo stem cell transplantation. But the results after azacitidine plus venetoclax is not good also, after intensive chemo, the results are not too good. So it’s why there is a discussion about is it really necessary to do an allo stem cell transplantation after this treatment? But I hope in the future with the new combinations, if we could obtain  deep CR as we know in the other AML patients. I think it’s the same in the TP53 mutated patients. MRD is a good surrogate marker for allo stem cell transplantation. So if we could obtain maybe more negative MRD using new combination therapy, maybe allo stem cell transplantation could be a good option. But today it’s not a good option because we have no good treatment before.

Okay.

And your opinions about the drugs targeting the SIRP-alpha, CD 47 axis, what are your thoughts, negative data with magrolimab, and AZA waiting for the results? I mean, do you think that that pathway, maybe not that drug, but targeting that pathway, still has legs for P53 mutant disease?

So I think the magrolimab is, it’s still, as I said during my talk, it’s still on the game. For me it’s a good drug, it’s a good drug it’s a safe drug if we manage well the drug using the guidelines. So I hope we could, finish the two Phase III clinical trials ongoing have the results and maybe for the first time a big improvement for the TP53 patients. So I think the magrolimab is, we still have hope. Yeah, so I hope, yeah, I hope of course, okay, we need to hope.

Maybe I can add that I do think that SIRP alpha antagonists do have a hope as well. At least, you know, preclinical data initially was developed by John Dick’s group, in fact, and their preclinical data similar to magrolimab, show efficacy in patients with complex karyotype P53 mutated disease. We don’t really understand the mechanism why this was, show efficacy in patients with complex karyotype P53 mutated disease. we just have to see which drug will be kind of making it to the finish line. But I think as a concept of inhibiting CD47, SIRP alpha interaction, I personally is a believer of that. And I hope we can find an agent that is safe and given with the appropriate backbone, also will have efficacy. Because additional discussions were of course, whether the backbone of AZA-ven with an intensive regimen is given now for 28 days of Venetoclax, whether that combination with Magrolimab would be having more side effects and whether different backbone would yield better outcomes. So that remains to be seen.

No, I agree. I mean, I think that just like the first FLT3 inhibitors that maybe we developed in, the clinic or in patients weren’t not successful potentially, maybe magrolimab isn’t necessarily gonna be the one, but there’s hope that there’s many other agents targeting that access that could work in those really dismal prognosis. So I agree that we should hang in there and be persistent. And I know that there are other drugs beyond magrolimab  that might be considered newer generation agents. and we can wait for those trials as well.

So thank you very much for taking the time to listen. I’d like to thank my esteemed colleagues, Dr Konopleva, Dr Cluzeau, for their time in discussing the key abstracts that they presented at this year’s iwAL 2023 meeting.