iwAL 2025 | Updates on established therapies in AML

Jessica Altman:

Good morning everybody. I’m Jessica Altman from Northwestern University in Chicago. I’m here speaking to you from iwAL in Washington, DC, with my esteemed colleagues and friends. I will allow each of them to introduce themselves.

Stéphane de Botton:

Stéphane de Botton from the Gustave Roussy Institute, Paris, France.

Tapan Kadia:

Hello. Tapan Kadia, MD Anderson, Houston, Texas.

Tara Lin:

I’m Tara Lin from the University of Kansas Cancer Center in Kansas City.

Jessica Altman:

We just got out of a really exciting and busy session regarding optimizing standard chemotherapeutics and the treatment of acute myeloid leukemia. I’d like to ask each of you to give a little kind of summary of your talk, and then after each one, we can go into some more discussion. I’ll have you start, Dr de Botton. 

Stéphane de Botton:

Thank you very much. So the purpose was to sum up papers for reduction of venetoclax, which has been done already in the VIALE-A protocol, but generally speaking, the experience in the real world and most of the experience we have are as follows: you delay the next cycle or you decrease the exposure in each cycle. So the effect is as follows: if you reduce the dose, generally speaking, you have less toxicity, and its durability is better, and the outcome might be exactly the same. We have seen reduction from 28 to 21 to 14 days, and yet to 7 days, without changing overall survival and event-free survival. The concern we may have is for genetically defined subgroups, which may benefit from adjunction of venetoclax to HMA, in which we could consider having longer exposure to venetoclax. The other message, which I think is important, is to delay the interval between the cycles, and it’s very safe without any concern. So four weeks is too short, for sure. Five weeks is very reasonable or more. And finally, in the very frail population, we should even decrease the regimen, and a metronomic way to administer each week, one day, is feasible for the very frail population and safe. 

Jessica Altman:

That’s great. Thank you. I think there’s a lot to get into, which we’ll want to talk about with our other colleagues as well. But I’ll start with one kind of practical question. When you are making the decision to delay the next cycle of HMA-VEN, what is your trigger to restart? Is it count recovery or other aspects of clinical? 

Stéphane de Botton:

Oh, mainly count recovery as usual. 

Jessica Altman:

And is there a specific count recovery you like to utilize in your benchmark? 

Stéphane de Botton:

As  in protocols, so, about 100,000 for platelets and 1,000 for neutrophils. It’s the minimum. 

Jessica Altman:

Great. Thank you. I think… I’m interested in your thoughts on the emerging clinical trial data and how… if there are specific studies that you’re waiting for, for results, for finalizing and incorporating treatment decisions. 

Stéphane de Botton:

So, the next step is already done in the US to compare 14 days to a classical way to administer VEN-AZA. And in Europe, next year, we’ll open a trial between France and Spain, a large randomized study comparing seven days versus a classical way to administer 28 days or 21 days according to ELN specifications for six cycles, and the endpoint will be the response rate at the six cycle. 

Jessica Altman:

Great. Thank you. I look forward to those results. Dr Kadia, kind of picking up on the low-intensity approach, I was hoping you could summarize the experience with cladribine with low-dose Ara-C and venetoclax, and maybe specifically when you’re recommending that regimen over an HMA-Ven. 

Tapan Kadia:

Yeah, thanks, Jessica. Great talks all around. So, you know, I think one of the realizations is that we really need to move to the next step in terms of low-intensity therapy. We’ve had great success with HMA-Ven. We’re optimizing that with the number of days of Venetoclax. But as we look more and more at these patients, and the ELN 2024 classification shows us, that there are subsets of patients who may not benefit from the addition of VEN to HMA. But what about the addition of VEN to other backbone regimens? And that’s where we developed this cladribine-low-dose cytarabine regimen; no anthracycline, low-dose cytarabine, with an additional purine analog, which may be effective in some of this monocytic subtype, RAS-mutated AML. And so we recently updated our study of 190 patients with newly diagnosed AML above the age of 60, and the median age in that cohort was 68 years. And among those patients, we had a CR-CRI rate of about 90%, 89%, with about 78% of those patients having MRD-negative complete remission. They had excellent tolerability. The early mortality was very low, less than 2%. And their survival, median survival in the entire population was 52 months in this older population. Now, this is not exactly the same population as VIALE-A because these were… although they were older than 60, and we looked at the 75 and older as well, they did just as well… some of these patients were fit, fit enough, for example, to receive allogeneic stem cell transplantation. And so the way we approach with this regimen, is we kind of thread the needle in those populations, probably the majority of our bulk of our population between the ages of 50 and 70, who are newly diagnosed, who are older, who you’re not sort of thrilled about giving anthracyclines and high-dose cytarabine-based therapy, but they can still be eligible for transplant, particularly when they’re in remission. And so that’s our approach in those 50 to 70 years old. They may not be fit for intensive chemotherapy, but they may be fit for transplant once they receive… once they achieve a complete remission. That’s where we are positioning it. About 40% of those patients on that study went to stem cell transplant. The others continued on study for a total of a maximum of six cycles, alternating with AZA-VEN, and then often went on to maintenance therapy or observation. 

Jessica Altman:

I think that’s great. Fascinating. I’m interested if there’s a patient population that you would feel comfortable randomizing HMA-Ven to your cladribine with low-dose Ara-C and venetoclax regimen with alternating. 

Tapan Kadia:

Absolutely. I think anyone 65 and older, if HMA-Ven is the backbone, I think 65 and older. It’s interesting. Amir Fathi is doing a randomized study of HMA-Ven with 7 + 3, where he’s actually taking even younger patients. So based on what that reads out, could it be possible that we can randomize even younger patients to Clad-LDAC-Ven versus HMA-Ven? I think the other question is, can we randomize Clad-LDAC-Ven to 7 + 3 among patients who are 50 and older? And I think that it’s going to be quite compelling if we can do that. 

Jessica Altman:

Great. So that leads to my final question for now, for now, and it picks up on some of the conversation we had in the main session. And you also have, and you’re welcome to summarize the data, also have significant experience and pioneered the use of CLIA-Ven for fit adults. So my question is, for the fit adults that’s 50 to 60, which regimen are you now recommending and why? 

Tapan Kadia:

Very difficult question, right? And so the way I approach that is, those patients who are between 50 and 60, they can be eligible for both. Among those patients who have a biology that I know is very sensitive to intensive chemotherapy and venetoclax, I tend to lean towards CLIA-venetoclax, you know, keeping in mind that they are fit for that intensive chemotherapy. Patients who maybe are less, their biology is less fit, I move them to the Clad-LDAC-Ven followed by stem cell transplantation. Examples include, I think the most obvious one, is an NPM1-mutated, whether or not they’re FLT3-mutated, I send them to CLIA-Venetoclax. Remission rates are excellent. The NPM1 NGS MRD goes to zero. And so I’m very comfortable with those patients receiving intensive chemo and no stem cell transplantation. So those are the kind of patients that I use. 

Jessica Altman:

That’s great. Thank you very much. Dr Lin, I’d love for you to summarize your discussion with us today. 

Tara Lin:

Sure. Great presentations all the way around. I was asked to give an update on secondary AML. We reviewed some data looking at outcomes for patients with CPX-351, the original data that led to the FDA approval back in 2017, with particular improvements for patients who had treatment-related AML from prior chemotherapy or radiation therapy, as well as those who had prior MDS but had not yet received an HMA. We looked at several real-world data sets that showed kind of the feasibility of giving CPX-351 to younger patients, and then some data sets from Europe looking at CPX-351 versus fludarabine-based regimens and looked at remission rates, MRD negativity, which favored CPX, as well as rates of getting patients to stem cell transplant. I do think it’s important when we think about secondary AML that transplant really needs to be a key part of our treatment paradigm, and there were some recent series from the EBMT looking at outcomes for patients with secondary AML who got haplotransplants with post-transplant cytoxin, and found that those outcomes were equivalent to post-transplant outcomes for de novo patients, suggesting that there might be something in particular about the haplotransplant procedure that would be helpful. 

Jessica Altman:

Yeah, I also found that really intriguing. Thank you for sharing that data. I’d like to ask you to comment on the MyeloMATCH high-risk study, because this really kind of gets at kind of a question that I asked Dr Kadia as well, is, you know, which patient population are you comfortable comparing CPX-351, which you spent a lot of time talking about, to an HMA-Ven? And what other modifications are you interested in looking at? 

Tara Lin:

So the MyeloMATCH high-risk study is open at 150 sites across the U.S., and it randomizes patients ages 18 to 59 to either 7 + 3, 7 + 3 plus venetoclax, AZA-VEN, CPX-351, or CPX-351 plus venetoclax. And I think it’s going to be a useful study because we’re going to be looking at all of these high-risk patients. They’re younger. Ideally, you know, we would be looking at transplants for them. And the outcome, the endpoint for the MyeloMATCH high-risk study is the rate of MRD-negative complete remission. And so we’re going to get a readout in younger patients looking at CPX, which we don’t really have, a readout looking at younger patients with AZA-VEN, which we don’t really have in this kind of setting. So if, you know, the sites that are accruing, continue to be good participants, and we can get these trials enrolled quickly, I think it’ll give us important data to go forward. I think one of the struggles with any large randomized trial is that, you know, in the best way possible, the leukemia field keeps moving, and it takes time to design these studies and do these studies and analyze these studies. So we can only pick our treatment arms with the data we have available on the day we lock down the trial. But, you know, right, certainly in the future to have other kinds of induction regimens put into larger randomized trials is the way we should try to go. 

Jessica Altman:

Great. Can you speak a little bit more about the MyeloMATCH program and not just kind of… So the primary endpoint of the study is an MRD negative response. But the MyeloMATCH program also offers us hopefully additional information about the biology of disease and what happens at relapse. Can you speak a little bit about that? 

Tara Lin:

That is one of the, probably the strongest and most defining feature of the MyeloMATCH program is that it’s really designed to be a precision medicine trial. And so while at a lot of academic centers, you can get rapid, complete diagnostic testing very quickly, for a lot of sites and centers across the country, that data is not as rapidly available. And so when patients enter the MyeloMATCH screening protocol, you get centrally read flow cytometry, centrally read cytogenetics, centrally read NGS, and we do get those results back in 72 hours. And so even for patients who aren’t assigned to a treatment arm, a sub-study on the MyeloMATCH program, we are collecting their data. We are collecting data on what non-trial treatments they’re getting, we are collecting survival data, and so it will allow us to get a better sense of, what are the mutations, what is… you know, to be able to look at patients in more individualized detail. Because certainly right now, the open trials in the younger buckets are high risk and intermediate risk. And as we know, that encompasses a lot of different kinds of subtypes and mutational profiles. So especially when we talk about secondary AML, to be able to go back to the high-risk study and look at the NGS data for all of the patients who were included, what treatments they got randomized to, what they got, and what their outcomes were. I think having that rich data set is going to be the real transformative part of the program. 

Jessica Altman:

I think those are really key points. And I’ll add to that, that in addition to the diagnostic data, we’re going to get an understanding of the architecture of the disease throughout the treatment course and what the disease features are like at the time of recurrence. So I think we’ll hopefully continue to be a rich data set for the future utilization as well. So a point was brought up during our session that I’d like you to respond in a little more detail to and get all of our colleagues’ thoughts, about what to do for patients with accelerated-phase MPN who have essentially acute leukemia, what essentially treatment and options exist? And importantly, should we be designing studies that allow all of these challenging patients, secondarily treated AML, AML secondary to an MPN, as I’ve mentioned, should they be incorporated into our upfront large studies? Should we be having dedicated trials for them? Tara, I’ll start with you, and then I’ll get down the line. 

Tara Lin:

That is a great question because as a clinical trialist, I bristle that we keep excluding the most difficult to treat patients from our clinical trials, right? Because we want to be able to produce data that would inform the treatment of all of our patients, not just the patients who have more favorable or intermediate risk features. I do think when you include those patients in an all-comer study and don’t stratify for them and look at them differently, you could dilute a positive signal, particularly of a new agent. And so I do think that I don’t know the answer, right? I don’t know that… I’m interested to hear opinions, but certainly a disease like accelerated phase MPN, we don’t know the right thing to do. We definitely need to have trials. And if we’re going to have a trial that’s exclusively for those patients, it’s going to take a lot of collaboration and a lot of centers, which can take a long time to get done versus having stratification and, you know, analyzing those patients a little bit differently when they’re enrolled on larger trials. 

Jessica Altman:

Great. Thanks. Tapan, what’s done at MD Anderson? You have a separate MPN trial. 

Tapan Kadia:

So, yeah. So, it’s a great question, an important question. I think that… I think there is room for considering these patients in separate cohorts in one trial. So we’ve done this in several patients where we have a trial for, let’s say, secondary AML. There’ll be a subset or they’ll be analyzed differently if they are post-MPN or if they’re treated secondary, which is post-HMA. So that’s one way to do it. And what that does is not only does it kind of really focus on how the outcomes are in this patient population, but it also spares some of the others, and if there is a signal of a drug that works in a secondary AML that’s untreated, you won’t miss it because there’s no averaging to the mean. So I think there is room for maybe analyzing these subgroups separately. In patients with post-MPN AML or accelerated phase, there’s data that they don’t respond as well to venetoclax-based therapy. And so we are actually moving away from using that and using more HMA-based or Clad-LDAC-based regimens in that patient population. And finally, I think those patients who have this treated secondary AML, there are many of these patients out there. I think, the more we treat HMA with MDS, the more we’re seeing treated secondary AML. So we actually have dedicated trials for treated secondary AML. We completed one. It accrued very fast. Within two years, we had a full accrual, and it’s completed now. So we can do trials, I think, because we have all these patients, we don’t know what to do with them. And I think it’s a ripe area for research, because although we call them newly diagnosed AML, in my mind, they act like they’re relapsed/refractory AML. So drug development can happen there. 

Jessica Altman:

Great. Thank you. And Stéphane, what’s happening in France? 

Stéphane de Botton:

In France, generally speaking, genetic rules decision is the exception of MPN. But they do have lots of common features. So it’s not too complicated to have a precision medicine for these patients. There’s just one comment for MPN. We recently published in myeloproliferative diseases transforming AML with IDH1 mutations. And with monotherapy, we observed excellent results in the field, obviously, which is by far much better than we saw with intensive chemo. So again, with genetics and targeted therapies, maybe there is a room for including in subgroups, as you say, such a type of patients. 

Jessica Altman:

Yeah. I think those are great points, right? In CMML patients, we frequently see three mutations, and so being able to characterize those patients better are excellent points. I want to thank the three of you for your outstanding comments during this meeting today. But clearly during our larger session, your talks were excellent, led to a lot of increased thought for all of us and hopefully continuing to move the field ahead. Thank you all. 

Tapan Kadia:

Thank you. 

Tara Lin:

Thank you. 

Stéphane de Botton:

Thank you very much. 

This transcript is AI-generated. While we strive for accuracy, please verify this copy with the video.