iwAL 2024 | Updates on established therapies in AML – Part 1

Eytan Stein:

Hi. I’m Eytan Stein from Memorial Sloan Kettering Cancer Center and I’m joined by three of my outstanding colleagues. We’re going to summarize for you one of the great sessions that we just had at the international workshop on acute leukemia. We’ll start with my colleague to the left and then we’ll go down and everyone should introduce themselves.

Tapan Kadia:

Sure. Hi, thanks Eytan. I’m Tapan Kadia. I’m currently a faculty at MD Anderson Cancer Center. Happy to be here in this great session.

Max Stahl:

I’m Max Stahl. I’m from Dana-Farber Cancer Institute in Boston.

Tara Lin:

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

Eytan Stein:

Okay, why don’t we get started? Tara, maybe you could tell us in three minutes or so what you talked about during your session.

Tara Lin:

Sure. So my topic today was to give an update on data with CPX-351. CPX-351 is a liposomal formulation of daunorubicin and cytarabine and it was FDA approved for the treatment of newly diagnosed patients with AML in 2017. The indication for upfront treatment is for patients with secondary or MDS-related changes types of AML. And this drug was approved because CPX-351 improved overall survival over patients who were treated with traditional 7+3 chemo. What we’ve seen in more recent years is that there are several studies looking at CPX-351 in combinations with venetoclax or with FLT3 inhibitors or with IDH inhibitors and that preliminary data has shown that it is safe and tolerable with full data on response rates still to come, which is expected later this year.

We also looked at some data looking at low dose CPX 351 in combination with venetoclax for older and unfit patients. In this study, the majority of patients went into a complete remission and many of those patients, up to 75% of those patients had an MRD negative complete remission as well. And those results are also expected to be published by the end of 2024. We then spent some time and talked about some upcoming and emerging clinical trials using CPX-351, importantly the NCI effort called myeloMATCH, which is for all newly diagnosed AML patients, has several arms that look at CPX-351 as a single agent or in combination with venetoclax.

And this combination is going to be tested in newly diagnosed high-risk patients. And that’s a five-arm study looking at 7+3, 7+3 plus venetoclax, CPX-351, CPX-351 plus venetoclax as well as venetoclax plus Azacitidine. And we’re really hopeful that we can have lots of sites across the US participate in myeloMATCH because it’s only going to be through a large group effort across the United States that we can get answers to some of these really challenging questions.

Eytan Stein:

Thanks, Tara. Max, go ahead.

Max Stahl:

Yeah. Thanks, Eytan. So I talked a little bit about maintenance therapy strategies in the non-transplant setting. So in order to keep patients in remission if they don’t go to transplant. I talked a little bit about the one approved agent, non-targeted agent, oral azacitidine and some of the findings of the trial. Maybe a couple to mention that were important is that in the trial, it’s a little bit unclear of how much patients benefit from maintenance therapy if they can complete all consolidation chemotherapy.

I talked a little bit about the MRD conversion rate with maintenance therapy, which was about 30% or so converted to MRD. But some of the shortcomings with MRD as well, that in the placebo arm of this trial there were also quite a few patients who converted to MRD negative. I talked then about HMA/venetoclax as a different regimen that we now use as induction consolidation and maintenance therapy. And I put particular focus, I think on new emerging data that with HMA/venetoclax-treated patients who either complete 12 months of therapy or have a deep MRD negative response, this therapy can be stopped in some patients, and those patients can have treatment-free remission. So I think there’s a lot of future developments in the maintenance field, a lot of clinical trials that are going on, and we had a lot of vivid discussion about this.

Eytan Stein:

Okay. Tap.

Tapan Kadia:

Yeah. Thanks, Eytan. So we had a great discussion today about… I talked about intensive chemotherapy and venetoclax. As you know, venetoclax is a BCL2 inhibitor that has demonstrated remarkable outcomes in older and unfit patients with low intensity therapy with either HMA or low dose cytarabine. What about bringing BCL2 inhibitors or venetoclax into young patients? And so how do you combine that with intensive chemotherapy? So we and others have done trials with this, including CLIA plus venetoclax or FLAG-IDA plus venetoclax at MD Anderson. Dr. Andrew Wei has pioneered this actually with 5+2 and venetoclax in older patients in Australia.

There are several studies in Europe including a German study with HAM, which is high dose cytarabine and mitoxantrone with venetoclax in patients who are relapsed and refractory. So intensive chemotherapy plus ven. So what things do we need? What strategies do we need to implement to make sure we deliver this safely? Currently, we know that we probably need less days of venetoclax than what’s on the label for low intensity therapy. So moving away from a 28 day venetoclax regimen down to even 7 days or 14 days of venetoclax. How do we mitigate some of the toxicities that we see, prolonged myelosuppression? Well, the use of things like GCSF, routine use of antibiotic prophylaxis to reduce risk of infections, which we see quite frequently with these regimens.

So we showed in all these studies, number one, response rates that are much higher than what we expect with intensive chemotherapy alone. So response rates, CR rates of 90 to 95% in newly diagnosed patients. But importantly, rates of MRD negative CR of higher than 80 to 85%, negative CR by flow cytometry across the board in most of these studies, suggesting that not only are we getting complete remissions, but we’re getting deep complete remissions. And so we reviewed some of the updated data from all these trials that are ongoing. Then we had a really nice feisty discussion about understanding number one, which patients do we treat with this. Certainly can’t give it to everyone.

Number two, if we give these regimens, do we really need to give one cycle of induction and four cycles of consolidation? Can we reduce the whole course to maybe one or two cycles of chemotherapy? Does ven need to be given with induction and throughout every consolidation or can we just give with induction, move to transplant or move to non-ven-based consolidation? So these are some of the strategies and arguments that we were having. We had a lively debate, which I think will inform how we design our future studies, some of which are ongoing. In Europe, there’s a 7+3 plus or minus venetoclax, as well as the study from Australia led by Andrew Wei looking at either 7+3 or 5+2, either with or without venetoclax in younger and older patients respectively. So I think really exciting discussion and hopefully the future of what we do in AML.

Eytan Stein:

So I had a couple of questions. I’m not going to spend too much time on questions because the time is limited, but I had a question first for Tara. Maybe it’s more a philosophical question than a data-driven question. I find in my neck of the woods in the Northeast, CPX is very controversial. I see some people who say we never use CPX for reasons I can’t understand because there’s a positive Phase III study. And then I see some groups that are using CPX for everything. So relapse post-transplant, give them CPX-351. So why do you think that people are using it in unapproved settings and why people are reluctant to use it in approved settings?

Tara Lin:

I think the data on CPX is best studied in the newly diagnosed setting, and we’re certainly seeing more data, single institution data coming out in other places. I think that we had this tremendous time in 2017, 2018 when we had all these new drugs approved and CPX-351 was part of that, followed soon after by venetoclax. And so when you about an older population who maybe a year before, you would’ve given CPX-351 to then you have this option of ven HMA. And so I think that that muddied the waters a little bit in terms of who do you give CPX to. In our practice for people who have therapy-related AML of any age, MDS who have not received a hypomethylating agent, we’re very much still giving CPX-351.

We are not using it so much in the relapsed setting outside of a clinical trial, but we also have active trials going on with CPX in different kinds of indications. So I think part of the difference in practice is that everything kind of got new all at the same time. And then I think part of the difference in practice is how much CPX have you given? What has the experience been in your own hands? And then certainly in the relapsed setting, this feeling that nothing’s really good. And if it’s something that we haven’t tried before. Particularly, so CPX is one of those drugs that could be effective in the marker negative patients, which is still the majority of our patients, don’t have a targeted agent that we could look to.

Eytan Stein:

Okay. That’s great. Max, I had a question for you. My understanding is that the MRD assays that were done during the QUAZAR study may not have been as sensitive as MRD assays we have now. How does that inform whether you might use on ONUREG® (azacitidine) or whether you might not use ONUREG®? That is if you have a patient now who is intermediate risk, but you’ve got a great assay that shows their MRD negative to tend to the negative six, and you’re not transplanting them. Are you going to use ONUREG® or you’re going to say, “No, this patient is cured?”

Max Stahl:

Yeah, I think that’s a great question. Let’s answer it with one thing. We don’t have such an assay in most situations. If we would be in a world of ALL, I think where we make a lot more rational decisions because we have clonoSEQ and it has sensitivity to ten to the minus six, and it’s applicable to pretty much any B and T-cell, ALL. We don’t have that in AML. We only have NPM1, which is really to that sensitivity that we can say… And co-abiding factor leukemias, but often that those we cure anyway. But for maintenance situations, really NPM1-mutated patients where we have that data. Flow clearly in QUAZAR showed that it is not a great marker. If 19% of patients with placebo get converted MRD negative versus 35% or in that realm, so pretty much half of those, it’s not a great marker. So it’s hard to make decisions based on very poor predictive marker.

Eytan Stein:

Right. And I would argue also that it has to do with the kinetics of MRD eradication. We measure it at one time and say either positive or negative. We don’t measure it serially, which is a problem. Tap, last question to you. I think in this country we have groups that use FLAG-IDA. We have groups that use 7+3. Do you think there’s going to be a difference, again, I’m asking you to hypothesize, whether venetoclax is added to 7+3 or added to FLAG-IDA? That is there something unique about FLAG-IDA that synergizes more with venetoclax or do you think you add venetoclax to any intensive chemotherapy regimen, it’s going to be the same?

Tapan Kadia:

I think what you said is correct. I think if you add venetoclax to any intensive chemotherapy regimen, it’s going to augment the underlying efficacy of that regimen. Now, people like the UK have shown that clearly FLAG-IDA is probably superior to 7+3. Many patients in terms of overall survival if they get full therapy. So in terms of that, if you add venetoclax to FLAG-IDA chemotherapy, that may be more effective than 7+3 added to venetoclax. The question you bring is what are people going to use in the country? I think that 7+3 has been a staple, if you will, for most AML doctors around the country, and it’s something that people are used to.

So I think that the first studies that are going to come out looking at 7+3 with venetoclax, I think that’s going to be the first sort of step. I think there are still groups out there who use higher-dose cytarabine-based induction. Several have shown that certainly in people in 46 years or age or younger, high-dose cytarabine induction does improve overall survival and relapse-free survival. And people who believe in that and who feel they can give it safely, will add venetoclax to that regimen. I think everyone else will use 7+3 and Ven. So I think that there’s opportunities for both, but I think that it augments whatever the underlying efficacy is to a certain extent.

Eytan Stein:

Okay. Thanks so much. Thank you so much for everyone’s time, and thanks for taking the time to have this little roundtable.

Tapan Kadia:

Thank you.

Max Stahl:

Thank you.

Tara Lin:

Thanks.