Top updates in MDS from ASH 2025: key trial updates and debated topics

WEBVTT
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Hello and welcome to the VJ Hemonk podcast, where we will be shining a light
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on the top updates in myelodysplastic syndromes from ASH 2025.
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This episode will feature key trial updates, including long-term follow-up from
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the iMerge trial, an interim analysis of the Vaxillus trial,
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a phase 1-2 trial of Vexmab, and more.
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As well as this, we'll delve into some of the debated topics and more controversial
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issues in the diagnosis and treatment of MDS.
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This podcast is part of the MDS channel on VJHEMOP, which is supported by Geron.
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This supporter has no influence over the production of the content.
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This podcast is intended for healthcare professionals only.
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So let's head to our first speaker, Amir Zayden, who will share his updates from the meeting.
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So MDS has been seeing a lot of, I think, important developments in the lower
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risk more than the higher risk disease. But in this ASH, I've actually been
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involved in a number, I think, of important presentations.
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The first one is called the maxillus trial, in which we are using Luspetracept at the maximum dose.
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So Luspetracept has been approved in lower-risk MDS in patients,
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both in the front line as well as the second line anemia-dependent or transusion-dependent anemia.
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However, the drug is given in a titrational mood, where you start with 1 mg,
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you go to 1.33, and then 1.75. But what happens is many patients fall off during
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the process and they never escalate because doctors forget about the escalation.
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So in this phase three trial that
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is a non-randomized phase 3 piece trial. We are presenting the starting at the
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highest dose from the beginning, and the data we show is actually demonstrating
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very good efficacy and very good safety.
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So I think that potentially could allow people to start with the highest dose
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from the get-go, which would be very important.
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Another representation I'm giving on MDS in the lower risk is a subgroup analysis
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or a secondary analysis from the IMERGE trial looking at the use of imitilistat.
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And imitilstat is an approved drug in refractory lapse AML after ESA,
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sorry, refractory lapse lower risk MDS after ESA failure.
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So in this analysis, we actually look at the correlation of the imitilstat-induced
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neutropenia and thrombocytopenia and the correlation with transhuman independence.
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And what we show is that patients who do get thrombocytopenia and neutropenia
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early on have a higher chance of achieving transhuman independence,
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which reflects basically on target mechanism,
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which is very reminiscent of what happens with linalidomide in deletion 5Q, lower-risk MDS.
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So this could allow people to use this as a predictor for response,
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but most importantly, for people not to get too scared when the patient gets
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thrombocytopenia or neutropenia because it's part of the mechanism of how the drug works.
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And the last oral presentation I have in MDS in ASH is actually in higher-risk
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MDS, where we are looking at the use of a new monoclonal antibody called bixmarilimab,
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which is an anti-cleaver one.
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Antibody, this is against macrophages.
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It leads to activation of the macrophages against the MDS cells.
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And we are showing data focused on TB53 mutated AML, where we show high response
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rate and durability of responses.
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So it's still a relatively short follow-up with a limited number of patients,
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but the data is very encouraging.
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And based on this data, actually, we are proceeding with a randomized phase
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2 slash phase 3 trial to test a combination of Bixmarilumab with Azacitidine,
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which will be a global registrational intent trial, which is a significant unmet
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need in high-risk MDS because we are still stuck with only HMA monotherapy.
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There were a couple of other presentations I'm involved in, which is a subgroup
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analysis of Verona trial that looked at is the Venn versus is alone and unfortunately
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was negative for us, where we're exploring subgroups where there might be more benefits,
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such as patients who have excess blasts and patients with certain mutations.
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Next, Valeria Santini will share further data from the IMERGE trial on the long-term
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survival outcomes of E-Metelstat in lower-risk MDS.
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Following this, Professor Santini will discuss a post-hoc analysis from the
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COMMANDS trial, which compared the efficacy of Luspaticept to Epootin-alpha in lower-risk MDS.
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The IMER trial is a study that is evaluating transfusion independence achievement
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in patients with IPSS intermediate or low-risk who have high-burden transfusion dependence,
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so more than four red blood cell units in eight weeks, and is comparing imetastat,
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a telomerase inhibitor, to a placebo.
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So the trial was successful, 40% of patients treated with imetastat achieved
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transfusion independence longer than eight weeks versus 15% in the placebo arm.
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So the drug has, it's very interesting because it may indeed induce So
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long duration of response, the majority of patients achieving the primary objective
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of transfusion independence for eight weeks will have six months of transfusion independence.
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And finally, of all the patients, the intention to treat patients,
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18 will have a transfusion independence longer than one year.
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So we focused on this subgroup of patients because we wanted to understand whether
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this long transfusion independence was mirrored by longer survival.
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So in the intention to treat all the patients versus placebo did not show a
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significant prolongation of survival.
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But when we look at the more than one year transfusion independent patients,
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you indeed have a signal, especially after 42 months of survival.
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So the study was not powered to evaluate overall survival, but there is a trend
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to obtain a better overall survival in treated patients.
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Now, this is just the beginning. We have to understand exactly the characteristics
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of patients, whether they had other treatment after imetastat,
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but it's an encouraging data.
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Also because this drug is endowed with disease-modifying effect.
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Meaning that the variant allele frequency of the somatic mutation present in
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the patients is decreasing significantly and this correlates with the response.
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We had a look of long-term survival in COMMANDS.
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The COMMANDS trial is a study that compares the efficacy of Luspatercept to
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that of EPO in patients who have low-risk MDS and are transfusion-dependent.
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And the primary endpoint, the primary objective is to verify after six months
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the achievement of transfusion independence,
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plus longer than 12 weeks, plus an increase of hemoglobin of 1.5 gram deciliter.
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And that's something that is seen in 60% of cases. So, in comparison to 35%
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of patients treated with EPO.
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So, having said so, we analyze in oral communication that is given here at ASH
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2025, we analyzed which were the patients who were more prone to respond.
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And what we saw is that indeed treating patients with the early characteristics
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of the disease, meaning higher hemoglobin level, of course, on the threshold of transfusion.
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So below eight or over eight makes a big difference.
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So the patients with higher level of hemoglobin, who have a lower transfusion
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burden, and who have a lower serum EPO level are the ones who are responding
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in a very high proportion of cases,
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nearly 80%, versus much lower cases.
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Again, in EPO, but also compared to patients who have different characteristics of the disease.
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And this is also reflected in the duration of response.
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So the idea that we have is that if you treat early these transfusion-dependent
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patients, if you do not wait that the disease is too specific,
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let's say advanced, even not progressed, but advanced, you can obtain really
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outstanding results in terms of achievement of transfusion independence.
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Now we will move on to discuss the phase three Verona trial.
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This trial evaluated venetoclax plus azacitidine in adult participants with
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newly diagnosed higher risk MDS.
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The study did not show a significant survival benefit and Jacqueline Garcia
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will share her insights into the interpretation of these findings.
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I would say Verona was a really important study. It taught us how we should
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try to adjust how we run clinical trial protocols for high-risk MDS in 2025.
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We've evolved how we take care of MDS patients and our expectations.
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So I would say the punchline is the addition of venetoclax to Azocied D is not
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for everybody, mostly because we don't see a change of survival benefit.
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However, there are a lot of details that have not yet emerged that require additional
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analyses, and we might have to learn from ongoing and recently presented real-world
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data to really supplement what the trial could not offer or provide yet.
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So as an example, during the life expectancy of this clinical trial of Verona,
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which was a trial for intermediate and high-risk patients, we found that it
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did not meet its primary endpoint of overall survival.
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It was essentially the same 22 versus 21 months for study versus standard of
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care azacitidine. We learned a few things.
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One, the combination regimen was not as toxic as everyone was worried about.
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The rate of febrile neutropenia was 23% versus 17%, which tells us we can take
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care of our patients. The scheduling was very safe.
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Importantly, there was no early treatment mortality, which was excellent.
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During the life expectancy of the clinical trial, our recommendations for higher risk MDS changed.
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And so based on BMT-CTN or a randomized study in the transplant setting,
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we learned that what our patients should get in frontline is really transplantation.
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So during the process of the clinical trial, our expectations have adjusted
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and have increased for patients with high risk MDS,
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meaning the chemotherapy or cytoreductive regimen that we give is merely a bridge
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or what we provide in route to a transplant for patients.
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Now, the majority of patients may not be eligible based on age or comorbidity,
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but it is something that we learned.
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So in this clinical trial, Verona, we did see that despite not meeting the survival
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endpoint, we learned several.
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Several things. One, there was a better modified overall response that included
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complete remission, which was the same in both cohorts, partial remission,
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and marrow complete remission.
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The marrow complete remission is a bit of a topical concept in itself because
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we removed it from the IWG 2023 response criteria.
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But the idea is that that means it's less than 5% blast and could represent
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an opportunity to then transplant somebody who has adequate disease control.
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And so in this clinical trial, we saw that the modified or overall response
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was higher with the study arm.
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And if we're wondering why didn't it translate to survival, I think it's several things.
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So one is patients were not as sick with study treatment.
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And so there is a chance because it's overall survival that people got additional
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therapies afterwards that might have led to them being able to have a longer
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survival, meaning our first regimen did not make them too sick,
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and so they could get a second-line therapy, if indicated.
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A second thing that we found is that, unfortunately, while we wanted to focus
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on higher-risk MDS patients, we included intermediate risk as well.
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And while they're very worthy of investigation, what we know about venetoclax
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is it's really a blast reducer, and that's what we learned in the acute myeloid leukemia setting.
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In MDS, it's a stem cell disease, and it is a different beast when it's less
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than 5% blast versus those with excess blast.
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When you look at the forest plot curves, when we look at multi-variable analyses,
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we're able to appreciate that with the study arm.
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By overall response, we see that it trends in favor of the combination.
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And when we take a look, and it was not powered for overall response,
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it was a secondary endpoint.
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But when we look at the forest plots for overall survival, it trended with a
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hazard ratio of 0.8, just barely crossing over 1 for those with greater than 5% blasts.
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So my hope was if we had patients that were truly high risk,
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higher or excess blasts, I think that we have not fully answered the question
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in the context of this randomized clinical trial because it's underpowered for
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this to ask the question of whether or not those with excess blasts greater
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than 10 percent, greater than 5 percent,
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or those with high or very high risk disease, do they benefit from a combination approach?
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I would argue that there's certainly flirtation of that based on the trends.
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It just did not meet significance. So I would say across the board,
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I don't universally recommend giving a net class.
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I would be very strategic on individual use. If it's being used to bridge someone
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to transplant, I think it could be worthwhile to consider because it does not add more toxicity.
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But if it's used as a sole agent, I don't think that it's necessary at this time from what we know.
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The last thing I'll say is what we've learned with the additional follow-up
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is only about 19% of patients went to transplant.
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That really speaks to that we had a really higher risk patient population that was older.
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When we look at the transplant data, it looks like patients are doing well overall.
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What we need a little bit more analyses on, which we hope to do for the manuscript,
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is to show were there any differences based on the first-line regimen that they received.
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All I could tell you is that from what we know with the data available is that
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on this trial, after their first treatment assignment, twice as many patients
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in the azacytidine placebo group did end up getting venetoclax at the end of the day.
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That might have helped to contribute to the curves over getting close to each
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other and not being significantly different, meaning they eventually got venetoclax,
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despite not getting it in the beginning.
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A second thing that was presented at the SOHO meeting in September is that for
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patients on the study arm, because it was doublet and there's a little bit more
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myelosuppression or lower cell counts, there was a bit more azacitidine reduction.
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So did we potentially underdose patients on the study arm because the other
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arm was placebo and so we had to dose-reduce azacitidine in the protocol?
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I think there was a lot of factors from inclusion of intermediate risk,
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patients getting post-trial venetoclax, the reduction of the azacytidine in
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the combination arm that contributed potentially to the survival benefit being unseen.
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On the results of the Phase 2 AMO trial of ASTX-727, an oral formulation of
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dacitabine with sedazuridine in CMML and other MDS-MPN overlap syndromes.
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I've presented the first results of the UK randomized trial called AMO,
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which stands for ASTX-727, which is versus hydroxycarbamide and best supportive
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care in MDS-MPN overlap syndromes.
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So this was a phase two trial in which we randomized patients with MDS-MPN overlaps
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in a two-to-one fashion to either receive ASTX727,
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which is an oral formulation of decitabine with sedgeziridine,
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which is a cytidine deaminase inhibitor, which allows it to be taken orally.
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And the standard of care for pretty much all of these diseases for decades has
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been hydroxycarbamide, but that's not particularly disease modifying.
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The results are not. very good, doesn't particularly delay progression,
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and it can actually exacerbate the other cytopenias that these patients often
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have by virtue of being overlapped.
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So we know that hypermethylating agents work in these diseases.
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What we don't have or didn't have is any prospective randomized data against that standard of care.
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So we took 77 patients recruited across 13 sites.
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Geographically spread across the UK, a very simple design, and we just treated
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them in a two-to-one ratio with 727, or they were able to receive best supportive
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care that in almost all cases included hydroxycarbamide.
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And we gave them six cycles of S6-727 or control, at which point those who were
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responding could continue until progression. And,
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If they weren't responding, they would come off study. There was no crossover
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from the best supportive care arm.
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We met our primary endpoint, which was great. The overall response rate was
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54% for the experimental arm versus 27% for hydroxycarbamide.
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Not very many CRs. It's about, I think, 10% versus 3.8%, which was basically
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one patient on the hydroxycarbamide arm.
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Which is actually fairly modest data, but probably what you'd expect for a hypermethylating
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agent in these diseases.
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But what was really pleasantly surprising, I think, was that the secondary end
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points of survival were all met with significant advantage in the ASTX-727.
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For example, overall survival for the full modified intention to treat population
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was 24.2 months for ASTX-727, but only 17 months in the hydroxycarblamide arm.
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And the hazard ratio was 0.45, which did reach significance.
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And we saw the same and sometimes better figures for progression-free survival,
00:17:53.906 --> 00:17:58.666
transformation-free survival, and again, slightly better results when we just
00:17:58.666 --> 00:18:03.566
looked at the majority of patients with CMML who took part in the study.
00:18:03.926 --> 00:18:07.806
So, you know, I think the question is why have we seen an advantage when other
00:18:07.806 --> 00:18:13.246
studies with hypermethylating agents, for example, the phase 3 Dakota trial of IV decitabine.
00:18:13.706 --> 00:18:17.926
Why have we seen significance? And I think one of the answers to that is to
00:18:17.926 --> 00:18:23.986
do with the fairly permissive dose reductions and dose delays and the better
00:18:23.986 --> 00:18:27.246
tolerability of the drug. This is an oral agent.
00:18:27.566 --> 00:18:32.406
IV decitabine is quite hard going for these elderly comorbid patients.
00:18:32.946 --> 00:18:36.666
And I think that's reflected in the fact that the median number of treatment
00:18:36.666 --> 00:18:42.046
cycles received by our patients was 10 versus around five in Dakota.
00:18:42.586 --> 00:18:47.686
And we were quite liberal about dose reductions from the initial five day to
00:18:47.686 --> 00:18:53.326
four to three, and often down even to two days per cycle, almost a sort of maintenance type approach.
00:18:53.706 --> 00:18:58.086
And as such, we've got responders still going on cycle 35 and beyond.
00:18:58.386 --> 00:19:02.386
And so I think that's probably part of it. And the tolerability profile was,
00:19:02.586 --> 00:19:06.726
as you might expect, this drug has been used widely in the US and elsewhere.
00:19:07.990 --> 00:19:13.430
And, you know, we saw 24% of patients with 77 suffered febrile neutropenia,
00:19:13.630 --> 00:19:16.290
typical but very manageable hematological toxicity.
00:19:16.770 --> 00:19:19.850
So, you know, we're really quite excited by this.
00:19:20.070 --> 00:19:25.330
It's a small advance perhaps, but it's the first randomized survival advantage
00:19:25.330 --> 00:19:30.370
for any drug in any MDS-MPN overlap syndrome for almost 30 years,
00:19:30.530 --> 00:19:32.710
the first one since hydroxycarbamide itself.
00:19:33.390 --> 00:19:37.330
And so, you know, we believe that this should be a new standard of care for
00:19:37.330 --> 00:19:43.930
advanced proliferative MDS-MPN overlaps beyond just CMML who need treatment.
00:19:44.845 --> 00:19:49.605
Finally, we turn back to Valeria Santini to discuss some of the debated and
00:19:49.605 --> 00:19:53.505
controversial topics in MDS that were discussed at this year's ASH.
00:19:54.025 --> 00:20:02.605
We had a very good discussion and confrontation during the Momentum Symposium of MDS Foundation.
00:20:02.745 --> 00:20:08.305
We actually discussed several hot topics in the management of MDS,
00:20:08.525 --> 00:20:09.985
both high risk and low risk.
00:20:09.985 --> 00:20:16.665
One debate was regarding the diagnosis, and I'm starting from it because I think
00:20:16.665 --> 00:20:20.065
that a good diagnosis can provide an optimal therapy.
00:20:20.325 --> 00:20:26.005
Diagnosis of MDS is complex, is based nowadays on morphology still,
00:20:26.225 --> 00:20:32.265
but the debate was exactly focusing on whether morphologies should still be
00:20:32.265 --> 00:20:39.185
the standard of diagnosis or whether we can shift to molecular characterization of MDS.
00:20:39.185 --> 00:20:45.905
Now, of course, the debate is open and hot and lively because we still do not
00:20:45.905 --> 00:20:53.585
have all the MDS classifiable by NGS, by presence of somatic mutation.
00:20:53.585 --> 00:20:58.285
But that was quite interesting as well as the second debate.
00:20:58.485 --> 00:21:03.965
The second debate was even more specialized in a way because it was discussing
00:21:03.965 --> 00:21:10.905
whether all patients with germline predisposition to MDS, so an assessment that
00:21:10.905 --> 00:21:13.245
is not routinely performed yet.
00:21:13.865 --> 00:21:19.285
Should undergo a pre-disease therapy, so a prophylactic therapy.
00:21:19.285 --> 00:21:25.745
And this is something really for the future, because we do not have the data of all patients.
00:21:25.985 --> 00:21:31.205
And of course, depending on the kind of germline predisposition that is present.
00:21:31.909 --> 00:21:38.089
In a substantial proportion of cases when studied routinely, should be performed.
00:21:38.309 --> 00:21:43.889
And especially, we should be very careful in when and how proposing stem cell transplant.
00:21:44.209 --> 00:21:48.649
So these were the two debates. And then we had a discussion.
00:21:48.869 --> 00:21:55.749
I actually had the presentation regarding the failures in high-risk MDS clinical trials.
00:21:55.929 --> 00:22:01.289
Unfortunately, in the last years, we did not succeed in finding a combination
00:22:01.289 --> 00:22:07.649
of azacitidine and other drugs that could improve survival in high-risk MDS.
00:22:07.989 --> 00:22:11.229
So what are the most promising drugs in high-risk MDS?
00:22:11.469 --> 00:22:17.029
I don't know, because I think we're still stuck with azacitidine or dicitabine
00:22:17.029 --> 00:22:20.549
as the main treatment and the standard treatment.
00:22:20.649 --> 00:22:26.269
I hope that we can find in the future a better designed study that will clarify
00:22:26.269 --> 00:22:32.649
what we can do to improve our patients' survival and live lives.