Listen to Rami Komrokji, MD, share expert perspectives on emerging data in myelodysplastic syndromes and myeloproliferative neoplasms from the ASH 2025 Annual Meeting.
In this podcast episode, Rami Komrokji, MD, reviews data from select presentations in myelodysplastic syndromes (MDS) and myeloproliferative neoplasms (MPNs) presented at the ASH 2025 Annual Meeting and shares expert perspectives on the clinical implications of these findings, including:
Presenter:
Rami Komrokji, MD
Senior Member, Vice Chair
Section Head – Leukemia and MDS
Department of Malignant Hematology
H. Lee Moffitt Cancer Center
Professor of Oncologic Sciences
University of South Florida
Tampa, Florida
Content based on an online CME program supported by educational grants from AstraZeneca, BeOne Medicines, Genentech, Geron Corporation, Incyte, Johnson & Johnson, Lilly, and Novartis Pharmaceuticals Corporation.
Link to full program:
https://bit.ly/48Ye45N
I'll start with myeloproliferative neoplasms. There were a lot of exciting data that I would like to highlight a few of them. The first one is the long-term follow-up of the MANIFEST 2 clinical trial.
This is a study looking at combination of ruxolitinib plus pelabresib in JAK2-naive myelofibrosis patients. The trial looked at, MF-naive, ruxo-naive patients randomized between pelabresib, ruxo versus placebo.
And we heard the 96-week update. The baseline characteristics were, as expected, well balanced between the two arms. This was one of the largest myelofibrosis studies—more than 400 patients randomized. The long-term follow-up really emphasizes the activity of the combination, we saw originally doubling almost of the spleen response that was well maintained through week 96. We saw also total symptom score improvement, albeit this was not statistically significant, because of the control arm, ruxolitinib being active in symptom control, and because of an almost ceiling phenomena that we can improve the symptoms to a certain point.
But when looked at a combination of patients that achieved a spleen response as well as a durable symptom improvement, we see superiority of pelabresib plus ruxolitinib compared to ruxolitinib alone. There were also, some data suggesting that the combination could be disease-modifying, with decrease in the fibrosis, reduction in the allele burden of the phenotype driver mutations.
The progression-free survival and death, looked better with the pelabresib ruxolitinib in combination, compared to ruxolitnib alone. The combination is well tolerated, no additional adverse events were noted in the trial. So this is really a longer follow-up, emphasizing the activity of the combination, showing improvement in the spleen response, potential disease modification, and this is moving now into a confirmatory phase 3 trial that will look at patients that have a little bit more symptom burden with the disease. This looks promising, and it will be a trial that we encourage referral to.
The other two abstracts I wanted to highlight in myeloproliferative neoplasms are targeting calreticulin mutation. Calreticulin mutation accounts for one-third of the phenotype driver mutations in patients with essential thrombocythemia. It's an immunogenic mutation that can be recognized by the immune system, and there had been different approaches to target the mutation. The first one was a monoclonal antibody that I'll be presenting the data, but there are also bispecific vaccine approaches to target the calreticulin.
The first study to highlight is really looking at the monoclonal antibody 033989 in patients with essential thrombocythemia. So, the study took patients that had high-risk ET that were resistant or intolerant to at least one prior line of therapy, and they were treated with a monoclonal antibody in dose escalation fashion. The primary endpoint of this study was looking at dose-limiting toxicities.
The study included 55 patients. Safety-wise, there were no DLTs observed, and the maximum tolerated dose was not reached. There was some myelosuppression with grade 3 anemia or neutropenia in 5 patients, but there was no grade 3 thrombocytopenia. Interestingly, we saw robust activity in controlling the platelet counts pretty quickly in patients treated on the study with a rapid and durable normalization and complete hematological responses.
But more importantly is really the potential disease modification, where we see a reduction in the allele burden of the mutation, wherein more than one-third of the patients had 50% or more reduction in the allele burden of the calreticulin mutation, and those happened typically within the first three to six months of the treatment. And there also were changes seen in the megakaryocytes that are calreticulin mutant with, reduction in the bone marrows. So this looks really promising. I think in ET, the path for drug approval will be dependent on potential disease modification, and in patients with calreticulin mutant ET, this is promising, and I'm sure we'll see the Phase 2, Phase 3 trial, ongoing, and it's, again, a trial that will be encouraging to refer patients to.
The next trial was with the monoclonal antibody against the calreticulin, but this was in patients with myelofibrosis. The study looked at either monotherapy in around 52 patients, or in combination with ruxolitinib. And it took patients that were intolerant, resistant to a JAK inhibitor, or not eligible, or patients that had a suboptimal response in the combination arm.
And similar to the ET trial, the treatment was relatively safe. There was no DLTs, and the main adverse events were myelosuppression, namely anemia and thrombocytopenia in a small subset of patients. We also noted in the monotherapy arm that there was encouraging activity, where almost one-third of the patients had a spleen volume reduction by 35% or more, and Almost 60% of the patient had more than 50% reduction in the total symptom score, addressing the symptom burden of this disease.
There were also, reductions in the allele burden, where around, 11% of the patients had 25% or more reduction in the allele burden, with the treatment. So, this is also, again, promising, in terms of potential disease modification, the authors noted, reductions in the mutant calreticulin megakaryocytes, and in the fibrosis in the bone marrow, and that correlated with some of the improvements noted.
So, again, early trials with monoclonal antibodies in calreticulin mutant ET and MF, but very promising, with, again, potential disease modification in those subset of patients.
Shifting to myelodysplastic syndromes, probably the most important trial to highlight in the higher risk MDS is the highly anticipated VERONA trial. The early data were presented at SOHO meeting, but the subset analysis was presented at ASH.
The VERONA trial looked at higher-risk MDS patients to be randomized between azacitidine venetoclax compared to azacitidine alone. This is obviously following on the steps of the VIALE trial that led to the approval of venetoclax in AML. The study did not meet the primary endpoint of overall survival, and that was earlier presented at the SOHO meeting. At ASH, we looked at subset analysis and subgroup analysis. The trial randomized 256 patients to the combination arm and 253 patients to the azacitidine alone arm.
In the subset analysis, there were trends of favorable overall survival, in patients younger than age of 75, in patients with a very high or high-risk IPSS-R, in patients with high blast more than 5%, and selected mutations. The overall response was actually favored in many of those patients, so it did yield to higher responses, did not translate to overall survival in all subsets, but it seems subgroups had a favorable overall survival, albeit the study was not powered to address that.
There had been several limitations of this study, mainly capping the number of patients that had proceeded to transplant. When we look at that group of patients, many of those patients off-study received venetoclax.
Also, almost 21% of the patients received venetoclax after the study. That could be confounding for the overall survival. There were dose reductions on the azacitidine before the venetoclax that also may have impacted the outcome. So, I think the verdict is still out on the role of venetoclax in patients with MDS, patients with higher blast percentage, higher risk as a bridge of transplant may benefit from this treatment, and hopefully we'll see confirmation of that. In practice, it's still used in those selected subsets with a very high blast percentage, certain mutations like ASXL1 as a bridge to transplant. I think there is still role for venetoclax among those patients.
In lower-risk MDS, there was a presentation on imetelstat showing a correlation between the cytopenia and response. Imetelstat got approved by the FDA for patients with lower-risk MDS after ESA failure in highly transfusion-dependent patients. The main challenge had been the myelosuppression that can be encountered with imetelstat in the first few cycles, where more than 50% of the patients will have grade 3 or 4 neutropenia thrombocytopenia. That, fortunately, actually does not translate to a substantial increased risk of febrile neutropenia or bleeding.
This analysis looked at the whole imetelstat program that included the Phase 2 trial, The iMerge Phase 3 randomized trial and an extension study, so almost 226 patients. It looked at, really, the cytopenias developing on treatment and correlation with outcome. So, first, they demonstrated that there was a linear correlation between the thrombocytopenia and neutropenia on treatment as a continuous variable, and the maximum hemoglobin increase.
And also, when we looked at a 50% reduction in the platelet, or more than 70% reduction in the neutrophils, there was a correlation with the maximum hemoglobin increase. There is also a correlation with the hemoglobin increase of 1.5 mg or more, with the platelet or neutrophil reduction.
This is important, obviously, clinically, that patients that are developing cytopenia on treatment, that's a probably sign of response. Some were suggesting that maybe if there is no cytopenia observed at all, that the chances of response are gonna be low. This doesn't mean that we push through, we still have to follow the package insert in terms of dose reduction on holding, but that cytopenia on treatment is actually a predictive of response in terms of transfusion independency, the maximum hemoglobin increase, and the one and a half or more hemoglobin increase. There was also nice correlation that the treatment emergent cytopenias, or platelet reduction, particularly correlated with the SF3B1 variant allele frequency reduction.
The last study to highlight is really a study that had been ongoing for a long time, trying to look at optimal dosing of hypomethylating agents in lower risk. This was a study conducted under the USA MDS Consortium years ago, and had matured to have the full data presented at ASH. This study took patients with lower risk MDS, there were two cohorts, either patients that are transfusion-dependent or transfusion-independent. And it looked at the role of hypomethylating agents that are used in the United States for lower-risk MDS. Patients were randomized to the classical 5 days azacitidine versus a shorter version, 3 days azacitidine or 3 days decitabine. In an earlier Phase 2, there were promising results from 3 days decitabine or 3 days azacitidine. The data were presented at this ash, showing long-term results of this analysis.
Collectively, all together, I think the best results were obtained with the 5 days azacitidine in terms of event-free survival, overall survival responses, and tolerability. Obviously, there were hematological responses observed with the 3 days azacitidine and 3 days decitabine, but collectively, it seemed that azacitidine, 5 days is the best regimen in terms of balance of activity, as well as adverse events. The study was conducted in the era before of some of the recent approved therapies, like luspatercept or imetelstat, so we still try to hold use of hypomethylating agents after failure of those therapies or in patients that have, you know, neutropenia or thrombocytopenia, that will exclude use of other therapies or need treatment. Obviously, the field is evolving. We heard also at ASH data on oral hypomethylating agents, azacitidine, cedazuridine combination, or a lower dose of decitabine, cedazuridine, combination. So we'll be seeing more, but in practice nowadays, if we are treating lower-risk MDS patients that need hypomethylating agents, I think 5 days azacitidine is probably, based on this data, is the best balance between efficacy and adverse events. So hopefully this was helpful to give you a quick, rapid tour of some of the important data presented at ASH in both myelodysplastic syndrome and myeloproliferative neoplasm. Thank you for listening.