Investigational Studies in MDS: Exploring Promising Therapies

David Sallman, MD

In the field of myelodysplastic syndromes (MDS), there are a number of investigational studies designed with the hope of changing the landscape of treatment, particularly for patients with high-risk disease. David Sallman, MD, discussed these developments during the 2024 Society of Hematologic Oncology Annual Meeting.

“There has been a significant understanding of disease states, classifications, and prognostics, but clinical drug development has been much slower. I really hope we will have a drug to push us forward so we can start thinking about that again,” explained Sallman, myeloid section head and associate member of the Malignant Hematology Department, H. Lee Moffitt Cancer Center and Research Institute, during an interview with Targeted Oncology^TM.

Historically, clinical trials in high-risk MDS have faced significant challenges, with most studies failing to show significant improvement in patient outcomes. However, a new wave of studies, including the highly anticipated VERONA (NCT04401748) and SELECT-MDS-1 (NCT04797780) trials, holds promise to reshape the standard of care for patients with high-risk MDS.

If positive, the results of these trials may help create a paradigm shift in MDS treatment, particularly for patients who are high risk. Even if the results are negative, Sallman explained that the insights gained from these trials will help refine future study designs.

In the interview, Sallman discussed the challenges and new studies of high-risk MDS therapies.

Targeted Oncology: Can you discuss some of the investigational studies in the MDS space?

Sallman: We, unfortunately, have a very long history of failed studies dating back, really since 2006. We have 1 landmark study that was a positive phase 3 trial that set the stage. We have had change in classification systems, change in prognostic systems, and at the same time, designing relatively similar trials. There [are] some modern studies that also unfortunately failed as well, and then [there are] 2 trials that we are eagerly awaiting the readouts for, which hopefully can change the standard-of-care therapy for patients with high-risk MDS.

What are some of the innovative therapies or strategies being investigated in these studies, and how did they differ from existing treatments?

The trial we are maybe most eagerly awaiting is the VERONA trial, which is a phase 3 trial of azacitidine with venetoclax [Venclexta] vs azacitidine therapy alone. Of course, in [acute myeloid leukemia (AML)], this has very much changed the standard of care for [older patients with] AML, although it is impacting many patients in all different situations. [VERONA] is a relatively similar design.

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I think in MDS, we know that the cytopenia toxicities are a little bit less well tolerated, and thus, we have a lower schedule of venetoclax. There has been a large phase 1, borderline phase 2 study presented by Jacqueline Garcia, MD, at [the American Society of Hematology (ASH) Annual Meeting] where there are 107 patients, and response rates, at least from composite [complete] response [CR] rates, are significantly higher. Data from our center that we published look relatively identical from that perspective. But…we need to improve overall survival. That is really the key primary end point of the trial, and so that is what we are currently waiting on.

I think particularly for patients that can go to allogeneic stem cell transplant, the therapy is very effective. I think it really does induce deeper and what I would call [minimal residual disease (MRD)]-negative remissions, which not has not really been a thing in myelodysplastic syndrome. But I think that the balance of what percentage of patients get there may tip whether the trial is positive or not. Although, I think the utilization, at least in the United States, will still be significantly high. They went over those data in detail. Again, we need that trial.

The other main study that we hope to have data by the end of the year is the SELECT-MDS-1, which is a phase 3 trial of azacitidine/tamibarotene [Amnolake] vs azacitidine alone. This is a little bit for a biomarker-specific group. You have to have what is called RARA overexpression, which is about 50% of [patients with MDS]. What we are going to know, at least by the end of the year, is the CR rate in the first 190 patients. The trial is actively accruing up to over 500 patients with a secondary end point of overall survival. Hopefully, we are going to have both of these data, maybe by the end of the year, and maybe finally, changing that frontline landscape because the whole field is a little bit in a lull, I would say, with a lot of negative trials, and then whether or not the standard of care is changing, or do we need to start from scratch and completely redesign these type of studies?

Is there anything kind of notable about the design of these trials, or the patients included?

I think we have underappreciated how heterogeneous these patients are. There are key molecular subgroups that are very different. As part of the session, p53-mutant disease is its own entity and should be classified as p53 MDS/AML, including everyone with 5% blasts or greater, complex karyotype, or any multihit or biallelic definition. This group probably needs to be studied separately. It can represent 20% to 30% of large phase 3 trials, potentially negatively impacting results, especially if there is an imbalance, as these studies have not been stratified for these patient groups.

One thing we are increasingly thinking about is that in AML, we still only have 1 new positive trial that is not for a specific AML subgroup—this is azacitidine plus venetoclax. However, the VIALE trial [NCT02993523] had a very specific population. Patients could not be fit for transplant, so they had to be over 75 or younger with specific comorbidities. Only 1 or 2 patients were transplanted. In phase 3 MDS trials, there are huge differences. In the ENHANCE magrolimab [Hu5F9-G4] trial [​​NCT04313881], 30% in the placebo group were bridged to stem cell transplant, whereas in the phase 3 STIMULUS sabatolimab [MBG453] trial [NCT03946670], it was 10%, equal between arms. In the magrolimab trial, the difference was dramatic. These imbalances can completely affect overall survival results.

Other than key subgroups, we may need to think more about strategies for truly unfit patients and those fit for transplant. The question is how to redo some of these studies. I think the differences, particularly around transplant, can significantly impact the results.

Are any of these studies exploring combination therapies for MDS?

In the high-risk setting, we are seeing doublet combinations. There is already talk and consideration around triplet therapies, which are becoming the main trial strategy in AML. Though there is not 100% consensus on whether all the drugs should be given together or in some sort of sequencing therapy, I personally favor administering all the drugs upfront. I think achieving the best response with the first treatment is key. But the challenge remains in developing new doublets. Until we have that, it is difficult to think beyond it, especially in the [hypomethylating agent (HMA)] failure setting.

Azacitidine is still our current treatment, and will continue to be, even with the emergence of doublets. In that subgroup, we're trying monotherapies, but efficacy in those patient groups has been quite poor. With updated response criteria, eliminating marrow blasts often results in response rates close to zero. So, the question arises: do we need combination strategies even in that setting? There are multiple pathways driving malignant cells and underproduction of blood counts.

In the lower-risk space, we are starting to explore combination therapies like luspatercept [Reblozyl] and [erythropoiesis-stimulating agents (ESAs)]. We have published on this, and several additional trials are showing promise. It can rescue patients who initially responded to luspatercept and then failed. Frontline combinations for non-ring sideroblast patients could be an issue, but we are combining many things. With other agents like lenalidomide and imetelstat [Rytelo] coming into play, there are questions about preclinical rationale, but it is exciting to see new therapies in the lower-risk space. The goal is not just to increase the percentage of patients who become transfusion-independent, but to raise hemoglobin levels to improve quality of life.

How do you foresee the results of these studies influencing clinical practice in the future?

In high-risk [disease], if we can finally achieve an overall survival improvement, it would definitely be a paradigm shift, and we could start building on that. There has been a significant understanding of disease states, classifications, and prognostics, but clinical drug development has been much slower. I really hope we will have a drug to push us forward so we can start thinking about that again.

If the results are negative, there will still be off-label use of venetoclax, but we may need to rethink how we optimally design trials. We have learned a lot from MDS-focused trials, especially when it comes to molecular subgroups and prognostication. Balancing transplant considerations is also key. Hopefully, with smarter trials and clearly active drugs, we can finally cross the threshold of having new therapies for our patients.

What do you believe are the most promising future directions for investigational studies in MDS?

I think, unfortunately, molecular targets are rare right now. We know that for patients with IDH mutations, there are approved treatments like ivosidenib [Tibsovo] and enasidenib [Idhifa], which show activity in that setting. We are trying to move these drugs more upfront. One area we have not discussed much is targeting “untargetables,” like p53 mutations. We helped lead eprenetapopt [APR-246], a first-in-class p53 reactivator, and would like to run new studies with exciting data, possibly combining it with an XPO1 inhibitor from a project at my institution. We are also rethinking posttransplant maintenance and exploring other specific inhibitors like RGT100, a Y220 p53 reactivator, used in solid tumors. Many key centers are interested in trying it in this setting.

For splicing mutations, which affect about 50% of [patients with] MDS, lab concepts have shown promise, though they have not translated to clinical activity yet. Targeting that could be a huge step forward. In lower-risk MDS, we understand more about pathogenic drivers, not just from mutations, but pathways like inflammasome activation. Trials involving IL-1 beta inhibitors [like] canakinumab [Ilaris] and NLRP3 inhibitors are starting. We hope to see results, but combinations might be necessary since blocking one pathway could activate another.

Can we change the natural history of [patients with] lower-risk MDS patients? That is a big question. Another step could involve exploring earlier end points to guide treatment, like using molecular clearance of minimal residual disease as a marker in MDS.

REFERENCE:
Sallman D. Investigational studies in MDS. Presented at: 2024 SOHO Annual Meeting. September 4-7, 2024; Houston, TX. MTP VII: MDS