Luspatercept’s Benefit in MDS: Dr Garcia-Manero on COMMANDS Trial

Luspatercept-aamt (Reblozyl) significantly improved overall survival (OS) and durable red blood cell transfusion independence (RBC-TI) compared with epoetin alfa in patients with transfusion-dependent, lower-risk myelodysplastic syndromes (MDS), according to updated data from the phase 3 COMMANDS trial (NCT03682536) presented at the 2025 American Society of Clinical Oncology (ASCO) Annual Meeting.¹

The rate of RBC-TI for at least 12 weeks was 76.4% with luspatercept vs 55.8% with epoetin alfa (OR, 2.8; P <.0001). Luspatercept also yielded significantly longer median duration of RBC-TI (126.6 vs 86.7 weeks; P =.0156) and cumulative duration of transfusion independence (150.0 vs 95.1 weeks; P =.0011). Safety remained comparable between arms, with a potential signal for lower progression to high-risk MDS in the luspatercept group.

These data represent a major shift in the treatment approach for erythropoiesis-stimulating agents-naive patients with very low-, low-, or intermediate-risk MDS, reframing luspatercept not just as a supportive care agent but as a potential disease-modifying therapy.

The global, randomized, open-label COMMANDS trial enrolled patients 18 years and older with revised IPSS very low- to intermediate-risk MDS, including those with or without ring sideroblasts, and serum erythropoietin levels <500 U/L. Patients were randomly assigned 1:1 to receive subcutaneous luspatercept every 3 weeks or epoetin alfa weekly, with titration based on clinical response. The study’s primary end point was RBC-TI for ≥12 weeks with ≥1.5 g/dL hemoglobin increase within 24 weeks. Secondary end points included OS, duration of RBC-TI, acute myeloid leukemia progression, and safety.

In an interview with Targeted Oncology, Guillermo Garcia-Manero, MD, lead study author and chief of the Section of Myelodysplastic Syndromes and deputy chair of Translational Research in the Department of Leukemia at The University of Texas MD Anderson Cancer Center in Houston, discussed the long-term results, emphasizing that luspatercept may now be considered a first-line standard for eligible patients with MDS.

Targeted Oncology: Can you provide some background on the COMMANDS trial?

Garcia-Manero: The COMMANDS trial is a phase 3 trial comparing luspatercept vs epoetin alfa. Luspatercept is a TGF-beta modulator that, in a prior study known as MEDALIST [NCT02631070], was shown to be active and safe in second-line transfusion-dependent patients with lower-risk MDS. COMMANDS is a study where we compare luspatercept vs the standard of care erythropoietic-stimulating agent, epoetin alfa, in previously untreated transfusion-dependent patients with low-risk MDS of any type. The low risk is defined by IPSS-R, basically less than 3.5 points.

The primary end point of the study was a dual end point looking at transfusion independency plus an increment in hemoglobin of at least 1.5 grams. The study was actually presented at ASCO a couple of years ago and I had the opportunity to do that. It met its primary end point, and it has become probably the standard of care for a significant fraction of patients with low-risk MDS that are transfusion dependent. It's approved in many countries all over the world.

Now, there were a number of preplanned analyses on COMMANDS that have been presented at [the American Society of Hematology Annual Meeting] and ASCO over the years. At ASCO 2025, I had the opportunity to present an update that is really important—a follow-up that now is quite significant in terms of its duration—where we show that not only, with more time, we saw that luspatercept keeps being a better agent in terms of limiting the rate of transfusions, but that it also improves the survival of our patients with low-risk MDS.

I think this is important because until now, most of the studies in low-risk MDS have focused [on] mitigating transfusions and maybe the complications of those transfusions. But here, for the first time, we are seeing a significant improvement in survival. And the question is: how does this happen? I think this is actually going to be transformative in this field.

What do these longer results suggest about the potential for luspatercept to extend life for these patients?
The survival for patients with low-risk MDS is relatively long, so you will not expect to see a difference in survival immediately. The curve that we saw at the ASCO meeting in one of the oral rapid session presentations shows that it takes around 36 months for this curve to separate. But this is actually expected. This is the natural history of this disease, so you will not expect untreated patients with low-risk MDS to die that quickly.

It takes some time, and then somehow this TGF-beta modulator is changing the biology of the disease in such a way that now this is resulting in an improvement in survival. Now, it could be that increasing hemoglobin or the lower rate of transfusions could, of course, be part of this, but I think it’s beyond this. I think that maybe modulating TGF-beta in other tissues like the heart or the lungs could have a role in this phenomenon. Now, we do not measure this in clinical trials, so we have to go back and figure out why this is happening. But this is very important because this will change our perspective of an intervention that is just to improve quality of life or decrease transfusions to maybe start thinking that these treatments could improve survival of patients with MDS.

Two-thirds of these patients, when they present, are in a low-risk situation. In the past, maybe we were not treating them as aggressively, or we were just thinking about transfusion support and so forth. I think now in the community, we are going to start thinking about, if I do this treatment, am I actually promoting longer survival? So, I think patients would be very interested in this.

How do these longer-term results translate into improved quality of life and reduced burden for patients?

This is very important. We actually do not have this data because, as opposed to myelofibrosis or other related diseases, it is very difficult to measure quality of life in [patients with] MDS. And then when you do this in the context of a study like this, where there's no placebo and you’re actually transfusing to a certain level, it is actually very difficult to measure that.

So that is a limitation that we see from these trials, and that is, how does this translate into better well-being. But I think, again, going back to if you ask a patient if they would be interested in living longer with an approach that is nontoxic, I think they would be very excited about it. Indeed, something that I failed to mention earlier is that the longer-term follow-up of the COMMANDS keeps showing that the toxicity profile between both arms is basically identical. There’s no excess toxicity. There is no excess mortality. Indeed, there is a signal that patients on the luspatercept arm have a decreased rate of transformation to high-risk myelodysplastic syndrome.

Were there any new safety signals or long-term considerations that have emerged?

Not at all. Indeed, maybe a little bit lower rate of transformation, which is interesting. So it may be that this improvement in survival is multifactorial—lower transfusions, increased hemoglobin, maybe lower rate of transformation.

How do you think these data will empower clinicians in shared decision-making conversations with their patients about initial treatment strategies?

This is actually a very interesting question that you're asking because the growth factors, the erythroid-stimulating agents, have been with us for as long as I remember, over 30 years. And they are great drugs. These drugs really help our patients for many years. Now we have a newer option that is far superior, in my opinion. But the reality is that we have used these growth factors for a long period of time. Another question is: How does the community change? And of course, these new drugs are more expensive, etc.

I think that this data on survival is going to be important for people to make these kinds of decisions, because now, when you see a patient and you're going to say, "I'm going to give the standard-of-care drug that we have for 20 years vs this one that improves survival," will that have an effect on your decision-making? I would hope so. We have had luspatercept now for a number of years, and I do not have any information in terms of how fast or slow this is being incorporated into practice. There are some issues with subsets of patients in these studies, particularly the ring sideroblastic-negative cohort, that some people said, "Well, maybe we can use the older erythropoietic drug," and so forth. But now you have survival data.

I don't know how this is going to change things, but I think survival data is something that physicians react very well to. Now, that said, survival was a secondary, preplanned end point. The study is really not designed to measure improvement in survival as a primary end point. So, I could still see that there may be some groups that benefit more or less, these kinds of things. But bottom line: This is a safe intervention that is more effective and is leading to longer survival of our patients.

Looking ahead, what further real-world evidence or long-term follow-up would be most valuable for other oncologists?

The next steps will be some type of combination, because if you know luspatercept gives you a response in around 60% to 70% of the patients, so if now I come with a combination that is safe, that gives me 90% response rate, maybe our patients will start living longer.

So, what is in my head is: What kind of rational combination will be out there that could really result in further improvements in responses? Hopefully, we will be better at measuring quality of life or some of these extra bone marrow effects that these drugs could have. And maybe we will have better and safer strategies for those patients. I think that's what is in my head. Time will tell. But I think for researchers in this area, that will be the next generation of studies.

REFERENCE:

Garcia-Manero G, Giovanni Della Porta M, Zeidan A, et al. Overall survival (OS) and duration of response for transfusion independence (TI) in erythropoiesis stimulating agent (ESA)–naive patients (pts) with very low-, low-, or intermediate-risk myelodysplastic syndromes (MDS) treated with luspatercept (LUSPA) vs epoetin alfa (EA) in the COMMANDS trial. J Clin Oncol. 2025;43(suppl 16):6512. doi:10.1200/JCO.2025.43.16_suppl.6512