Outcomes With Luspatercept Not Affected by Mutational Profile in MDS

Alternative approaches to management of low-risk myelodysplastic syndromes (MDS) have accumulated positive trial data and FDA approvals in recent years. During an in-person Case-Based Roundtable meeting for oncologists in Raleigh, North Carolina, Thomas W. LeBlanc, MD, MA, associate professor of medicine in the Duke University School of Medicine, reviewed the key trials and real-world analyses showing the importance of dose modification on achieving transfusion independence and maintaining quality of life. He emphasized fine-tuning the dose of therapy to achieve transfusion independence in these patients and also addressed the question of whether novel therapy responds differently based on the mutational profile of MDS.

This article is part 2 of a 2-part series from a Case-Based Roundtable event.

Targeted Oncology: When would you use dose escalation of luspatercept (Reblozyl) in a patient who did not respond?

Thomas W. LeBlanc, MD, MA: The earliest you can dose escalate is after 2 doses of the starting dose level. You give your first dose, 3 weeks later you give the second dose; [then] you could dose escalate, if you need to, if they're not transfusion independent. Six weeks in is the earliest you could do it.¹

Sometimes what happens is people will have symptom or adverse event issues in the first couple doses. I don't always go up with dose 3. If somebody's having tolerability issues and I'm concerned about that, I might give them another dose at the starting dose level to make sure that they're not going to quit, because that's the worst thing. If they quit before you dose escalate, then you're never going to get the benefit. I'll sometimes dose escalate after a third or fourth dose. But the key is, you do have to dose escalate to get efficacy with this therapy. In the COMMANDS trial [NCT03682536], approximately [70%] of patients needed a dose escalation.² Not everybody [achieves] transfusion independence, but approximately 60% will, so you want to dose escalate to get that benefit.

What do you do for a patient who achieved transfusion independence after 1 dose increase?

I would keep it at the same dose. The goal is transfusion independence, until you get to the maximum dose. If you need it to go to the maximum dose you would be looking for any signs of benefit, just like you do with erythropoietin-stimulating agent (ESA). Let's say they're still requiring blood transfusions and they're at the maximum dose, but they're needing only 1 [unit] of blood a month, instead of 2 [units] every 2 weeks. That's an improvement. You keep luspatercept going, and you would give them the transfusions as needed as well.

With the broader frontline indication for luspatercept, how do you decide to use it vs ESA?

I keep things simple. There's too much going on, and with data and practice, this is a therapy that I can give less often that's at least as effective in the worst subgroup, so that’s probably what I'm going to do. Especially when you consider the longer duration of follow-up, and there are some data [showing] you get longer duration of responses in some of those people who are ring sideroblast–negative, even though the response rate may be about the same as ESA.³ I think there's probably more reason to use this therapy for all comers in the frontline. That keeps it simple.

What is your sense of community practices in terms of their comfort level with luspatercept?

I've found it's very variable. There are some physicians and practices where they just don't know about luspatercept and they haven't used it at all, vs others who are mostly using it up front. I still see and hear a lot of people using ESA first line and going to luspatercept second line, and when you look at the data, I don't think there's a good rationale for that anymore. There was before, but now, knowing what we know from COMMANDS, and now that the longer-term follow-up data have come out, I think it's just going to take a little bit more time for everybody to learn more about this and then get comfortable using it because we've all been using ESA for so long.

How does the mutation profile of MDS affect outcomes in the COMMANDS trial?

Looking at mutation burden, this is preliminary, but you don't get the sense there is some big group of patients who are driving the benefit or not deriving any benefit at all. There are a lot of confidence intervals that cross the line of no difference, because these are all small groups, but [the analysis included] the mutations that we commonly see in myeloid malignancies like MDS. The only one that's standing out as not favoring luspatercept is CBL, and it's 5 patients, a small number. That's not something we see very often.⁴

In myeloid malignancies, generally by the time patients come to attention with an MDS or acute myeloid leukemia [AML] diagnosis, they have multiple clones. There's a predominant clone and there's at least 1 or 2 subclones, and so we commonly find 2 to 3 myeloid mutations once a person has AML or often MDS as well. Because of the theory of how clonal hematopoiesis leads to MDS or AML, you accumulate mutations like DNMT3A which is a clonal hematopoiesis of indeterminate potential mutation. It's not a leukemogenic or MDS-causing mutation. It becomes prevalent in almost all the myeloid cells. Then another mutation happens in just a subset, and then that becomes predominant, and maybe that causes disease and manifestations, but all those other ones are sitting there. It's rare that we see 1 of these diseases with just 1 mutation, and until we have single-cell sequencing data, we're never going to know which is the predominant clone. That's where things will get more sophisticated in the future.

I think this can give you confidence that you don't have to worry as much about the mutational profile. If it’s low-risk MDS, and if the person is requiring transfusion, luspatercept is probably going to be the right therapy for them. As you go up in number of mutations, the response rate goes down, whether ESA or luspatercept, but with 1, 2 and 3 different mutations, there was a higher response rate to luspatercept than to ESA. Once you get to 4, it drops off, and with 5 or 6, it's effectively 0%. MDS with lots of mutations…is not going to respond as well. But in a typical MDS where you have 2 or 3 mutations, these patients do better in general with luspatercept than with than ESA.

DISCLOSURES: LeBlanc previously reported honoraria for consulting/advisory boards from AbbVie, Agilix, Agios/Servier, Apellis, Astellas, AstraZeneca, Beigene, BlueNote, BMS/Celgene, CareVive, Daiichi-Sankyo, Flatiron, Genentech, Geron, Gilead, GSK, Incyte, Lilly, Meter Health, Menarini-Stemline, Novartis, Pfizer, Rigel, Seattle Genetics, Syndax; speaking related honoraria from AbbVie, Agios, Astellas, BMS/Celgene, and Incyte.

REFERENCES:

1. Reblozyl. Prescribing information. Celgene Corporation; 2024. Accessed July 7, 2025. https://tinyurl.com/2w5eykwt

2. Komrokji RS, Platzbecker U, Della Porta M, et al. MDS-234 reduction of transfusion burden (TB), hemoglobin increase, and dose titration in the COMMANDS study of luspatercept versus epoetin alfa (EA) in erythropoietin-stimulating agent (ESA)-naive patients with transfusion-dependent (TD) lower-risk myelodysplastic syndromes (LR-MDS). Clin Lymph Myel Leuk. 2023;23(suppl 1):S184. doi:10.1016/S2152-2650(23)00608-0

3. Garcia-Manero G, Santini V, Zeidan AM, et al. Long-term transfusion independence with luspatercept versus epoetin alfa in erythropoiesis-stimulating agent-naive, lower-risk myelodysplastic syndromes in the COMMANDS trial. Adv Ther. 2025;42(7):3576-3589. doi:10.1007/s12325-025-03208-5

4. Komrokji RS, Guerrero MU, Garcia-Manero G, et al. Impact of genomic landscape and mutational burden on primary endpoint responses in the COMMANDS study. Blood. 2023;142(suppl 1):4591. doi:10.1182/blood-2023-178689