Building on data from the phase 3 COMMANDS (NCT03682536) and MEDALIST (NCT02631070) trials, further analyses of data for the use of luspatercept-aamt (Reblozyl) for the treatment of anemia in patients with lower-risk myelodysplastic syndromes (MDS) could help refine patient selection and drive personalized treatment decisions for this population, according to Jan Philipp Bewersdorf, MD, FACP.
“Treatment for patients with MDS is being increasingly individualized,” Bewersdorf said. “If you look at, for example, the National Comprehensive Cancer Network Guidelines, there is a big flow chart with a lot of different options that are available for our patients, so it’s important to keep in mind which patients were included in the COMMANDS trial vs which patients were not in that trial.”
Data from a meta-analysis examining outcomes from 7 clinical trials and 13 cohort studies for luspatercept in the treatment of anemia in patients with lower-risk MDS showed that evaluable patients from 15 studies (n = 2090) achieved an 8-week red blood cell (RBC) transfusion independence rate of 50.2% (95% CI, 39.9%-60.4%; I2 = 94.9%).1 The 8-week RBC transfusion independence rate was 57.9% (95% CI, 47.4%-67.7%; I2 = 86%) among patients with ring sideroblast (RS)–positive disease treated in 8 studies (n = 765) vs 43.0% (95% CI, 30.3%-56.7%; I2 = 81.2%) for patients with RS-negative disease for 4 studies (n = 383; P = .004).
In an interview with OncLive®, Bewersdorf detailed the rationale and design of the meta-analysis, expanded on the key outcomes reported, and explained how these findings add to data regarding the use of luspatercept for the treatment of anemia in patients with lower-risk MDS following its frontline approval by the FDA in August 2023.2
Bewersdorf is an assistant professor of medicine (hematology) at the Yale School of Medicine in New Haven, Connecticut.
OncLive: How has the first-line approval of luspatercept for the treatment of anemia in patients with lower-risk MDS affected the MDS treatment paradigm?
Bewersdorf: [MDS] is primarily a disease of older adults, with an average age at diagnosis in the mid-70s, and approximately two-thirds of the patients present with lower-risk MDS. The most common clinical manifestation of lower-risk MDS is anemia, so this is an area of significant clinical need because it affects a lot of patients. Our treatment options before the approval of luspatercept were essentially erythropoiesis-stimulating agents [ESAs], with the exception of patients who have 5q deletions, who are treated with lenalidomide [Revlimid]. Outside of [the subgroup of patients with 5q deletions], there were limited treatment options available, and with ESAs, treatment responses are all transient. Some patients have no response at all right from the beginning, and the patients who do respond eventually lose their response.
A few years before the first-line approval of luspatercept, there was a similar study called the MEDALIST trial that evaluated luspatercept against placebo in a second-line setting for ESA-refractory patients, or patients with a high serum EPO level who were therefore unlikely to respond to ESA. What they showed in that study was that luspatercept was more effective than placebo in improving anemia among patients with lower-risk MDS who had RS-positive disease or an SF3B1 mutation, and usually those things go hand in hand and constitute most patients with lower-risk MDS. Based on [the MEDALIST] data, luspatercept got approved by the FDA and by the European Medicines Agency for second-line management of anemia in MDS.
However, there is no reason why luspatercept shouldn’t work in a first-line setting. That led to the COMMANDS trial, which evaluated luspatercept vs ESA for patients with transfusion-dependent anemia secondary to lower-risk MDS, independent of their RS or SF3B1 mutation status. What the COMMANDS trial showed was that in that unselected patient population, luspatercept led to higher rates of RBC transfusion independence with a concurrent improvement in hemoglobin [levels], and that was mainly driven by the patients with RS-positive disease and SF3B1 mutations. Regardless, the trial as a whole was positive, so luspatercept also got approved for the frontline management of anemia in lower-risk MDS.
Growing Body of Evidence for Luspatercept for Anemia in Lower-Risk MDS
- A meta-analysis showed that luspatercept drove RBC transfusion independence in the treatment of anemia in patients with lower-risk MDS, particularly for patients with RS-positive disease.
- The 8-week RBC transfusion independence rate was 51.2% among all evaluable patients.
- In August 2023, the FDA approved luspatercept for the treatment of anemia without prior use of an ESA in adult patients with very low–to-intermediate-risk MDS who may require RBC transfusions.
What was the rationale of conducting a meta-analysis to further delve into studies of luspatercept in patients with lower-risk MDS?
The question we’re struggling with a bit in clinical trials vs real-life practice is: How transferable and applicable are the results from clinical trials to most patients we see in routine clinical practice? Clinical trial enrollment might not be representative of the patient population as a whole, and it’s also important to keep in mind that there were several real-world studies that were already published before the COMMANDS trial. Therefore, we tried to synthesize all those data to get a more comprehensive sense of how effective luspatercept is for the management of anemia in lower-risk MDS, across treatment settings and across mutational/RS status. [Additionally], we looked at safety because this is an older patient population that frequently has comorbidities. Treatment workflows—luspatercept or ESA—are meant to provide palliation and symptomatic improvement. Safety is always a major consideration.
What data were gathered for the meta-analysis, and how were they reviewed?
We developed a search strategy with a medical librarian that was also peer-reviewed. We searched 6 different databases, looking for medical subject terms [related to] evaluating the management of lower-risk MDS. We identified a total of 1672 records, and some of them were duplicates; ultimately, we ended up with 854 [records]. You always go through a title and abstract, and then you look for exclusion criteria. We ended up with 199 studies available for full-text inclusion, and then we had a set of predefined exclusion criteria, where we essentially look for the quality of the studies, making sure they’ve reported our primary outcome of RBC transfusion independence. We ended up with a total of 20 studies that were included in this [analysis]: 7 of those were clinical trials, and 13 were cohort studies.
What were some of the key takeaways from this meta-analysis of luspatercept for anemia in lower-risk MDS?
It’s always a bit challenging to interpret those data because it’s a heterogeneous input that you have into this analysis. You have retrospective studies, you have clinical trials with different inclusion criteria, and sometimes you have different end point reporting. However, our primary end point was the rate of 8-week RBC transfusion independence, and we found that this was met in 50.2% of patients across this [analysis] population—15 studies were included here out of those 20, with 2090 patients. [This was] a bigger number than what we see with any clinical trial. Similar to what we see in clinical trials, response rates were higher in patients with RS-positive disease vs RS-negative disease [at] [57.9]% vs 43.0%, [respectively]. This is nice because this is also close to what we see with the COMMANDS trial, so this is real-world supporting evidence that we generated here, reassuring that the data that have been reported also seem to be applicable to real-world practice.
Turning to safety, what was observed with the use of luspatercept and how it compared with clinical trial data from COMMANDS and MEDALIST?
[Safety] is an important consideration in our patient population. Overall, luspatercept is a medication that’s well tolerated. There are [adverse] effects [AEs] that are attributable to the medication, but they’re usually of lower grade, and only a few cases lead to drug discontinuation. The most common AEs we saw [in the meta-analysis] were peripheral edema in [17.8% (95% CI, 11.4%-26.8%)] of patients, [along with common AEs of] back pain and diarrhea.
[Findings are] always a bit different in clinical trials vs real-world studies, and in general, we found that AE rates are higher in clinical trials, which is just a reflection that patients on clinical trials are more carefully monitored and AE [reporting] is being more frequently solicited compared with in real-world studies. Overall, it was reasonably well tolerated. The rate of serious AEs was 28% across studies.
Were there any limitations with this meta-analysis?
There are always limitations inherent with [this type of] study design. There is selection bias, more so than in retrospective studies. Additionally, how frequently is AE [reporting] solicited? The other issue is the heterogeneity across study populations. We pooled aggregate data, so we did not have access to patient-level data, which would be nice and would have allowed for even more granular subgroup analyses. This needs to be kept in mind, [along with] differences in how data were reported for other rarer outcomes, [such as] more long-term RBC transfusion independence, disease progression to higher-risk acute myeloid leukemia [AML] or higher-risk MDS, or even AML overall survival. Those outcomes are harder to ascertain, so we cannot comment on them.
Lastly, quality-of-life data are interesting in this patient population, but it’s also not available. Therefore, we focused here on the most most robust end point, which was the 8-week RBC transfusion independence rate and the rates of hematologic improvement, and that’s where we feel confident in the validity of our results with the other analyses. We just have to keep the limitations of the study design in mind and be careful how we interpret.
How does this analysis add to the body of evidence driving the use of luspatercept in clinical practice for the treatment of anemia in patients with lower-risk MDS?
Patients with 5q deletions were not included in [the COMMANDS] trial, and they have an effective treatment option with lenalidomide available. Those [patients] should not be treated with luspatercept in the frontline setting. For patients with elevated EPO levels, things can get a little bit trickier, because the COMMANDS trial also required a low serum EPO level. If a patient at baseline already has an elevated EPO level of 500 [IU/L] or higher, data for luspatercept in the frontline setting are a bit more limited. If a patient has a high serum EPO level [plus] RS[-negative disease] and no SF3B1 mutation, there’s another medication available: imetelstat [Rytelo]. That might be an option for those patients, but for all other patients, luspatercept is a good choice. [It is] the preferred choice for a patient with a low serum EPO level who has an SF3B1 mutation or RS-positive [disease], which is superior to ESA.
For the minority of patients with RS-negative, SF3B1 wild-type [disease] with a low serum EPO level, there’s a bit of a decision and discussion with the patient about ESA vs luspatercept, but the [frontline] approval [of luspatercept] still includes those patients. I frequently use luspatercept in those [patients] in a frontline setting, and if there’s no response, you can still transition to an ESA afterward. The opposite is technically not possible, because the second-line approval [of luspatercept] is for RS-positive patients only. Luspatercept is a good option for most patients [in the frontline setting].
References
- Alhajahjeh A, Woite NL, Rolles B, et al. Luspatercept for patients with lower-risk myelodysplastic syndromes/neoplasms: a systematic review and meta-analysis. Blood Adv. 2025;9(24):6511-6523. doi:10.1182/bloodadvances.2025017611
- US FDA approves Bristol Myers Squibb’s Reblozyl (luspatercept-aamt) as first-line treatment of anemia in adults with lower-risk myelodysplastic syndromes (MDS) who may require transfusions. News release. Bristol Myers Squibb. August 28, 2023. Accessed April 6, 2026. https://news.bms.com/news/details/2023/U.S.-FDA-Approves-Bristol-Myers-Squibbs-Reblozyl-luspatercept-aamt-as-First-Line-Treatment-of-Anemia-in-Adults-with-Lower-Risk-Myelodysplastic-Syndromes-MDS-Who-May-Require-Transfusions/default.aspx
