Meta-Analysis Underscores Role of Luspatercept for Anemia in Lower-Risk MDS

Data from a systematic review and meta-analysis of 20 studies demonstrated that luspatercept-aamt (Reblozyl) yielded high red blood cell transfusion-independence (RBC-TI) rates and a favorable safety profile in the treatment of anemia in patients with transfusion-dependent, lower-risk myelodysplastic syndromes (MDS), particularly among those with ring sideroblast (RS)–positive disease and low transfusion burden.¹

In a report published in Blood Advances, the 20 identified studies included in the meta-analysis comprised 7 clinical trials and 13 cohort studies.

Findings showed that evaluable patients from 15 studies (n = 2090) achieved an 8-week RBC-TI rate of 50.2% (95% CI, 39.9%-60.4%; I² = 94.9%). Among patients with RS-positive disease treated across 8 studies (n = 765), the 8-week RBC-TI rate was 57.9% (95% CI, 47.4%-67.7%; I² = 86%) compared with 43.0% (95% CI, 30.3%-56.7%; I² = 81.2%) in patients with RS-negative disease treated across 4 studies (n = 383; P = .004).

Additionally, patients with low transfusion burden—defined as less than 4 units in 16 weeks prior to the start of treatment—who were treated across 3 studies (n = 45) experienced an 8-week RBC-TI rate of 72.9% (95% CI, 60.4%-82.6%; I² = 0%) compared with 38.7% (95% CI, 24.1%-55.7%; I² = 77.1%) for patients with high transfusion burden treated across 4 studies (n = 165; P = .004). In 12 studies that included cohorts of patients with mixed RS and varying transfusion burdens (n = 1789), the 8-week RBC-TI rate was 47.6% (95% CI, 36.4%-59.0%; I² = 95%).

“Luspatercept has demonstrated superior RBC-TI and hematologic improvement–erythroid [HI-E] rates compared [with] available alternatives, along with a more favorable safety profile, especially in real-world settings,” lead study author Abdulrahman Alhajahjeh, MD, of the Internal Medicine Department in the School of Medicine at the University of Jordan in Amman, and the Section of Hematology in the Department of Internal Medicine at Yale School of Medicine in New Haven, Connecticut, and colleagues wrote in the publication. “These findings support the use of luspatercept for patients with transfusion-dependent, lower-risk MDS for whom achieving early and sustained TI is the primary therapeutic goal.”

How was this meta-analysis of luspatercept conducted?

In August 2023, the FDA approved luspatercept for the treatment of anemia without prior use of an erythropoiesis-stimulating agent (ESA) in adult patients with very low–to-intermediate-risk MDS who may require RBC transfusions.² This regulatory decision was supported by data from the phase 3 COMMANDS trial (NCT03682536), in which luspatercept generated improvements in RBC-TI and increased hemoglobin levels vs epoetin alfa, irrespective of RS status.

In this meta-analysis, investigators sought to provide a comprehensive evaluation of the efficacy and safety of luspatercept in patients with lower-risk MDS via data from clinical trials and real-world studies.¹

Using database searches, investigators identified studies evaluating luspatercept that included more than 15 patients with transfusion-dependent lower-risk MDS. Investigators then excluded any studies that met any of the following criteria:

• Studies that investigated luspatercept in patients with diseases other than lower-risk MDS
• Review articles, meta-analyses, or systematic reviews
• Preclinical studies
• Duplicate publications from the same cohort of patients
• Studies where more than half the patients were transfusion independent
• Studies with insufficient reported data regarding the primary outcome of RBC-TI
• Studies published in languages other than English

In total, 854 unique studies were identified after duplicate records were removed; 655 were ultimately excluded. Further evaluation of the remaining studies left 20 available for the meta-analysis.

The primary objective of the analysis was to evaluate the proportion of patients achieving RBC-TI at 8 weeks. Secondary end points included 12- and 24-week RBC-TI rates; 8-week HI-E response rate; and safety.

In the 20 studies (n = 3455), patients had a mean age of 73.6 years, and 41.5% were female. Revised International Prognostic Scoring System scores included very low risk (22.49%) and low risk (67.07%). Additionally, 67.39% of patients had RS-positive disease, and 76.41% of patients had prior exposure to an ESA.

What additional efficacy outcomes were reported in the meta-analysis of luspatercept in lower-risk MDS?

Among evaluable patients from 11 studies (n = 1431), the 12-week RBC-TI rate was 57.0% (95% CI, 48.1%-65.5%; I² = 90%). Notably, data from a meta-regression analysis showed that a history of ESA use was associated with a negative effect on 12-week RBC-TI rates (P < .001). Findings from a subsequent subgroup analysis showed that in 5 studies where more than 90% of patients (n = 1335) had prior ESA exposure, the 12-week RBC-TI rate was 43.1% (95% CI, 34.8%-51.9%; I² = 89.6%) compared with 58% (95% CI, 49.4%-66.1%; I² = 67%) in 5 studies where less than 90% of patients (n = 576) had prior ESA exposure (P = .017).

In evaluable patients across 8 studies (n = 1047), the 24-week RBC-TI rate was 35.8% (95% CI, 28.7%-43.6%; I² = 82.1%), and subgroup analyses showed varying response rates based on patient characteristics (P < .001). In 2 studies, patients (n = 212) with ESA-naive, RS-positive disease achieved a 24-week RBC-TI rate of 49.1% (95% CI, 42.4%-55.8%; I² = 0%). Conversely, patients (n = 381) with ESA-exposed, RS-positive disease treated across 3 studies experienced a 24-week RBC-TI rate of 30.5% (95% CI, 25.2%-36.3%; I² = 25.6%). In 2 studies that included patients (n = 334) with RS-positive disease, irrespective of prior ESA exposure, the 24-week RBC-TI rate was 38.3% (95% CI, 22.6%-57.0%; I² = 84.4%). In a single study that included patients (n = 120) with ESA-refractory, RS-negative disease, the 24-week RBC-TI rate was 22.9% (95% CI, 16.2%-31.2%).

Regarding HI-E responses, the overall rate was 51.3% (95% CI, 41.3%-61.2%; I² = 93%) in evaluable patients (n = 1647) treated across 12 studies, with patient characteristics again associated with significant differences in these rates (P < .001). Patients (n = 182) with ESA-naive, RS-positive disease from a single study achieved an HI-E rate of 74.2% (95% CI, 67.4%-80.0%), and patients (n = 659) with ESA-refractory, RS-positive disease treated across 5 studies experienced an HI-E rate of 51.3% (95% CI, 32%-70.2%; I² = 95%). In 4 studies that included patients (n = 537) with ESA-refractory disease and varying RS status, the HI-E rate was 51.5% (95% CI, 39.5%-63.6%; I² = 86%). In 3 studies with patients (n = 269) with ESA-refractory, RS-negative disease, this rate was 42.7% (95% CI, 24.9%-62.7%; I² = 83.8%).

What safety data were reported for luspatercept?

The most common adverse effects (AEs) reported with luspatercept included peripheral edema (3 studies, n = 365; 17.8%; 95% CI, 11.4%-26.8%; I² = 65.9%), diarrhea (4 studies, n = 473; 15.6%; 95% CI, 8.2%-27.7%; I² = 85.6%), and back pain (2 studies, n = 335; 16.1%; 95% CI, 9.2%-26.8%; I² = 76.7%). Serious AEs were reported in 28% of patients (n = 1088) across 5 studies (95% CI, 12.8%-50.7%; I² = 97.2%) and were generally manageable and not life threatening. Notably, no significant difference in the rate of serious AEs was reported for patients treated in a clinical trial (32.1%; 95% CI, 15.5%-54.8%) vs those treated in real-world cohorts (22.9%; 95% CI, 3.5%-70.6%; P = .691).

“Notably, the frequency of AEs was lower in real-world studies than clinical trials, indicating good tolerability in routine clinical practice,” the study authors wrote. “In contrast, other agents used in lower-risk MDS, such as imetelstat [Rytelo], low-dose azacitidine, and lenalidomide [Revlimid], have been associated with higher rates of hematologic toxicities, particularly thrombocytopenia and neutropenia, which increases the risk of serious infections and can potentially negatively affect long-term treatment adherence.”

Study authors noted that this meta-analysis was limited by factors, including limited access to patient-level data to fully explore the effects of treatment across various subgroups; availability of some data only through abstracts; and inconsistent reporting of some clinical end points beyond the 8-week RBC-TI rate.

References

1. 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
2. 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 February 19, 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