Moving Beyond Transfusion Dependence in the MDS Landscape

The management of myelodysplastic syndromes (MDS) has entered a period of rapid evolution, marked by a shift toward personalized therapy and the entry of novel mechanisms of action into the frontline setting. In this interview, Yasmin Abaza, MD, assistant professor, Feinberg School of Medicine, Northwestern University in Chicago, Illinois, discusses the critical distinctions in risk stratification, the clinical impact of recent phase 3 data, and practical strategies for managing treatment-related toxicities.

As higher-risk MDS (HR MDS) is characterized by high blast counts with a standard of care involving hypomethylating agents (HMAs) and transplant, lower-risk MDS (LR MDS) focuses on mitigation of anemia.

“There are multiple datasets that show that the worse the patient’s hemoglobin and the higher the transfusion burden, the worse the survival with LR MDS,” Abaza said. Historically, erythroid-stimulating agents (ESAs) were the only frontline option. However, 2 phase 3 trials, COMMANDS (NCT03682536) and IMerge (NCT02598661), have altered the therapeutic landscape.

In the COMMANDS trial,¹ luspatercept-aamt (Reblozyl), a transforming growth factor-beta (TGF-b) ligand trap that restores erythroid maturation, was compared with the ESA epoetin alfa in patients with LR MDS who were ESA naïve.

Findings showed the experimental agent to be superior to the ESA, “pushing it to the frontline setting in a majority of subgroups,” Abaza said. “An ongoing debate revolves around the ring sideroblast (RS)–negative population, where subgroup analysis suggests luspatercept and ESAs may be equivalent,” Abaza continued.

For patients with a higher transfusion burden, defined as 4 or more units in 8 weeks, who are ineligible for or failed ESAs, imetelstat (Rytelo), a first-in-class telomerase inhibitor has emerged as a potent option.

According to results from the IMerge trial,² 39.8% of patients treated with imetelstat achieved 8 weeks of transfusion independence compared with 15.0% of patients treated with placebo. Respondents also experienced a mean hemoglobin rise of 3.6 g/dL.

Titration and Toxicities

Abaza emphasized that clinical success with these agents depends on diligent monitoring and a willingness to optimize dosing. For lustpatercept, a common pitfall in community practice is remaining at the starting dose of 1.0 mg/kg. “About 80% of patients in the COMMANDS study did require a dose escalation,” Abaza noted. She recommends escalating every 2 doses, moving to 1.33 mg/kg and then 1.75 mg/kg, if no improvement in hemoglobin is seen.

In the phase 3 MAXILUS trial (NCT06045689), the maximum dose of luspatercept at 1.75 mg/kg was well tolerated, with no new safety signals.³ At the data cutoff of April 14, 2025, 105 patients composed the safety population of patients who received 1 or more doses of luspatercept. The median duration of follow-up was 5.8 months (range, 3.3-8.2) in the ESA-naïve cohort and 7.4 months (range, 5.6-9.2) in the ESA relapsed/refractory or intolerant cohort. The primary end point was red blood cell transfusion independence (RBC TI) at 8 or greater weeks, with a concurrent mean hemoglobin increase of 1.0 or more g/dL from weeks 1 to 24. Secondary end points included RBC TI at 12 or more weeks (weeks 1-24) and safety.

“In patients who I believe may not be as sensitive, either RS-negative patients or those with borderline transfusion burden, I sometimes start at 1.75 mg/kg from the beginning,” Abaza said.

Managing Imetelstat Cytopenias

Although luspatercept is associated with low-grade fatigue/asthenia in about 25% of patients, imetelstat presents a different challenge: significant but transient cytopenias. In the IMerge study, grade 3/4 neutropenia and thrombocytopenia occurred in roughly 75% of patients.

However, Abaza views these as a sign of efficacy. “I like seeing them, because it tells me that the drug is actually going to work,” she explained, citing a pooled analysis⁴ evaluating the correlation between treatment-emergent cytopenias and response presented during the 67th American Society of Hematology (ASH) Annual Meeting.

In the study, patients with 75% or greater neutrophil count reductions or 50% or greater platelet reductions in the first 2 cycles were more likely to have a greater hemoglobin increase from pretreatment or to achieve a hematologic improvement-erythroid response.

Looking Ahead

Despite recent successes, the RS-negative population remains a major clinical gap because of its heterogeneity. Abaza pointed toward emerging targets, such as IRAK1/4 inhibitors, which have shown preliminary activity in a phase 1 dose escalation/dose expansion trial (NCT05308264) presented by Guillermo Garcia-Manero, MD, at ASH 2025.⁵

R835 is a selective dual inhibitor of IRAK 1/4 that blocks TLR4 and IL-1R–dependent cytokine release in vitro and in vivo, which potentially may suppress inflammation and leukemic stem/progenitor cell function and restore normal hematopoiesis in MDS.

Abaza also emphasized a shift towards intervention in the transfusion-independent population, noting the ELEMENT-MDS study (NCT05949684),⁶ which is currently investigating whether early treatment with luspatercept in symptomatic, non-transfusion-dependent patients can improve quality of life and long-term survival.

Collaborating on care, especially among patients with complex cases such as del(5q) with complex karyotypes, in which misdiagnosis can lead to suboptimal therapy, remains critical, Abaza concluded.

REFERENCES

1. Della Porta MG, Garcia-Manero G, Santini V, et al. Luspatercept versus epoetin alfa in erythropoiesis-stimulating agent-naive, transfusion-dependent, lower-risk myelodysplastic syndromes (COMMANDS): primary analysis of a phase 3, open-label, randomised, controlled trial. Lancet Haematol. 2024;11(9):e646-e658. doi:10.1016/S2352-3026(24)00203-5

2. Zeidan AM, Platzberger MW, Santini V, et al. IMerge: Results from a phase 3, randomized, double-blind, placebo-controlled study of imetelstat in patients (pts) with heavily transfusion dependent (TD) non-del(5q) lower-risk myelodysplastic syndromes (LR-MDS) relapsed/refractory (R/R) to erythropoiesis stimulating agents (ESA). J Clin Oncol. 2023;41(suppl 16):7004. doi:10.1200/JCO.2023.41.16

3. Zeidan A, Diez-Campelo M, Santini V, et al. Luspatercept initiated at the maximum-approved dose in transfusion-dependent lower-risk myelodysplastic syndromes: Interim analysis from MAXILUS. Blood. 2025;146 (suppl 1): 789. doi:10.1182/blood-2025-789

4. Zeidan Am Santini V, Diez-Campelo M, et al. Correlation between treatment-emergent cytopenias and clinical response with imetelstat (IME) in patients (Pts) with lower-risk myelodysplastic syndromes (LR-MDS): Analysis from the imerge Trial. Blood. 2025;146(suppl 1):490. doi:10.1182/blood-2025-490

5. Garcia-Manero G, Madanat Y, Sekeres M, et al. Safety and efficacy results from A phase 1b study of R289, a dual IRAK 1/4 inhibitor, in patients with relapsed/refractory (R/R) lower risk myelodysplastic syndrome (LR-MDS). Blood. 2025;146(suppl 1):489. doi:10.1182/blood-2025-489

6. Zeidan AM, Komrokji RS, Buckstein R, et al. The ELEMENT-MDS trial: a phase 3 randomized study evaluating luspatercept versus epoetin alfa in erythropoiesis-stimulating agent-naive, non-transfusion-dependent, lower-risk myelodysplastic syndromes. Blood. 2023;142(suppl 1):6503. doi:10.1182/blood-2023-178635