The European Hematology Association (EHA) annual meeting, one of the most influential international academic conferences in the field of hematology, gathers numerous experts and scholars worldwide every year. The aim is to share and deeply discuss innovative ideas and the latest scientific and clinical research advancements in hematology, thereby promoting continuous progress in the field. This year’s conference unveiled the latest results from studies on the use of the erythroid maturation agent luspatercept in the treatment of lower-risk myelodysplastic syndromes (LR-MDS), demonstrating promising therapeutic potential. Oncology Frontier - Hematology Frontier invited Dr. Chungkang Chang , Director of the Hematology Department at Shanghai Sixth People’s Hospital Affiliated to Shanghai JiaoTong University and Deputy Director of the Shanghai Blood Research Institute, to provide an in-depth analysis of the field's current status and research content, aiming to offer valuable references for clinical practice.Overview of the Field and Prospects for Luspatercept
LR-MDS, a common subtype of MDS, has garnered increasing attention in recent years. Professor Chang emphasized that the rapid advancements in cytogenetics and molecular biology have provided new perspectives and treatment methods for a deeper understanding of MDS. The medical community now recognizes that while MDS and leukemia are related, there are significant differences. The recent refinement of MDS classification has notably improved diagnostic accuracy.
However, Professor Chang pointed out that there are still numerous unmet clinical needs in the treatment of MDS, especially since about 90% of LR-MDS patients suffer from anemia. Traditional treatments are relatively limited, primarily relying on the supplementation of hematopoietic materials and erythropoiesis-stimulating agents (ESA). In terms of component transfusions, there are gaps between domestic and international standards, and issues like blood shortages and uneven distribution make it difficult to meet patients’ actual needs. Additionally, patients undergoing transfusion therapy face increased risks of complications such as infections and cardiovascular diseases.
Clinically, about 50% to 60% of patients receive erythropoietin (EPO) therapy. However, with the widespread use of EPO, its limitations have become increasingly apparent. For example, if a patient’s EPO level is high before treatment, it may indicate a poor response to EPO drugs. Furthermore, EPO resistance may develop after about two years of treatment. Therefore, from a clinical perspective, there is an urgent need for new treatment breakthroughs.
In this context, the erythroid maturation agent luspatercept emerges as an innovative therapy, offering hope for MDS patients. Luspatercept is a recombinant fusion protein composed of the modified extracellular domain of Activin Receptor Type IIB (ActR IIB) and the Fc domain of human immunoglobulin G1. It can reduce the SMAD2/3 signaling that inhibits erythroid maturation, downregulate the TGF-β signaling pathway, release terminal differentiation blockage, and ultimately promote late-stage erythroid maturation. Luspatercept has shown significant clinical effects in MDS patients.
For MDS patients, the application of innovative drugs like erythroid maturation agents holds the promise of overcoming existing treatment limitations, meeting unmet clinical needs, reducing dependency on transfusions, improving quality of life, extending survival, and effectively delaying the progression to high-risk MDS or leukemia.
Increasing Efficacy of Luspatercept
The COMMANDS study compared luspatercept head-to-head with ESA to investigate its efficacy and safety in treating LR-MDS. According to the latest research data released at EHA (P785), the benefits of luspatercept became increasingly evident with longer follow-up, further confirming its high efficiency and lasting therapeutic benefits for transfusion-dependent LR-MDS patients, with controllable safety.
For primary endpoints, 70.9% of patients in the luspatercept group achieved ≥12 weeks of red blood cell transfusion independence (RBC-TI) with an average hemoglobin (Hb) increase of ≥1.5 g/dL, compared to only 43.1% in the ESA group. In secondary endpoints, luspatercept demonstrated better benefits across RBC-TI ≥12 weeks, RBC-TI ≥24 weeks, and hematologic improvement-erythroid (HI-E) ≥8 weeks. Notably, in the evaluation of ≥50% reduction in red blood cell transfusion volume sustained for ≥12 weeks, the luspatercept group had an effectiveness rate of 83.0%, significantly higher than the ESA group’s 66.9%. Additionally, the median response duration for RBC-TI ≥12 weeks was 126.6 weeks for the luspatercept group, nearly one year longer than the ESA group’s 75.6 weeks (P=0.0055). These results strongly indicate that luspatercept treatment can significantly and sustainably delay and reduce transfusion requirements.
Luspatercept excelled in effectively elevating and sustaining Hb levels, significantly increasing Hb levels compared to the ESA group. During the 1-24 week period, 74.2% of patients treated with luspatercept achieved an Hb increase of ≥1.5 g/dL, compared to only 52.5% in the ESA group (P<0.0001). Specifically, the average Hb level increase was 2.0 g/dL (SD, 1.14) for the luspatercept group, compared to 1.5 g/dL (SD, 1.12) for the ESA group.
Professor Chang highlighted that for patients heavily reliant on transfusions, their quality of life is severely restricted, even affecting basic daily activities. The COMMANDS study explored the relationship between Hb levels and quality of life (P774), showing that improving Hb levels is crucial for alleviating anemia symptoms and enhancing quality of life, particularly when Hb levels reach ≥10 g/dL. Encouragingly, the luspatercept group not only surpassed the ESA group in increasing Hb levels but also had a significantly higher proportion of patients reaching the critical threshold of 10 g/dL. This indicates that the luspatercept group has greater potential in improving patients’ quality of life and anemia-related symptoms compared to the ESA group. Additionally, even though some patients in both treatment groups experienced dose increases, for those who did not reach the target range of 10-12 g/dL after receiving 1.0 mg/kg of luspatercept and whose Hb level increased by less than 1.5 g/dL during treatment, increasing the dose effectively raised Hb levels for most of these patients.
The COMMANDS study not only revealed the positive impact of luspatercept on erythroid improvement but also explored its effects on neutrophils and megakaryocytes (P780). Results showed that during weeks 1-24 and 1-48, the proportion of patients achieving hematologic improvement-neutrophil response (HI-N) and hematologic improvement-platelet response (HI-P) was higher in the luspatercept group, with significantly higher average growth levels compared to the ESA group. This data suggests that luspatercept treatment has a notable positive impact on the trilineage cells in LR-MDS patients.
In summary, the COMMANDS study provides solid evidence for the efficacy of luspatercept as a first-line treatment for LR-MDS, proving that luspatercept not only outperforms ESA in effectiveness but also shows outstanding results in improving patients’ quality of life.
Bridging East and West, Equal Benefits
As a bridging study to MEDALIST, the MDS-004 study aimed to evaluate the efficacy and safety of luspatercept in transfusion-dependent LR-MDS patients with ring sideroblasts (RS) in Asia (including China) (P1898). Professor Chang shared the differences in baseline characteristics between the patients enrolled in these two studies. First, the average age of Chinese patients was 63 years, relatively younger than the 71 years in the MEDALIST study. Second, the average Hb level for Chinese patients was only 5.2 g/dL, lower than the 7.6 g/dL in the MEDALIST study. Additionally, it is noteworthy that 95% of Chinese patients had EPO levels ≥500 U/L, much higher than the 14% in the MEDALIST study. Moreover, 45% of Chinese patients had not received ESA treatment before (compared to 3% in the MEDALIST study), and 55% of those who had received ESA treatment were refractory or poorly tolerant to ESA. These baseline data reveal that the Chinese patient population in the MDS-004 study had more severe conditions.
Despite facing more severe challenges, luspatercept still showed excellent efficacy. The MDS-004 study indicated that the overall results for luspatercept in the Asian population were consistent with those observed in the MEDALIST study. Among ITT patients, 60% achieved RBC-TI ≥8 weeks, with a median duration of 24.4 weeks. The proportion of patients achieving RBC-TI ≥12 weeks was 43%, and the mHI-E rate was 63%. In the safety evaluation, the safety profile was consistent with previous findings, with no new safety signals. During treatment, 33% of patients experienced grade 3/4 treatment-emergent adverse events (TEAEs), with no reported grade 5 TEAEs. The most common TEAEs included COVID-19 (33%), upper respiratory tract infection (23%), and diarrhea (17%). Remarkably, no cases progressed to acute myeloid leukemia (AML) or higher-risk MDS during treatment. These findings suggest that luspatercept offers a promising treatment option for LR-MDS-RS patients with high baseline EPO levels who are unsuitable for ESA treatment, serving as an effective and well-tolerated alternative.
Currently, the new indication for luspatercept in the MDS field has been accepted for approval. Professor Chang envisions that once the MDS indication for luspatercept is officially approved and included in the medical insurance system, the accessibility of the drug will significantly improve, more effectively meeting the urgent needs of Chinese patients who cannot receive transfusions and whose anemia is difficult to ameliorate.
Promising Future Ahead
Nowadays, the treatment strategies for MDS are becoming increasingly diversified. The introduction of luspatercept has undoubtedly brought a revolutionary change to the MDS treatment field, not only in terms of therapeutic effects but also in its profound impact on the overall treatment landscape. Professor Chang noted that internationally, luspatercept has become a recommended first-line treatment option. For patients with EPO levels ≥500 U/L and lacking effective treatment methods, the application of luspatercept is equally crucial and holds the potential to help them out of their predicament. The ELEMENT-MDS study and the MAXILUS trial have expanded the application range of luspatercept to new horizons. The ELEMENT-MDS study aims to explore the efficacy of luspatercept in non-transfusion-dependent patients, while the MAXILUS trial further investigates the efficacy and safety of initiating luspatercept at the maximum dose in transfusion-dependent lower-risk MDS patients. The subsequent progress of these studies is expected to further revolutionize the treatment model for MDS, bringing hope to more patients. Additionally, with the continuous development of new drugs, more innovative medications are anticipated to be gradually incorporated into the treatment system, providing patients with more comprehensive and effective treatment options.
With the in-depth implementation of standardized treatment systems and steady development of medical technology in China, significant progress has been made in the field of MDS treatment, gradually narrowing the gap between China’s and international advanced treatment levels. Professor Chang mentioned that more and more domestic medical centers are actively participating in international clinical trials for MDS. This initiative not only greatly enhances the management and treatment level of MDS but also highlights China’s significant contribution to international medical research. We have every reason to believe that with the widespread application of new drugs like luspatercept and the successful development of more innovative medications, the field of MDS treatment will witness a brighter and more hopeful future.
Dr. Chungkang Chang
- Chief Physician, Doctoral Supervisor
- Director of the Hematology Department, Shanghai Sixth People’s Hospital Affiliated to Shanghai JiaoTong University
- Deputy Director, Shanghai Blood Research Institute
- Vice President, Chinese Society of Gerontology and Geriatrics Hematology
- Chairman, MDS Committee
- Member, Chinese Association of Hematologists
- Member, Red Cell Group, Chinese Society of Hematology
- Member, Hematology Society, Chinese Medical Promotion Association
- Deputy Leader, MDS/MPN Group, Chinese Anti-Cancer Association (CACA)
- Member, CSCO Chinese Anti-Leukemia Alliance
- Member, Chinese Society of Immunohematology
- Member, Chinese Rare Blood Disease Working Group
- Deputy Chairman, Shanghai Hematology Society
- Chairman, Red Cell Group
- Director, Shanghai Anti-Cancer Association (CACA)
- Deputy Chairman, Shanghai Hematology Oncology Society
- Shanghai Leading Medical Talent
- Editorial Board Member, Chinese Journal of Hematology
- Editorial Board Member, Chinese Journal of Experimental Hematology
- Published over 300 papers in core domestic and international journals, including more than 100 SCI papers in Nature Communications, Blood, PNAS, Hematologica, and BJH
