Myelodysplastic syndromes (MDS) are a heterogenous group hematological disorders, also called ‘bone marrow failure disorders.’ They are characterized by bone marrow that produces too many immature or defective blood cells that crowd out healthy white blood cells, red blood cells, and platelets.
The hallmark of MDS is low blood cell count, referred to cytopenias. These cytopenias are responsible for the typical symptoms experienced by patients, including infection, anemia, spontaneous bleeding, or easy bruising. Patients diagnosed with MDS also have a greater risk of death or disease progression to acute myeloid leukemia (AML).
Although the disease can affect younger people, the majority of patients diagnosed with MDS are older than 60 years of age. And with the lack of curative therapies (other than hematopoietic stem cell transplant or HSCT, which is limited to a relatively small minority of patients), these patients generally have a poor long-term overall survival (OS).
Lower-risk myelodysplastic syndrome
About two-thirds of all patients diagnosed with MDS present with lower-risk myelodysplastic syndrome (LR-MDS). This means that the disease shows minor clinical symptoms with mild cytopenias. In turn, these patients have a relatively lower risk of death or progression to acute myeloid leukemia immediately following diagnosis. However, some of these patients have a symptom burden, including anemia, and complications related to cytopenias, transfusions, and inflammation, beyond that of what should be expected based on their ‘lower-risk’ laboratory parameters. Despite this ‘lower-riks,’ the presence of these symptoms can negatively affect co-morbid conditions and contribute to an general decreased health related Quality of Life. Overall, patients diagnosed with LR-MDS have a median survival of approximately 3 to 10 years. In contrast, patients with higher-risk disease have a median survival of less than 3 years. 
Rapid and accurate diagnosis of MDS is critical to distinguish between disease severity and treatment options. In addition, a diagnosis of the specific subtype of MDS is key in categorizing the particular disease associated with lower or higher risk for acute myeloid leukemia transformation. In turn, rapid and accurate diagnoses help with therapy selection.
Whether the primary clinical characteristic of the disease is anemia, thrombocytopenia, or neutropenia, for patients diagnosed with LR-MDS the treatment objectives have traditionally been designed to improve cytopenias, and health related Quality of Life (hrQoL). In these patients, disease management focuses on treating symptoms, while, at the same time, reducing the number of required transfusions. In LR-MDS, patients may receive erythropoiesis stimulating agents (ESAa), the current standard of care. This may iinclude treatment with recombinant humanized erythropoietin or the longer-acting erythropoietin darbepoetin alfa (Aranesp®; Amgen). This treatment option can improve anemia in about 15% to 40% of patients diagnosed with LR-MDR for between of 8 to 23 months. 
However, a new study shows that patients diagnosed with LR-MDS who received luspatercept (Reblozyl®; Celgene Corporation, a Bristol Myers Squibb company) to treat anemia instead of erythropoiesis-stimulating agents (ESAs), needed even fewer blood transfusions and clinic visits.
Data presented at the annual meeting of the American Society of Clinical Oncology (ASCO) held June 2 – 6, 2023, in Chicago, Illinois, supports a potential role for early intervention in delaying transfusion dependency.
In 2020, luspatercept, an erythroid maturation agent that helps the bone marrow grow erythroid cells (immature red blood cells) into functional, mature red blood cells, received approval from the U.S. Food and Drug Administration (FDA) for the treatment of anemia among patients with lower-risk MDS after erythropoiesis-stimulating agents (ESAs) had stopped working or for patients who cannot receive ESAs. The drug was originally developed by Acceleron Pharma and Celgene Corporation (now part of Bristol Myers Squibb).
The global, open-label, randomized phase 3 COMMANDS clinical trial (ClinicalTrials.gov identifier: NCT03682536) included participants from more than 20 countries. Participating patients included adults aged 18 years and older. The median age of the participants was 74 years, and most were White (80%) and men (56%).
Furthermore, all participating patients had lower-risk MDS as classified by the revised International Prognostic Scoring System (IPSS-R). None had received previous treatment with an erythropoiesis-stimulating agents and needed to receive transfusions of red blood cells.
The global phase 3 included 354 people who had lower-risk MDS and required red blood cell transfusions to treat anemia. The participants in this study had not previously received treatment with an erythropoiesis-stimulating agent.
The participants were divided into two groups: 178 received luspatercept by injection once every 3 weeks for at least 24 weeks, and 176 received epoetin alfa (an ESA) by injection once a week for at least 24 weeks. After median treatment durations of 41.6 weeks for luspatercept and 27 weeks for epoetin alfa, there were 301 participants included in the planned interim data analysis. The primary endpoint of this study was transfusion independence for ≥12 weeks with concurrent mean hemoglobin increase ≥1.5 g/dL within the first 24 weeks of treatment.
At the time of this planned interim data analysis, 58.5% of people receiving luspatercept achieved this endpoint, compared to 31.2% of those receiving epoetin alfa.
The secondary endpoints in the study included hematologic improvement-erythroid (HI-E) response ≥8 weeks and transfusion independence at 24 weeks and ≥12 weeks. HI-E response is an indicator of how much hemoglobin is increased in the blood. Better HI-E responses can suggest that a person may be developing less reliance on transfusions or require fewer transfusions. Across these endpoints, luspatercept was more effective than epoetin alfa: 74.1% vs. 51.3% for HI-E response, respectively; 47.6% vs. 29.2% for 24-week transfusion independence; and 66.7% vs. 46.1% for ≥12-week transfusion independence.
“In this study, people who received luspatercept were significantly more likely to experience freedom from transfusions of red blood cells than those who received epoetin alfa. This is important, as ESAs have been the first-line treatment for patients with lower-risk MDS for decades,” said lead author Guillermo Garcia-Manero, MD, professor in the Department of Leukemia and chief of the Section of Myelodysplastic Syndromes at The University of Texas MD Anderson Cancer Center in Houston, Texas.
“Luspatercept could potentially alter this treatment landscape such that patients could receive luspatercept first instead of ESAs. Patients will need to visit the clinic less often and receive blood transfusions less frequently. They will benefit from improved quality of life and better outcomes,” Garcia-Manero added.
In the study, treatment-emergent adverse events were slightly more common among those who received luspatercept (164 patients, 92.1%) than those who received epoetin alfa (150 patients, 85.2%). These treatment-emergent adverse events led 8 (4.5%) people in the luspatercept group and 4 (2.3%) people in the epoetin alfa group to stop treatment.
More participants receiving luspatercept reported treatment-related adverse events than those receiving epoetin alfa (30.3% vs. 17.6%, respectively). The most common adverse events suspected to be related to treatment with luspatercept were nausea (5.1%), fatigue (3.9%), shortness of breath (dyspnea, 3.4%), and high blood pressure (hypertension, 3.4%). There were 4 (2.2%) participants receiving luspatercept and 5 (2.8%) participants receiving epoetin alfa whose disease progressed to acute myeloid leukemia (AML). Overall death rates were comparable between both treatment groups (18% luspatercept vs. 18.2% epoetin alfa).
These results are from a scheduled data analysis done before the completion of the study. It represents findings from approximately 80% of the study participants. The next steps will be to evaluate the data from all patients who completed 24 weeks of treatment. In addition, all participants will be observed for up to 5 years to monitor how they are doing.
A Study to Compare the Efficacy and Safety of Luspatercept (ACE-536) Versus Epoetin Alfa for the Treatment of Anemia Due to IPSS-R Very Low, Low, or Intermediate Risk Myelodysplastic Syndromes (MDS) Participants Who Require Red Blood Cell Transfusions and Are ESA Naïve (COMMANDS) – NCT03682536.
Highlights of prescribing information
Luspatercept (Reblozyl®; Celgene Corporation, a Bristol Myers Squibb company) [Prescribing Information]
Darbepoetin alfa (Aranesp®; Amgen) [Prescribing Information]
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Featured image: NCI Director Monica Bertagnolli, MD, during Opening Session of ASCO 2023 in Chicago, IL. Photo courtesy: © 2023 ASCO/Todd Buchanan.