Luspatercept Yields Improved Transfusion Independence Compared With Epoetin Alfa in Patients With Lower-Risk MDS

Chicago, IL—Interim results from the phase 3 COMMANDS trial demonstrated that first-line treatment with luspatercept-aamt (Reblozyl) increased hemoglobin levels and enabled nearly twice as many patients with transfusion-dependent, lower-risk myelodysplastic syndromes (MDS) to avoid red blood cell (RBC) transfusions during the first 24 weeks of the study compared with standard-of-care epoetin alfa. These findings were presented by Guillermo Garcia-Manero, MD, Professor, Leukemia; Chief, Section of Myelodysplastic Syndromes, Department of Leukemia; and Deputy Chair, Translational Research, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, and the study’s principal investigator, during a press conference prior to the 2023 American Society of Clinical Oncology Annual Meeting.¹

Background

MDS are a group of closely related blood cancers characterized by ineffective production of healthy RBCs, white blood cells, and platelets, which can result in anemia and frequent or severe infections.^2,3 Patients with MDS who develop anemia frequently require regular blood transfusions to increase the number of healthy RBCs in circulation.⁴

“Transfusions are a significant burden to our patients based on the time spent in transfusion units, the potential for infectious complications, iron accumulation, transfusion reactions that can be quite severe, and eventually failure to respond to the transfusions. In addition, transfusions have a significant economic impact,” said Dr Garcia-Manero.

The first-line treatment option for patients with MDS and anemia is epoetin alfa, an erythropoiesis stimulating agent (ESA) that has limited efficacy and durability.

Luspatercept, an erythroid maturation agent, is currently FDA approved for the treatment of anemia requiring 2 or more RBC units over 8 weeks in adult patients with very low- to intermediate-risk MDS with ring sideroblasts, but only after failure of an ESA.⁵ The COMMANDS trial specifically focused on the first-line use of luspatercept to treat anemia in ESA-naïve patients with transfusion-dependent, lower-risk MDS.

Study Details

The global phase 3 COMMANDS trial included 354 patients with lower-risk MDS as defined by the revised International Prognostic Scoring System criteria. Patients were ESA naïve, had <5% bone marrow blasts and serum erythropoietin levels <500 U/L, and required RBC transfusions (defined as 2-6 units/8 weeks for at least 8 weeks immediately prior to randomization).

Patients were randomized to receive luspatercept once every 3 weeks for at least 24 weeks (n=178) or epoetin alfa once a week for at least 24 weeks (n=176). The median treatment duration (as of the cutoff date of August 31, 2022) was 41.6 weeks in the luspatercept arm and 27 weeks in the epoetin alfa arm. Baseline characteristics were well balanced across treatment arms.

Achieving RBC transfusion independence of at least 12 weeks within the first 24 weeks of treatment, with a concurrent mean hemoglobin increase of at least 1.5 g/dL, served as the study’s primary end point. Secondary end points included safety and durability of RBC transfusion independence.

The trial met its primary end point by showing a clinically superior increase in the proportion of patients who achieved transfusion independence of at least 12 weeks, with a concurrent mean hemoglobin increase of at least 1.5 g/dL in the luspatercept and epoetin alfa arms (58.5% vs 31.2%, respectively; P<.0001).

Patients treated with luspatercept also demonstrated significantly longer median duration of transfusion independence compared with those treated with epoetin alfa (126.6 weeks vs 77 weeks, respectively).

“The COMMANDS results could transform how we approach the treatment of anemia in patients with lower-risk MDS. [These results] suggest that luspatercept could represent the standard of care as first-line therapy for a significant fraction of patients with anemia and lower-risk disease,” Dr Garcia-Manero said.

Treatment-emergent adverse events (AEs) were more frequent among patients treated with luspatercept versus those treated with epoetin alfa (92.1% vs 85.2%, respectively). However, patients treated with luspatercept remained on therapy much longer than those treated with epoetin alfa (median, 41.6 vs 27.0 weeks, respectively).

The rates of hematologic and other AEs were similar between the 2 treatment arms. Only 8 of 78 luspatercept discontinuations were attributed to AEs. The rates of progression to high-risk MDS (2.8% vs 4.0%, respectively), progression to acute myeloid leukemia (2.2% vs 2.8%, respectively), and overall mortality (18.0% vs 18.2%, respectively) were also comparable between the luspatercept and epoetin alfa arms.

Expert Commentary

Anand Ashwin Patel, MD, Assistant Professor, Medicine, and Medical Director, Inpatient Leukemia Service, University of Chicago, IL, noted, “I believe that the findings of this trial establish luspatercept as the standard of care for ESA-naïve, lower-risk MDS patients [who] do not have del(5q) with transfusion-dependent anemia.”

References

1. Garcia-Manero G, Platzbecker U, Santini V, et al. Efficacy and safety results from the COMMANDS trial: a phase 3 study evaluating luspatercept vs epoetin alfa in erythropoiesis-stimulating agent (ESA)‑naive transfusion-dependent (TD) patients (pts) with lower‑risk myelodysplastic syndromes (LR-MDS). J Clin Oncol. 2023;41(suppl 16):7003.
2. Mount Sinai. Myelodysplastic syndrome. www.mountsinai.org/care/cancer/services/mds. Accessed June 21, 2023.
3. Myelodysplastic Syndromes Foundation. What are myelodysplastic syndromes? Updated January 22, 2018. www.cancer.org/cancer/myelodysplastic-syndrome/about/what-is-mds.html. Accessed June 21, 2023.
4. Johns Hopkins Medicine. Myelodysplastic syndrome. www.hopkinsmedicine.org/kimmel_cancer_center/types_cancer/myelodysplastic_syndrome.html. Accessed June 21, 2023.
5. US Food & Drug Administration. FDA approves luspatercept-aamt for anemia in adults with MDS. April 3, 2020. www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-luspatercept-aamt-anemia-adults-mds. Accessed June 23, 2023.