Results from the phase 3 COMMANDS trial indicate luspatercept may more effectively treat anemia than erythropoiesis-stimulating agents (ESAs) as first-line agents in transfusion-dependent patients with lower-risk myelodysplastic syndromes (MDS).1 Guillermo Garcia-Manero, MD, of the University of Texas MD Anderson Cancer Center in Houston, presented the findings from the global study at an American Society of Clinical Oncology (ASCO) Annual Meeting oral abstract session on June 2.
Some patients with MDS fail to respond to ESAs, and the response period is limited in those who do. The recombinant fusion protein luspatercept binds select ligands in the transforming growth factor β family to decrease signaling of Smad 2/3, thereby increasing erythroid maturation.
Luspatercept is currently approved by the U.S. Food and Drug Administration for patients with low- to intermediate-risk MDS with ring sideroblasts (RS) that has failed to respond to ESAs. However, previous phase II work has shown that it may also be effective in some RS-negative patients with a low transfusion burden, including patients previously not treated with ESAs.2
Thus, Dr. Garcia-Manero and colleagues compared luspatercept with epoetin alpha in low-to-intermediate risk, transfusion-dependent patients with MDS who were naïve to ESAs. For unplanned reasons, the study included more than two and a half as many RS-positive patients as RS-negative ones, but this was balanced across the treatment groups, as were other baseline patient characteristics.
Dr. Garcia-Manero remarked, “Luspatercept basically doubled the possibility that the patient would achieve the primary endpoint.” Of patients receiving luspatercept, 58.5% achieved transfusion independence for at least a 12-week consecutive period within the first 24 weeks, along with an increase in hemoglobin of at least 1.5 g/dL. This contrasted with only 31.2% of patients receiving epoetin alpha.
These results held in subgroup comparisons of baseline serum erythropoietin and baseline transfusion burden. However, patients did respond differently with respect to RS; 65% of RS positive patients on luspatercept achieved the primary endpoint compared to 26% on the ESA, but in RS-negative patients, slightly more achieved it on the ESA (46% vs. 41%).
Luspatercept also demonstrated superiority in secondary endpoints, and the median time of transfusion independence was 126 weeks in patients on luspatercept compared to 77 for those on the ESA (hazard ratio [HR] = 0.46).
However, this trend also differed with respect to RS status. RS-positive patients on luspatercept achieved transfusion independence for a median of 121 weeks compared to 47 weeks for the ESA (HR = 0.63), but RS-negative patients receiving luspatercept did not show such improvement on luspatercept compared to the ESA.
Although treatment-emergent adverse events were common in both groups, Dr. Garcia-Manero noted they found no clear differences, including grade 3 or grade 4 events, and no difference in progression to high-risk MDS or acute myeloid leukemia. He added, “This drug has a manageable and predictable safety profile consistent with prior clinical experience.”
Dr. Garcia-Manero concluded, “This is the first and only therapy to demonstrate superiority in a head-to-head study against an ESA, and it potentially brings a paradigm shift in the treatment of low-risk [MDS].” However, the role of luspatercept versus ESAs in transfusion-dependent patients with lower-risk MDS without ringed sideroblasts remains less clear.
Any conflicts of interest declared by the authors can be found in the original abstract.
References
- Garcia-Manero G, Plazbecker 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 transfusiondependent (TD) patients (pts) with lower-risk myelodysplastic syndromes (LR-MDS). Abstract 7003. Presented at the 2023 American Society of Clinical Oncology Annual Meeting; June 2, 2023; Chicago, Illinois.
- Platzbecker U, Götze KS, Kiewe P, et al. Long-term efficacy and safety of luspatercept for anemia treatment in patients with lower-risk myelodysplastic syndromes: The phase II PACE-MDS Study. J Clin Oncol. 2022;40(33):3800-3807.
