Are we ready to ring in a new upfront therapy in lower-risk myelodysplastic syndromes?

[...]the goals in treating patients with lower-risk myelodysplastic syndromes are often focused on improving cytopenias and quality of life. Response to ESA-based therapy can be as high as 70%,1 but if serum erythropoietin is higher than 500 U/L, the expected response rate (defined as packed red blood cell transfusion independence or a rise in haemoglobin ≥1·5 g/L, or both for at least an 8–16-week time period)2,3 is lower than 10%.1 In several phase 3 randomised trials comparing erythropoietin versus supportive care, the expected response rate was as high as 47% with erythropoietin.4,5 Similar results were seen in a phase 3 placebo-controlled study of darbepoetin alfa with a response rate of 35%.6 A pooled analysis of more than 500 patients with lower-risk myelodysplastic syndromes revealed that the majority of clinical responses to ESA therapies occurred within 3 months of treatment and had a median duration of 17 months.7 In April, 2020, luspatercept—an erythroid maturation agent with a mechanism of action distinct from ESA therapy—was approved by the US Food and Drug Administration for patients with lower-risk myelodysplastic syndromes (with the presence of ring sideroblasts and or SF3B1 mutation) who were transfusion dependent with disease refractory to or unlikely to respond to ESA-based therapy. [...]for patients who do not have a clinical response to luspatercept therapy in an upfront setting, should ESA therapy be administered, and, if so, what is the likelihood of response? [...]will mutational profiling help direct the choice between which drug is the best upfront therapy or alleviate concern for clonal evolution (ie, the emergence of resistant clones that lead to disease progression) with one or the other approach?