Luspatercept in Myelodysplastic Syndromes With Ring Sideroblasts: Long Term Outcome and Impact on Non‐Erythroid Blood Counts

Long-term real-world data on Luspatercept (Luspa) in lower-risk myelodysplastic syndromes with ring sideroblasts (MDS-RS) and transfusion-dependent anemia (RBC-TD) who are refractory or ineligible to erythropoiesis-stimulating agents (ESAs) remain limited. Despite evidence of efficacy from clinical trials and real-world studies, long-term data in routine clinical practice are scarce, particularly regarding its effects on non-erythroid lineages. Furthermore, there is currently no consensus on the total duration of treatment, especially in non-responding cases. Thus, we analyzed 48 patients with low-risk MDS-RS treated with Luspa for ESA-refractory RBC-TD. Response was assessed at 6 months, 1 year, and 2 years according to International Working Group (IWG) 2018 criteria. At 6 months, 23/42 (54.8%) and 15/42 (35.7%) patients reached a response and transfusion independence, respectively. At 1 year, 16/30 (53.3%) patients showed a response, including 12 who already responded at 6 months. At 2 years, 10/20 (50%) patients maintained response and 2/20 (10%) were de novo responders. Treatment was well tolerated, with no significant adverse events reported; 21 (43.8%) patients discontinued Luspa, principally due to lack of response. After a median follow-up of 29.8 months (95% CI: 24.4–35.2), 6-month responders had longer overall survival in a landmark analysis. Exploratory analyses identified associations of 6-month response with additional somatic mutations and the SF3B1 hotspot mutation, the latter retained in the multivariable model; monocyte count was associated with 2-year response. Neutrophil counts significantly increased at 1 year compared with baseline, while platelet counts remained stable. Intriguingly, monocytes were increased at the three time points compared to baseline. Specifically, long-term responders presented higher levels of neutrophils and monocytes, as well decreased level of LDH, compared with non-responders. Responses were observed during long-term treatment, mainly in patients who had responded at earlier assessments. Decreasing evaluable sample sizes and the retrospective design limit interpretation. Associations with survival and non-erythroid blood counts require confirmation and should not be interpreted as causal effects.