Luspatercept in lower-myelodysplastic syndromes (MDS): real-world data from the Gruppo Romano-Laziale Mielodisplasie (GROM-L) and review of literature

Introduction: Luspatercept is a recombinant fusion protein that binds transforming growth factor β superfamily ligands, leading to red blood cells (RBC) maturation. The MEDALIST trial evaluated activity of this molecule showing encouraging results in terms of transfusion independence in lower-risk MDS with ring sideroblast. Methods: We retrospectively analyzed patients treated in the Lazio Region, according to clinical practice, between 2021 and 2024. Eligible patients were 18 years of age or older affected by lower-risk MDS with ring sideroblasts, refractory to erythropoiesis-stimulating agents (ESA) and transfusion dependent. Responses were defined by the IWG 2006 criteria. Results: We evaluated 40 patients (pts) (25 M, 15 F), with a median age at diagnosis of 70 years (range 56-85). According to IPSS-R classification 9/40 (22,5%), 24/40 (60%) and 7/40 (17.5%) pts were very low, low and intermediate risk, respectively. Median Hb at diagnosis and at treatment was 10.8 g/dL and 7.7 g/dL, respectively. All pts received ESA before treatment (median time 21 months, range 1-206 months). Concomitant iron chelation therapy was administered to 27/40 pts (67.5%). Baseline serum EPO level was <200 U/l in 13/40 pts (32.5%). Baseline transfusion burden was equal to or greater than 6 units every 8 weeks in 32/40 pts (80%), whereas it was less than 6 units every 8 weeks in 8/40 (20%). SF3B1 mutation was detected in 15/40 (37,5%) pts. NGS study was available in 21 patients; mutation of ASXL1, CSF3R, DNMT3A and JAK2 V617F were found in 4/21 (19%), 1/21 (5%), 5/21 (24%) and 2/21 (10%) patients, respectively. Median follow up was 14.6 months (range 1-87 months). Transfusion independence for 8 weeks or longer was observed in 13/40 pts (32,5%). Erythroid response occurred in 12/40 pts (30%) during the first 24 weeks. A dosage increase was required in 33/40 pts (82,5%), with the highest response found at 1.75 mg/kg. Median number of infusions was 13 (range 1-50). Median duration of response was 6 months (range 1.5-26). Overall, 14/40 (35%) pts stopped treatment due to no response (36%), lack of response (43%), toxicity (7%), and personal preference (14%). None of the pts progressed to acute myeloid leukaemia. Fatigue (7%) and arthralgia (10%) were the most frequent reported side effects. Conclusion: Our study confirmed luspatercept efficacy in one third of cases in a cohort of heavily transfusion-dependent patients. It was well tolerated in the absence of major side effects.