Luspatercept for the treatment of myelodysplastic syndrome: A retrospective cohort study utilizing trinetx

Abstract Introduction Myelodysplastic syndromes (MDS) are clonal hematopoietic stem cell disorders defined by ineffective hematopoiesis, peripheral cytopenias, and dysplasia across one or more myeloid lineages. The underlying pathophysiology involves impaired maturation of hematopoietic progenitors resulting in progressive bone marrow failure. Luspatercept is a recombinant fusion protein approved for the treatment of anemia in adults with very low- to intermediate-risk MDS, particularly in MDS with ring sideroblasts (MDS-RS), including both patients who are erythropoiesis-stimulating agent (ESA)-naïve and patients who failed prior ESA therapy. The mechanism of action of luspatercept involves inhibition of TGF-β superfamily ligands, diminishing Smad2/3 signaling, promoting late-stage erythroid maturation via an increase in the percentage of normoblasts in the bone marrow. While clinical trials have demonstrated efficacy and safety, there is limited real-world data evaluating its use in routine practice. This large-scale retrospective study utilizing TriNetX aimed to assess the safety and efficacy of luspatercept for the treatment of CAD. Methods This multicenter retrospective single cohort study evaluated patients with very low- to intermediate-risk MDS in the TriNetX Network, a global database of deidentified electronic medical records from 104 large healthcare organizations encompassing over 140 million patient records. Eligible patients were identified using ICD-10 codes representative of very low- to intermediate-risk MDS with and without ring sideroblasts. All patients were ESA (epoetin alfa or darbepoetin) refractory, defined as being initiated on luspatercept therapy 3 months after the start of ESA agents. The primary outcome was red blood cell transfusion independence (RBC-TI) at 8 weeks, 16 weeks, and 1 year. Secondary outcomes included overall mortality, transition to hypomethylating agent therapy (decitabine or azacitidine), and the need for allogeneic stem cell transplant. Results and Discussion A total of 418 patients met the inclusion criteria, of which 132 patients (32%) had MDS-RS, and 13 patients (3%) had a documented SF3B1 mutation. At 8 weeks, 16 weeks, and 1 year, the percentage of patients who achieved RBC-TI was 28.5%, 21.0%, and 11.0% respectively, demonstrating a gradual decline in RBC-TI over time. 17% of patients progressed to treatment with a hypomethylating agent (azacitidine or decitabine) within the first year of treatment. 3% of patients underwent allogeneic hematopoietic stem cell transplantation. Survival analysis demonstrated an estimated 1-year Kaplan–Meier overall survival probability of 73.3%. The phase 3 MEDALIST trial, which included patients with very low to intermediate-risk MDS-RS who were transfusion-dependent and refractory or unlikely to respond to ESAs, demonstrated that luspatercept significantly improved red blood cell transfusion independence (RBC-TI) compared to placebo, at ≥8 weeks during weeks 1-24 (37.9% vs. 13.2%, p<0.0001). The MEDALIST study demonstrated durable response and favorable safety profile with most adverse events being low-grade such as fatigue, diarrhea, nausea, and dizziness, and decreasing over time. The COMMANDS trial further confirmed the superiority of luspatercept over epoetin alfa in ESA-naïve, transfusion-dependent lower-risk MDS, with a higher rate of RBC-TI ≥12 weeks and a concurrent mean hemoglobin increase ≥1.5 g/dL during weeks 1–24 (60% vs. 35%, p<0.0001). To these authors knowledge, this study represents the largest single-cohort data evaluating the efficacy of luspatercept. In our study, patients were notably not ESA-naive and encompassed very low to intermediate-risk MDS patients who underwent treatment with luspatercept. Response was assessed over the entire one-year period versus increments of the overall defined period, as in prior studies. Conclusion Our findings suggest that luspatercept can provide meaningful and durable benefits for a substantial subset of patients and may serve as an important component of therapy in appropriately selected individuals with very low to intermediate-risk MDS. Future studies are necessary to evaluate which patients would most benefit from treatment with luspatercept.