Luspatercept: A New Tool for the Treatment of Anemia Related to β-Thalassemia, Myelodysplastic Syndromes and Primary Myelofibrosis

Abstract

Anemia is a common feature of both benign and malignant hematologic diseases. Beta-thalassemia (β-thalassemia) syndromes are a group of hereditary disorders characterized by ineffective erythropoiesis, due to a genetic deficiency in the synthesis of the beta chains of hemoglobin, often accompanied by severe anemia and the need for red blood cell (RBC) transfusions. Myelodysplastic syndromes (MDS) are characterized by cytopenia(s) and ineffective hematopoiesis, despite a hypercellular bone marrow. Primary myelofibrosis (PMF) is a clonal myeloproliferative neoplasm characterized by reactive fibrosis of the bone marrow, accompanied by extramedullary hematopoiesis. Luspatercept, previously known as ACE-536, is a fusion protein that combines a modified activin receptor IIB (ActRIIB), a member of the transforming growth factor-β (TGF-β) superfamily, with the Fc domain of human immunoglobulin G (IgG1). It has shown efficacy in the treatment of anemia due to beta β-thalassemia, MDS and PMF and recently gained approval by the Federal Drug Agency (FDA) and the European Medicines Agency (EMA) for transfusion-dependent (TD) patients with β-thalassemia and very low to intermediate-risk patients with MDS with ringed sideroblasts who have failed to respond to, or are ineligible for, an erythropoiesis-stimulating agent. In this review, we describe the key pathways involved in normal hematopoiesis and the possible mechanism of action of luspatercept, present its development and data from the most recent clinical trials in β-thalassemia, MDS and PMF, and discuss its potential use in the treatment of these hematological disorders.

Luspatercept's use in a patient with transfusion‐dependent beta‐thalassemia and intrathoracic extramedullary hematopoiesis (EMH)

“…19 It was also noted by Taher and colleagues 20 that patients with thalassemia intermedia also show an increased risk of thrombotic/thromboembolic events, especially those who had splenectomies. Although it is advised to start thromboprophylaxis if patients with splenectomy start on luspatercept, 21 our patient was reluctant and refused to start due to fears of aspirin side effects. Her course after starting treatment was uneventful from a thrombotic events point of view.…”

ACVR1: A Novel Therapeutic Target to Treat Anemia in Myelofibrosis

“…Luspatercept, a recombinant fusion protein that decreases SMAD2/3 signaling, promotes erythroid maturation and improves anemia. Luspatercept was approved as a treatment for anemia in patients with very low- to intermediate-risk myelodysplastic syndromes (MDS) with ring sideroblasts or MDS/MPN with ring sideroblasts and thrombocytosis (April 2020); lower-risk MDS and requirement for RBC transfusions (August 2023); and β-thalassemia with necessity for RBC transfusions (November 2019) [ 99 ]. Future treatments of MF patients with anemia may include regimens combining luspatercept with JAK inhibitors.…”

Association of Myelofibrosis Phenotypes with Clinical Manifestations, Molecular Profiles, and Treatments

“…Notably, retrospective analyses demonstrated that momelotinib maintained its efficacy in thrombocytopenic patients in the two SIMPLIFY-1 and SIMPLIFY-2 trials [140] as well as in the MOMENTUM trial (Table 2) [136,141]. Luspatercept (activin receptor-ligand trap enhancing late-stage erythropoiesis [142]) was evaluated in MF patients with anemia in a phase 2 trial (NCT03194542): in Cohort 3B (transfusion-dependent patients on a stable dose of ruxolitinib), RBC transfusionindependence was achieved in 27% and 36% of the patients, respectively, over any the entire treatment period was assessed; RBC transfusion burden decreased by ≥50% over at least 12 weeks in 46% of the patients [143]. At present, luspatercept is being evaluated in the registrational, phase 3 trial INDEPENDENCE (NCT04717414) in MF patients who are receiving a stable dose of a JAK inhibitor and require RBC transfusions [144].…”