Luspatercept in the Treatment of Lower-Risk Myelodysplastic Syndromes

Abstract

Transforming growth factor beta (TGF-β) signaling pathway is key to hematopoiesis regulation. Increased activation of this pathway contributes to ineffective terminal erythroid differentiation in myelodysplastic syndromes (MDS). Luspatercept is a novel fusion protein that traps TGF-β ligands preventing them from binding to Type II TGF-β receptors, thereby decreasing phosphorylated SMAD2/3 resulting in the downstream effect of promoting erythropoiesis. Seminal clinical trials using luspatercept, PACE-MD and MEDALIST, demonstrated impressive efficacy in the treatment of transfusion-dependent anemia in intermediate risk or lower MDS had led to the US FDA approval for this indication. This review summarizes luspatercept mechanisms of action, efficacy/safety data supporting its use and ongoing clinical trials in MDS.

Phase 1/2 study evaluating the safety and efficacy of DSP‐7888 dosing emulsion in myelodysplastic syndromes

“…Lenalidomide is approved for a small subset of MDS patients with chromosome 5q deletion 9 . In April 2020, luspatercept was approved by the US Food and Drug Administration for patients with very low to intermediate (Int) risk MDS 11 . AZA and decitabine have demonstrated improved response rates and prolonged time to AML transformation and survival compared to conventional care in randomized phase 3 trials, 12‐14 and both are indicated in higher‐risk patients, although decitabine is not approved in Japan 15,16 .…”

“… 9 In April 2020, luspatercept was approved by the US Food and Drug Administration for patients with very low to intermediate (Int) risk MDS. 11 AZA and decitabine have demonstrated improved response rates and prolonged time to AML transformation and survival compared to conventional care in randomized phase 3 trials, 12 , 13 , 14 and both are indicated in higher‐risk patients, although decitabine is not approved in Japan. 15 , 16 Approximately 40% of patients fail to respond to HMA, 17 and most responders experience disease relapse within 2 years.…”