Why Erythroid Maturation May Not Translate into Clinical Response: A Falsifiable Multilayer Hypothesis for Luspatercept in Myelodysplastic Neoplasms

Luspatercept improves anemia in many patients with lower-risk myelodysplastic neoplasms by promoting late-stage erythroid maturation, but clinical benefit remains heterogeneous. We propose that inadequate response in a biologically defined subset may occur despite a downstream erythroid biological effect when upstream or parallel constraints remain rate-limiting. The model integrates four interacting layers: clonal and epigenetic architecture, marrow-niche remodeling and fibrosis, inflammatory and iron-regulatory state, and ineffective erythropoiesis as the final system output.