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

Abstract

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. None of these layers is proposed as an established isolated cause of luspatercept resistance. The central testable prediction is biological-output discordance: some patients may show a measurable downstream erythroid biological response without a proportional hemoglobin or transfusion benefit. This prediction should be tested prospectively against conventional predictors including transfusion burden, disease severity and molecular risk. The hypothesis should be rejected or narrowed if downstream biological and clinical responses are tightly concordant, or if multilayer measurements add no reproducible explanatory or predictive information beyond established clinical and molecular variables. The framework therefore shifts the question from whether luspatercept “works” in a non-responder to which biological layer remains rate-limiting after the maturation constraint is relieved.