Recovering from a therapeutic stall in higher-risk myelodysplastic syndromes: re-examining biology, backbones and study designs

Abstract

Therapeutic progress in higher-risk myelodysplastic syndromes (HR-MDS) has stalled. Despite repeated attempts to improve outcomes through incremental refinements to classification systems and hypomethylating agent (HMA)-based backbones, no phase 3 study since AZA-001 has replicated even the modest survival benefit observed with azacitidine. We propose that this stagnation results from a fundamental mismatch between the biological realities of HR-MDS and the assumptions underpinning contemporary drug development. HR-MDS encompasses biologically diverse ecosystems characterised by distinct clonal architectures, evolutionary trajectories and marrow microenvironmental dysfunction, despite overlapping phenotypic and genotypic features. Treating this heterogeneity as a single entity anchored to a hypomethylating agent backbone, risks obscuring therapeutic signals and misinterpreting responses. Here, we examine the potential biological, microenvironmental, and methodological drivers of therapeutic insufficiency in HR-MDS, to advocate for biologically coherent adaptive platform trials using biomarker-enriched patient selection, and propose shifting away from default HMA backbones. Only by redesigning strategy around biology, rather than prioritising ease of recruitment, or historical precedent, can we restore momentum and lift in HR-MDS drug development.