P030 | Imetelstat restores erythroid maturation in responding low risk myelodysplastic disorders patients

Background. Imetelstat is a first-in-class human telomerase (hTERT) inhibitor, decreasing the upregulated telomerase activity of neoplastic hematopoietic stem and progenitor cells (HSPCs). By suppressing hTERT, Imetelstat selectively eliminates dysplastic clones, enabling restoration of normal hematopoiesis. Recently approved by the FDA for the treatment of red blood cell transfusion–dependent (RBC-TD) lower-risk myelodysplastic syndromes (LR-MDS) patients after erythropoiesis-stimulating agent (ESA) failure, its precise mechanism of action remains unclear. We provide the first in vivo evidence that Imetelstat enhances erythroid maturation by alleviating ineffective erythropoiesis and reducing bone marrow (BM) clonal burden in responding LR-MDS patients.Methods. Comprehensive erythroid flow cytometry (FC) and targeted next-generation sequencing (t-NGS) analyses were performed on BM samples from LR-MDS patients enrolled in the phase III IMerge trial (. NCT02598661). FC analysis included total CD71⁺ erythroid cells (Erytot), early CD34+/CD117⁺, and late CD117⁻ erythroid precursors. The erythroid ratio (ER) was defined as the ratio of late to early precursors. BM erythroid indices and variant allele frequency (VAF) of driver somatic mutations were longitudinally assessed at baseline, +6 and +12 months after Imetelstat initiation; extended FC data were available at +24 months for one ongoing responder.Results. Four representative cases were analyzed: (a) a long responder (>1 year RBC transfusion independence), (b) a transient responder (