IPSS-M risk and specific sex-associated somatic mutations predict response to ESA therapy in LR-MDS: building a new score.

This study evaluated genetic markers predicting the response to erythropoiesis-stimulating agents (ESAs) in lower-risk myelodysplastic syndromes (LR-MDS) using targeted next-generation sequencing in a European cohort of 535 patients.

Key findings include:

• Improved prediction: Incorporating the molecular IPSS-M score with serum erythropoietin levels and transfusion dependence improved prediction of ESA response (AUC 0.71 vs 0.63).
• Development of ESA-PSS-M score: A composite molecular predictive score was developed and externally validated, showing reasonable specificity (76%) and sensitivity (57%).
• Gene mutation insights: No individual gene mutation broadly predicted ESA response, but STAG2 mutations on the X chromosome were significantly associated with ESA resistance in males.

This work highlights the value of integrating molecular risk scoring and sex-specific genetic information to better guide first-line anemia treatments in LR-MDS.