Dyserythropoiesis Evaluated by Red Score and Hepcidin/Ferritin Levels Predicts Response to Erythropoietin in Lower Risk Myelodysplastic Syndromes

INTRODUCTION: Erythropoiesis stimulating agents (ESA) are generally the first line of treatment of anaemia in lower risk myelodysplastic syndrome (MDS) patients. We prospectively investigated the predictive value of somatic mutations, and biomarkers of ineffective erythropoiesis including flow cytometry RED score, serum GDF-15, and hepcidin levels. METHODS: Inclusion criteria were: ESA naive, IPSS low or intermediate-1 MDS with Hemoglobin (Hb) level< 10g/dL. Patients received epoetin zeta 40 000 IU/week and erythroid response (HI-E, IWG 2006 criteria) was assessed at W12. sEPO level, iron parameters and hepcidin, flow cytometry (FC) Ogata and Red Score (RS), GDF-15, and molecular analysis by NGS were determined at baseline. RESULTS: 70 patients were included. Median age was 78 years. There were 22 RCMD, 19 RCUD, 14 RARS, 4 RAEB-1, 6 CMML, 2 del 5q-, 3 unclassifiable, R-IPSS was 13 very low, 47 low, 9 intermediate and high. Twenty patients were transfusion-dependent. HI-E was 48% and median duration of response was 26 months. At baseline, non-responders had significantly higher FC Red Score, lower hepcidin/ferritin ratio, lower IPSS.  In multivariate analysis, only RS>4 at T0 (p=0.05) and hepcidin/ferritin 2000 pg/ml and hepcidin/ferritin<9 (P=0.0008, and p=0.01, respectively). In multivariate analysis, both variables were associated with a shorter duration of response. CONCLUSION: Erythroid response to epoetin zeta was similar to that obtained with other ESAs. It was correlated with higher baseline hepcidin/ferritin ratio and lower Red score. Clinical Trial Number: Clinical trial Gov as NCT03598582. Funding Statement: This study received the support of a research grant from Hospira/Pfizer, the institutional support of Assistance Publique-Hopitaux de Paris through the Unite de Recherche Clinique Paris Descartes Necker Cochin. Declaration of Interests: Sophie Park has received research funding from Hospira/Pfizer. The remaining authors declare no competing financial interests. Ethic Approval Statement: All patients gave their written informed consent for biological investigations according to the recommendations of the local ethics committee (Comite de Protection des Personnes Paris V, CPP N° RCB 212-A01395-38, EUDRACT 2012-002990-7338) and the study was conducted in accordance with the Helsinki Declaration.