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Dyserythropoiesis evaluated by the RED score and hepcidin:ferritin ratio predicts response to erythropoietin in lower-risk myelodysplastic syndromes

Sophie Park 1 Olivier Kosmider 2 Fréderic Maloisel 3 Bernard Drénou 4 Nicolas Chapuis 2 Thibaud Lefebvre 5 Zoubida Karim 5 Hervé Puy 6 Anne Sophie Alary Sarah Ducamp 7 Frédérique Verdier 2 Cécile Bouilloux Alice Rousseau 8 Marie-Christine Jacob 9 Agathe Debliquis 10 Agnès Charpentier Emmanuel Gyan 11 Bruno Anglaret 12 Cécile Leyronnas 13 Selim Corm 14 Borhane Slama 15 Stéphane Cheze 16 Kamel Laribi 17 Shanti Amé 18 Christian Rose Florence Lachenal 19 Andrea Toma 20 Gian Matteo Pica Martin Carre Frederic Garban Clara Mariette 21 Jean-Yves Cahn 22 Mathieu Meunier 23 Olivier Herault 24 Pierre Fenaux 25 Orianne Wagner-Ballon 26 Valérie Bardet 27 François Dreyfus 28 Michaela Fontenay 2
Abstract : Erythropoiesis-stimulating agents are generally the first line of treatment of anemia in patients with lower-risk myelodysplastic syndrome. We prospectively investigated the predictive value of somatic mutations, and biomarkers of ineffective erythropoiesis including the flow cytometry RED score, serum growth-differentiation factor-15, and hepcidin levels. Inclusion criteria were no prior treatment with erythropoiesis-stimulating agents, low- or intermediate-1-risk myelodysplastic syndrome according to the International Prognostic Scoring System, and a hemoglobin level <10 g/dL. Patients could be red blood cell transfusion-dependent or not and were given epoetin zeta 40 000 IU/week. Serum erythropoietin level, iron parameters, hepcidin, flow cytometry Ogata and RED scores, and growth-differentiation factor-15 levels were determined at baseline, and molecular analysis by next-generation sequencing was also conducted. Erythroid response (defined according to the International Working Group 2006 criteria) was assessed at week 12. Seventy patients, with a median age of 78 years, were included in the study. There were 22 patients with refractory cytopenia with multilineage dysplasia, 19 with refractory cytopenia with unilineage dysplasia, 14 with refractory anemia with ring sideroblasts, four with refractory anemia with excess blasts-1, six with chronic myelomonocytic leukemia, two with del5q-and three with unclassifiable myelodysplastic syndrome. According to the revised International Prognostic Scoring System, 13 had very low risk, 47 had low risk, nine intermediate risk and one had high-risk disease. Twenty patients were transfusion dependent. Forty-eight percent had an erythroid response and the median duration of the response was 26 months. At baseline, non-responders had significantly higher RED scores and lower hepcidin:ferritin ratios. In multivariate analysis, only a RED score >4 (P=0.05) and a hepcidin:ferritin ratio <9 (P=0.02) were statistically significantly associated with worse erythroid response. The median response duration was shorter in patients with growth-differentiation factor-15 >2000 pg/mL and a hepcidin:ferritin ratio <9 (P=0.0008 and P=0.01, respectively). In multivariate analysis, both variables were associated with shorter response duration. Erythroid response to epoetin zeta was similar to that obtained with other erythropoiesis-stimulating agents and was correlated with higher baseline hepcidin:ferritin ratio and lower RED score. ClinicalTrials.gov registration: NCT 03598582.
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Submitted on : Monday, December 14, 2020 - 10:50:36 PM
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Sophie Park, Olivier Kosmider, Fréderic Maloisel, Bernard Drénou, Nicolas Chapuis, et al.. Dyserythropoiesis evaluated by the RED score and hepcidin:ferritin ratio predicts response to erythropoietin in lower-risk myelodysplastic syndromes. Haematologica, Ferrata Storti Foundation, 2019, 104 (3), pp.497-504. ⟨10.3324/haematol.2018.203158⟩. ⟨hal-02351432⟩

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