APG101 efficiently rescues erythropoiesis in lower risk myelodysplastic syndromes with severe impairment of hematopoiesis

// Anna Raimbault 1, 2, 3, 4, 5, * , Cecile Pierre-Eugene 1, * , Alexandra Rouquette 6 , Celine Deudon 1 , Lise Willems 7 , Nicolas Chapuis 1, 2, 3, 4, 5 , Stephanie Mathis 1, 2, 3, 4, 5 , Claudia Kunz 8 , Harald Fricke 8 , Olivier Kosmider 1, 2, 3, 4, 5 , Valerie Bardet 1, 2, 3, 4, 5 , Michaela Fontenay 1, 2, 3, 4, 5 , on behalf of the Groupe Francophone des Myelodysplasies 1 Assistance Publique-Hopitaux de Paris, Service d’Hematologie Biologique, Hopitaux Universitaires Paris Centre, Hopital Cochin, Paris, France 2 Universite Paris Descartes, Faculte de Medecine, Paris, France 3 Institut National de la Sante et de la Recherche Medicale (INSERM) U1016, Paris, France 4 Centre National de la Recherche Scientifique, Unite Mixte de Recherche 8104, Paris, France 5 Institut Cochin, Department of Development, Reproduction and Cancer, Paris, France 6 Departement d’Epidemiologie et de Biostatistiques, Hopitaux Universitaires Paris Centre, Paris, France 7 Assistance Publique-Hopitaux de Paris, Service d’Hematologie Clinique, Hopitaux Universitaires Paris Centre, Hopital Cochin, Paris, France 8 APOGENIX, GmbH, Heidelberg, Germany * These authors have contributed equally to this work Correspondence to: Michaela Fontenay, e-mail: michaela.fontenay@inserm.fr Keywords: myelodysplastic syndromes, erythropoiesis, CD95, CD95 ligand, anemia Received: September 07, 2015     Accepted: January 02, 2016     Published: February 18, 2016 ABSTRACT CD95, a member of the death receptor family initiates a caspase-dependent apoptosis, when activated by its ligand CD95L, thought to negatively regulate erythrocyte production in the bone marrow. We have previously shown that CD95 is overexpressed in two thirds of patients with a lower risk myelodysplastic syndrome (MDS) and that resistance to erythropoiesis-stimulating agents (ESA) is linked to poor residual erythropoiesis. In the present study, we show that CD95 overexpression and previous transfusion are independent predictive factors of ESA resistance. To investigate an alternative therapeutic strategy of anemia in ESA-resistant patients, we have conducted a preclinical study of the effects of APG101, a fusion protein consisting of the extracellular domain of human CD95 and the Fc region of human IgG1 on MDS erythropoiesis in vitro . APG101 increases the number of burst-forming unit-erythroid (BFU-E) progenitors derived from CD34 + progenitors in liquid culture and improves overall proliferation rate of erythroid precursors by inhibiting apoptosis. APG101 rescues BFU-E growth in MDS patients presenting with attrition of erythroid progenitors at baseline, independently of CD95 or CD95L expression level. Our data show that overexpression of CD95 at diagnosis is a hallmark of ESA resistance and that severe impairment of erythropoiesis is predictive of erythroid response to APG101 in vitro . These data provide a rationale for further clinical investigation of APG101 in an attempt to treat anemia in lower risk MDS patients.