title: A randomized phase II trial of azacitidine +/- epoetin-β in lower-risk myelodysplastic syndromes resistant to erythropoietic stimulating agents.
abstract: The efficacy of azacitidine in patients with anemia and with lower-risk myelodysplastic syndromes, if relapsing after or resistant to erythropoietic stimulating agents, and the benefit of combining these agents to azacitidine in this setting are not well known. We prospectively compared the outcomes of patients, all of them having the characteristics of this subset of lower-risk myelodysplastic syndrome, if randomly treated with azacitidine alone or azacitidine combined with epoetin-β. High-resolution cytogenetics and gene mutation analysis were performed at entry. The primary study endpoint was the achievement of red blood cell transfusion independence after six cycles. Ninety-eight patients were randomised (49 in each arm). Median age was 72 years. In an intention to treat analysis, transfusion independence was obtained after 6 cycles in 16.3% versus 14.3% of patients in the azacitidine and azacitidine plus epoetin-β arms, respectively (P=1.00). Overall erythroid response rate (minor and major responses according to IWG 2000 criteria) was 34.7% vs. 24.5% in the azacitidine and azacitidine plus epoetin-β arms, respectively (P=0.38). Mutations of the SF3B1 gene were the only ones associated with a significant erythroid response, 29/59 (49%) versus 6/27 (22%) in SF3B1 mutated and unmutated patients, respectively, P=0.02. Detection of at least one "epigenetic mutation" and of an abnormal single nucleotide polymorphism array profile were the only factors associated with significantly poorer overall survival by multivariate analysis. The transfusion independence rate observed with azacitidine in this lower-risk population, but resistant to erythropoietic stimulating agents, was lower than expected, with no observed benefit of added epoetin, (clinicaltrials.gov identifier: 01015352).
authors.affiliation: Service d'Hématologie Clinique, Hôpital Avicenne, Assistance Publique-Hôpitaux de Paris (AP-HP), and Université Paris 13, Bobigny, France.
authors.forename: Sylvain
authors.initials: S
authors.lastname: Thépot
authors.affiliation: Laboratoire d'hématologie, CHRU de Lille, France.
authors.forename: Raouf
authors.initials: R
authors.lastname: Ben Abdelali
authors.affiliation: Service de biostatistique et information médicale, Hôpital Saint-Louis, AP-HP and Université Paris 7, France.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Chevret
authors.affiliation: Laboratoire d'hématologie, CHRU de Lille, France.
authors.forename: Aline
authors.initials: A
authors.lastname: Renneville
authors.affiliation: Service d'Hématologie Clinique, Centre Hospitalier Universitaire, Toulouse, France.
authors.forename: Odile
authors.initials: O
authors.lastname: Beyne-Rauzy
authors.affiliation: Département d'Hématologie, Institut Paoli-Calmettes, Marseille, France.
authors.forename: Thomas
authors.initials: T
authors.lastname: Prébet
authors.affiliation: Service d'Hématologie Clinique, Hôpital Cochin, AP-HP and Université Paris 5, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Park
authors.affiliation: Service d'Hématologie, Centre Henri Becquerel, Rouen, France.
authors.forename: Aspasia
authors.initials: A
authors.lastname: Stamatoullas
authors.affiliation: Service d'Hématologie Clinique, Centre Hospitalier Universitaire, Nancy, France.
authors.forename: Agnes
authors.initials: A
authors.lastname: Guerci-Bresler
authors.affiliation: Service d'Hématologie Clinique, Centre Hospitalier Universitaire, Caen, France.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Cheze
authors.affiliation: Service de médecine interne, Hôpital du kremlin-Bicetre, AP-HP and Université Paris, France.
authors.forename: Gérard
authors.initials: G
authors.lastname: Tertian
authors.affiliation: Service d'Hématologie Clinique, Hôpital de Boulogne sur mer, France.
authors.forename: Bachra
authors.initials: B
authors.lastname: Choufi
authors.affiliation: Service d'Hématologie, Centre Hospitalier Universitaire, Nice, France.
authors.forename: Laurence
authors.initials: L
authors.lastname: Legros
authors.affiliation: Service d'Hématologie Clinique, Centre Hospitalier Universitaire, Dijon, France.
authors.forename: Jean Noel
authors.initials: JN
authors.lastname: Bastié
authors.affiliation: Service d'Hématologie, Centre Hospitalier Universitaire, Nantes, France.
authors.forename: Jacques
authors.initials: J
authors.lastname: Delaunay
authors.affiliation: Service d'Hématologie Clinique, Centre Hospitalier Universitaire, Limoges, France.
authors.forename: Marie Pierre
authors.initials: MP
authors.lastname: Chaury
authors.affiliation: Service d'Hématologie, Centre Hospitalier, Perpignan, France.
authors.forename: Laurence
authors.initials: L
authors.lastname: Sanhes
authors.affiliation: Service d'Hématologie, Hôpital Universitaire Lyon Sud, Lyon, France.
authors.forename: Eric
authors.initials: E
authors.lastname: Wattel
authors.affiliation: Service d'Hématologie Clinique, Hôpital Cochin, AP-HP and Université Paris 5, France.
authors.forename: Francois
authors.initials: F
authors.lastname: Dreyfus
authors.affiliation: Département d'Hématologie, Institut Paoli-Calmettes, Marseille, France.
authors.forename: Norbert
authors.initials: N
authors.lastname: Vey
authors.affiliation: Groupe francophone des Myélodysplasies, Hôpital Saint-Louis, AP-HP, France.
authors.forename: Fatiha
authors.initials: F
authors.lastname: Chermat
authors.affiliation: Laboratoire d'hématologie, CHRU de Lille, France.
authors.forename: Claude
authors.initials: C
authors.lastname: Preudhomme
authors.affiliation: Service d'Hématologie Clinique senior, Hôpital Saint-Louis, AP-HP and Université Paris 7, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Fenaux
authors.affiliation: Service d'Hématologie Clinique, Hôpital Avicenne, Assistance Publique-Hôpitaux de Paris (AP-HP), and Université Paris 13, Bobigny, France claude.gardin@avc.aphp.fr.
authors.forename: Claude
authors.initials: C
authors.lastname: Gardin
mesh_terms: D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001374:Azacitidine / Q000008:administration & dosage / Q000627:therapeutic use*; D015415:Biomarkers; D020732:Cytogenetic Analysis; D004252:DNA Mutational Analysis; D004351:Drug Resistance; D004921:Erythropoietin / Q000008:administration & dosage; D005260:Female; D006397:Hematinics / Q000627:therapeutic use; D006801:Humans; D008297:Male; D008875:Middle Aged; D009190:Myelodysplastic Syndromes / Q000175:diagnosis / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality; D020641:Polymorphism, Single Nucleotide; D011994:Recombinant Proteins / Q000008:administration & dosage; D016019:Survival Analysis; D016896:Treatment Outcome
chemical_list: D015415:Biomarkers; D006397:Hematinics; D011994:Recombinant Proteins; C103998:epoetin beta; D004921:Erythropoietin; D001374:Azacitidine