title: Decitabine improves progression-free survival in older high-risk MDS patients with multiple autosomal monosomies: results of a subgroup analysis of the randomized phase III study 06011 of the EORTC Leukemia Cooperative Group and German MDS Study Group.
abstract: In a study of elderly AML patients treated with the hypomethylating agent decitabine (DAC), we noted a surprisingly favorable outcome in the (usually very unfavorable) subgroup with two or more autosomal monosomies (MK2+) within a complex karyotype (Lübbert et al., Haematologica 97:393-401, 2012). We now analyzed 206 myelodysplastic syndrome (MDS) patients (88 % of 233 patients randomized in the EORTC/GMDSSG phase III trial 06011, 61 of them with RAEBt, i.e. AML by WHO) with cytogenetics informative for MK status.. Endpoints are the following: complete/partial (CR/PR) and overall response rate (ORR) and progression-free (PFS) and overall survival (OS). Cytogenetic subgroups are the following: 63 cytogenetically normal (CN) patients, 143 with cytogenetic abnormalities, 73 of them MK-negative (MK-), and 70 MK-positive (MK+). These MK+ patients could be divided into 17 with a single autosomal monosomy (MK1) and 53 with at least two monosomies (MK2+). ORR with DAC in CN patients: 36.1 %, in MK- patients: 16.7 %, in MK+ patients: 43.6 % (MK1: 44.4 %, MK2+ 43.3 %). PFS was prolonged by DAC compared to best supportive care (BSC) in the CN (hazard ratio (HR) 0.55, 99 % confidence interval (CI), 0.26; 1.15, p = 0.03) and MK2+ (HR 0.50; 99 % CI, 0.23; 1.06, p = 0.016) but not in the MK-, MK+, and MK1 subgroups. OS was not improved by DAC in any subgroup. In conclusion, we demonstrate for the first time in a randomized phase III trial that high-risk MDS patients with complex karyotypes harboring two or more autosomal monosomies attain encouraging responses and have improved PFS with DAC treatment compared to BSC.
authors.affiliation: Division of Hematology, Oncology and Stem Cell Transplantation, University of Freiburg Medical Center, Freiburg, Germany. michael.luebbert@uniklinik-freiburg.de.
authors.forename: Michael
authors.initials: M
authors.lastname: Lübbert
authors.affiliation: European Organisation for Research and Treatment of Cancer Headquarters, Brussels, Belgium.
authors.forename: Stefan
authors.initials: S
authors.lastname: Suciu
authors.affiliation: Department of Human Genetics, University Hospital, University of Leuven, Leuven, Belgium.
authors.forename: Anne
authors.initials: A
authors.lastname: Hagemeijer
authors.affiliation: Division of Hematology, Oncology and Stem Cell Transplantation, University of Freiburg Medical Center, Freiburg, Germany.
authors.forename: Björn
authors.initials: B
authors.lastname: Rüter
authors.affiliation: Department of Hematology and Oncology, University of Dresden, Dresden, Germany.
authors.forename: Uwe
authors.initials: U
authors.lastname: Platzbecker
authors.affiliation: Department of Hematology and Oncology, Marienhospital, Düsseldorf, Germany.
authors.forename: Aristoteles
authors.initials: A
authors.lastname: Giagounidis
authors.affiliation: Department of Hematology, AZ Sint-Jan Brugge-Oostende, Brugge, Belgium.
authors.forename: Dominik
authors.initials: D
authors.lastname: Selleslag
authors.affiliation: University Hospital Center Rebro, Zagreb, Croatia.
authors.forename: Boris
authors.initials: B
authors.lastname: Labar
authors.affiliation: Department of Hematology, Oncology and Clinical Immunology, Heinrich-Heine-University, Düsseldorf, Germany.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Germing
authors.affiliation: Department of Hematology/Oncology, Eberhard Karls University, Tübingen, Germany.
authors.forename: Helmut R
authors.initials: HR
authors.lastname: Salih
authors.affiliation: Department of Hematology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
authors.forename: Petra
authors.initials: P
authors.lastname: Muus
authors.affiliation: Department of Medicine II, DIAKO Bremen, Bremen, Germany.
authors.forename: Karl-Heinz
authors.initials: KH
authors.lastname: Pflüger
authors.affiliation: Institute of Pathology, University of Freiburg, Freiburg, Germany.
authors.forename: Hans-Eckart
authors.initials: HE
authors.lastname: Schaefer
authors.affiliation: Division of Hematology, Oncology and Stem Cell Transplantation, University of Freiburg Medical Center, Freiburg, Germany.|Institute for Medical Biometry and Medical Informatics, University of Freiburg, Freiburg, Germany.
authors.forename: Lioudmila
authors.initials: L
authors.lastname: Bogatyreva
authors.affiliation: Hematology, Oncology, and Clinical Immunology, St Johannes Hospital, Duisburg, Germany.
authors.forename: Carlo
authors.initials: C
authors.lastname: Aul
authors.affiliation: Department of Tumor Immunology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
authors.forename: Theo
authors.initials: T
authors.lastname: de Witte
authors.affiliation: Department of Hematology, Hemostasis, Oncology, and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany.
authors.forename: Arnold
authors.initials: A
authors.lastname: Ganser
authors.affiliation: Division of Hematology, Oncology and Stem Cell Transplantation, University of Freiburg Medical Center, Freiburg, Germany.
authors.forename: Heiko
authors.initials: H
authors.lastname: Becker
authors.affiliation: Department of Hematology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.|Department of Hematology, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Gerwin
authors.initials: G
authors.lastname: Huls
authors.affiliation: Department of Hematology, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Lieke
authors.initials: L
authors.lastname: van der Helm
authors.affiliation: Department of Hematology, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Edo
authors.initials: E
authors.lastname: Vellenga
authors.affiliation: C.H.U. Sart-Tilman, Liège, Belgium.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Baron
authors.affiliation: UPMC, UMRS 872 and Saint-Antoine Hospital, AP-HP, Paris, France.
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Marie
authors.affiliation: Department of Hematology, Haga Hospital, The Hague, The Netherlands.
authors.forename: Pierre W
authors.initials: PW
authors.lastname: Wijermans
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000964:Antimetabolites, Antineoplastic / Q000627:therapeutic use*; D001374:Azacitidine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D000077209:Decitabine; D018450:Disease Progression; D018572:Disease-Free Survival; D005260:Female; D005858:Germany / Q000453:epidemiology; D006801:Humans; D007938:Leukemia / Q000175:diagnosis / Q000188:drug therapy / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009006:Monosomy / Q000235:genetics*; D009190:Myelodysplastic Syndromes / Q000175:diagnosis / Q000188:drug therapy* / Q000235:genetics*; D012307:Risk Factors
chemical_list: D000964:Antimetabolites, Antineoplastic; D000077209:Decitabine; D001374:Azacitidine
keywords: Adverse cytogenetics; Azacytidine; Elderly patients; Epigenetic therapy; Hypomethylating agents; Monosomal karyotype