title: Therapeutic value of clofarabine in younger and middle-aged (18-65 years) adults with newly diagnosed AML.
abstract: Clofarabine has demonstrated antileukemic activity in acute myeloid leukemia (AML) but has yet to be critically evaluated in younger adults in the frontline with standard chemotherapy. We compared 2 induction regimens in newly diagnosed patients ages 18 to 65 with acute myeloid leukemia (AML)/high-risk myelodysplastic syndromes, that is, idarubicine-cytarabine (cycle I) and amsacrine-cytarabine (cycle II) without or with clofarabine (10 mg/m2on days 1-5 of each of both cycles). Consolidation involved chemotherapy with or without hematopoietic stem cell transplantation. Event-free survival (EFS, primary endpoint) and other clinical endpoints and toxicities were assessed. We randomized 402 and 393 evaluable patients to the control or clofarabine induction treatment arms. Complete remission rates (89%) did not differ but were attained faster with clofarabine (66% vs 75% after cycle I). Clofarabine added grades 3 to 4 toxicities and delayed hematological recovery. At a median follow-up of 36 months, the study reveals no differences in overall survival and EFS between the control (EFS, 35% ± 3 [standard error] at 4 years) and clofarabine treatments (38% ± 3) but a markedly reduced relapse rate (44% ± 3 vs 35% ± 3) in favor of clofarabine and an increased death probability in remission (15% ± 2 vs 22% ± 3). In the subgroup analyses, clofarabine improved overall survival and EFS for European Leukemia Net (ELN) 2010 intermediate I prognostic risk AML (EFS, 26% ± 4 vs 40% ± 5 at 4 years; CoxP= .002) and for the intermediate risk genotypeNPM1wild-type/FLT3without internal-tandem duplications (EFS, 18% ± 5 vs 40% ± 7; CoxP< .001). Clofarabine improves survival in subsets of intermediate-risk AML only. HOVON-102 study is registered at Netherlands Trial Registry #NTR2187.
authors.affiliation: Department of Hematology, Erasmus University Medical Center (MC), Rotterdam, The Netherlands.
authors.forename: Bob
authors.initials: B
authors.lastname: Löwenberg
authors.affiliation: Inselspital, Bern, Switzerland.
authors.forename: Thomas
authors.initials: T
authors.lastname: Pabst
authors.affiliation: Department of Hematology, University Hospital Gasthuisberg, Leuven, Belgium.
authors.forename: Johan
authors.initials: J
authors.lastname: Maertens
authors.affiliation: HOVON Data Center, Erasmus University MC Cancer Institute, Rotterdam, The Netherlands.
authors.forename: Yvette
authors.initials: Y
authors.lastname: van Norden
authors.affiliation: Department of Hematology, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Bart J
authors.initials: BJ
authors.lastname: Biemond
authors.affiliation: Department of Hematology, University Hospital, Maastricht, The Netherlands.
authors.forename: Harry C
authors.initials: HC
authors.lastname: Schouten
authors.affiliation: Department of Hematology, University Hospital, Lausanne, Switzerland.
authors.forename: Olivier
authors.initials: O
authors.lastname: Spertini
authors.affiliation: Department of Hematology, University Medical Center, Groningen, The Netherlands.
authors.forename: Edo
authors.initials: E
authors.lastname: Vellenga
authors.affiliation: UCL Namur (Godinne), Yvoir, Belgium.
authors.forename: Carlos
authors.initials: C
authors.lastname: Graux
authors.affiliation: Department of Hematology, Hôpital St. Luc, Brussels, Belgium.
authors.forename: Violaine
authors.initials: V
authors.lastname: Havelange
authors.affiliation: Department of Hematology, Erasmus University Medical Center (MC), Rotterdam, The Netherlands.
authors.forename: Georgine E
authors.initials: GE
authors.lastname: de Greef
authors.affiliation: St. Antonius Hospital, Nieuwegein, The Netherlands.
authors.forename: Okke
authors.initials: O
authors.lastname: de Weerdt
authors.affiliation: Medisch Spectrum Twente, Enschede, The Netherlands.
authors.forename: Marie-Cecile J C
authors.initials: MJ
authors.lastname: Legdeur
authors.affiliation: Department of Hematology, University Medical Center, Utrecht, The Netherlands.
authors.forename: Juergen
authors.initials: J
authors.lastname: Kuball
authors.affiliation: Isala Hospital, Zwolle, The Netherlands.
authors.forename: Marinus van Marwijk
authors.initials: MV
authors.lastname: Kooy
authors.affiliation: Haukeland University Hospital, Bergen, Norway.
authors.forename: Bjorn T
authors.initials: BT
authors.lastname: Gjertsen
authors.affiliation: Department of Hematology, Erasmus University Medical Center (MC), Rotterdam, The Netherlands.
authors.forename: Mojca
authors.initials: M
authors.lastname: Jongen-Lavrencic
authors.affiliation: Department of Hematology, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Arjan A
authors.initials: AA
authors.lastname: van de Loosdrecht
authors.affiliation: Haga Hospital, The Hague, The Netherlands.
authors.forename: Daniëlle
authors.initials: D
authors.lastname: van Lammeren-Venema
authors.affiliation: Hôpital Citadelle, Liège, Belgium.
authors.forename: Beata
authors.initials: B
authors.lastname: Hodossy
authors.affiliation: Ziekenhuis Netwerk Antwerpen, Antwerp, Belgium.
authors.forename: Dimitri A
authors.initials: DA
authors.lastname: Breems
authors.affiliation: Department of Hematology, University Hospital and University of Geneva, Geneva, Switzerland.
authors.forename: Yves
authors.initials: Y
authors.lastname: Chalandon
authors.affiliation: Department of Hematology, University Hospital, Basel, Switzerland; and.
authors.forename: Jakob
authors.initials: J
authors.lastname: Passweg
authors.affiliation: Department of Hematology, Erasmus University Medical Center (MC), Rotterdam, The Netherlands.
authors.forename: Peter J M
authors.initials: PJ
authors.lastname: Valk
authors.affiliation: Department of Hematology, University Hospital, Zurich, Switzerland.
authors.forename: Markus G
authors.initials: MG
authors.lastname: Manz
authors.affiliation: Department of Hematology, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Gert J
authors.initials: GJ
authors.lastname: Ossenkoppele
mesh_terms: D000227:Adenine Nucleotides / Q000009:adverse effects / Q000627:therapeutic use*; D000293:Adolescent; D000328:Adult; D000368:Aged; D000964:Antimetabolites, Antineoplastic / Q000009:adverse effects / Q000627:therapeutic use*; D001087:Arabinonucleosides / Q000009:adverse effects / Q000627:therapeutic use*; D000077866:Clofarabine; D060830:Consolidation Chemotherapy / Q000379:methods; D006801:Humans; D060828:Induction Chemotherapy / Q000379:methods; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000401:mortality; D008875:Middle Aged; D000090243:Nucleophosmin; D012074:Remission Induction; D012306:Risk; D015996:Survival Rate; D055815:Young Adult
chemical_list: D000227:Adenine Nucleotides; D000964:Antimetabolites, Antineoplastic; D001087:Arabinonucleosides; C000716967:NPM1 protein, human; D000090243:Nucleophosmin; D000077866:Clofarabine