title: High-dose cytarabine in induction treatment improves the outcome of adult patients younger than age 46 years with acute myeloid leukemia: results of the EORTC-GIMEMA AML-12 trial.
abstract: OBJECTIVE
  Cytarabine plays a pivotal role in the treatment of patients with acute myeloid leukemia (AML). Most centers use 7 to 10 days of cytarabine at a daily dose of 100 to 200 mg/m(2) for remission induction. Consensus has not been reached on the benefit of higher dosages of cytarabine.
  
  
  METHODS
  The European Organisation for Research and Treatment of Cancer (EORTC) and Gruppo Italiano Malattie Ematologiche dell' Adulto (GIMEMA) Leukemia Groups conducted a randomized trial (AML-12; Combination Chemotherapy, Stem Cell Transplant and Interleukin-2 in Treating Patients With Acute Myeloid Leukemia) in 1,942 newly diagnosed patients with AML, age 15 to 60 years, comparing remission induction treatment containing daunorubicin, etoposide, and either standard-dose (SD) cytarabine (100 mg/m(2) per day by continuous infusion for 10 days) or high-dose (HD) cytarabine (3,000 mg/m(2) every 12 hours by 3-hour infusion on days 1, 3, 5, and 7). Patients in complete remission (CR) received a single consolidation cycle containing daunorubicin and intermediate-dose cytarabine (500 mg/m(2) every 12 hours for 6 days). Subsequently, a stem-cell transplantation was planned. The primary end point was survival.
  
  
  RESULTS
  At a median follow-up of 6 years, overall survival was 38.7% for patients randomly assigned to SD cytarabine and 42.5% for those randomly assigned to HD cytarabine (log-rank test P = .06; multivariable analysis P = .009). For patients younger than age 46 years, survival was 43.3% and 51.9%, respectively (P = .009; multivariable analysis P = .003), and for patients age 46 to 60 years, survival was 33.9% and 32.9%, respectively (P = .91). CR rates were 72.0% and 78.7%, respectively (P < .001) and were 75.6% and 82.4% for patients younger than age 46 years (P = .01) and 68.3% and 74.8% for patients age 46 years and older (P = .03). Patients of all ages with very-bad-risk cytogenetic abnormalities and/or FLT3-ITD (internal tandem duplication) mutation, or with secondary AML benefitted from HD cytarabine.
  
  
  CONCLUSIONS
  HD cytarabine produces higher remission and survival rates than SD cytarabine, especially in patients younger than age 46 years.
authors.affiliation: Roelof Willemze, Constantijn J.M. Halkes, and Erik W.A. Marijt, Leiden University Medical Center, Leiden; Petra Muus, Joop Jansen, and Theo de Witte, Radboud University Nijmegen Medical Center, Nijmegen, the Netherlands; Stefan Suciu and Liv Meert, European Organisation for Research and Treatment of Cancer Headquarters; Dominique Bron, Hôpital Universitaire, Bordet-Erasme, Brussels; Dominik L.D. Selleslag, Algemeen Ziekenhuis Sint-Jan, Brugge; Zwi Berneman, Universitair Ziekenhuis, Antwerpen; Georges Fillet, Centre Hospitalier Universitaire du Sart-Tilman, Liège; Anne Hagemeijer, Center for Human Genetics, University of Leuven, Leuven, Belgium; Giovanna Meloni, Marco Mancini, Silvia Maria Trisolini, and Franco Mandelli, "Sapienza" University; Sergio Amadori and Adriano Venditti, Tor Vergata University Hospital; Simona Sica, Università Cattolica del Sacro Cuore, Policlinico A. Gemelli; Paola Fazi and Marco Vignetti, Gruppo Italiano Malattie Ematologiche dell' Adulto Foundation, Central Office, Rome; Giorgina Specchia, Università degli Studi di Bari, Bari; Francesco Fabbiano, Ospedali Riuniti "Villa Sofia-Cervello"; Maria Enza Mitra, Policlinico "Paolo Giaccone," Palermo; Francesco Nobile, Azienda Ospedaliera Bianchi-Melacrino-Morelli, Reggio Calabria; Marco Sborgia, Azienda Unitá Sanitaria Locale di Pescara, Pescara; Andrea Camera, L'A.O. Universitaria-Università degli Studi di Napoli "Federico II," Napoli; Domenico Magro, A.O. Pugliese Ciaccio, Catanzaro; Nicola Cantore, A.O. San Giuseppe Moscati, Avellino; Lorella Melillo, Istituto Di Ricovero e Cura a Carattere Scientifico Casa Sollievo della Sofferenza, San Giovanni Rotondo; Pietro Leoni, A.O. Nuovo Ospedale Torrette, Ancona; Mario Luppi, A.O. Universitaria di Modena, Modena; Daniela Cilloni, University of Torino, Torino, Italy; Boris Labar, University Hospital Center-Rebro, Zagreb, Croatia; Jean-Pierre Marie, Saint-Antoine Hospital, Assistance Publique-Hopitaux de Paris and University Paris 6; Francois Lef
authors.forename: Roelof
authors.initials: R
authors.lastname: Willemze
authors.forename: Stefan
authors.initials: S
authors.lastname: Suciu
authors.forename: Giovanna
authors.initials: G
authors.lastname: Meloni
authors.forename: Boris
authors.initials: B
authors.lastname: Labar
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Marie
authors.forename: Constantijn J M
authors.initials: CJ
authors.lastname: Halkes
authors.forename: Petra
authors.initials: P
authors.lastname: Muus
authors.forename: Martin
authors.initials: M
authors.lastname: Mistrik
authors.forename: Sergio
authors.initials: S
authors.lastname: Amadori
authors.forename: Giorgina
authors.initials: G
authors.lastname: Specchia
authors.forename: Francesco
authors.initials: F
authors.lastname: Fabbiano
authors.forename: Francesco
authors.initials: F
authors.lastname: Nobile
authors.forename: Marco
authors.initials: M
authors.lastname: Sborgia
authors.forename: Andrea
authors.initials: A
authors.lastname: Camera
authors.forename: Dominik L D
authors.initials: DL
authors.lastname: Selleslag
authors.forename: Francois
authors.initials: F
authors.lastname: Lefrère
authors.forename: Domenico
authors.initials: D
authors.lastname: Magro
authors.forename: Simona
authors.initials: S
authors.lastname: Sica
authors.forename: Nicola
authors.initials: N
authors.lastname: Cantore
authors.forename: Meral
authors.initials: M
authors.lastname: Beksac
authors.forename: Zwi
authors.initials: Z
authors.lastname: Berneman
authors.forename: Xavier
authors.initials: X
authors.lastname: Thomas
authors.forename: Lorella
authors.initials: L
authors.lastname: Melillo
authors.forename: Jose E
authors.initials: JE
authors.lastname: Guimaraes
authors.forename: Pietro
authors.initials: P
authors.lastname: Leoni
authors.forename: Mario
authors.initials: M
authors.lastname: Luppi
authors.forename: Maria E
authors.initials: ME
authors.lastname: Mitra
authors.forename: Dominique
authors.initials: D
authors.lastname: Bron
authors.forename: Georges
authors.initials: G
authors.lastname: Fillet
authors.forename: Erik W A
authors.initials: EW
authors.lastname: Marijt
authors.forename: Adriano
authors.initials: A
authors.lastname: Venditti
authors.forename: Anne
authors.initials: A
authors.lastname: Hagemeijer
authors.forename: Marco
authors.initials: M
authors.lastname: Mancini
authors.forename: Joop
authors.initials: J
authors.lastname: Jansen
authors.forename: Daniela
authors.initials: D
authors.lastname: Cilloni
authors.forename: Liv
authors.initials: L
authors.lastname: Meert
authors.forename: Paola
authors.initials: P
authors.lastname: Fazi
authors.forename: Marco
authors.initials: M
authors.lastname: Vignetti
authors.forename: Silvia M
authors.initials: SM
authors.lastname: Trisolini
authors.forename: Franco
authors.initials: F
authors.lastname: Mandelli
authors.forename: Theo
authors.initials: T
authors.lastname: de Witte
mesh_terms: D000293:Adolescent; D000328:Adult; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D060830:Consolidation Chemotherapy; D003561:Cytarabine / Q000008:administration & dosage*; D003630:Daunorubicin / Q000008:administration & dosage; D004334:Drug Administration Schedule; D005047:Etoposide / Q000008:administration & dosage; D005060:Europe; D005260:Female; D006801:Humans; D060828:Induction Chemotherapy / Q000379:methods*; D007262:Infusions, Intravenous; D015470:Leukemia, Myeloid, Acute / Q000175:diagnosis / Q000188:drug therapy* / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009154:Mutation; D018570:Risk Assessment; D012307:Risk Factors; D016896:Treatment Outcome
chemical_list: D000964:Antimetabolites, Antineoplastic; D003561:Cytarabine; D005047:Etoposide; D003630:Daunorubicin