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J Clin Oncol. 2014 Jan 20;32(3):219-28. doi: 10.1200/JCO.2013.51.8571. Epub 2013 Dec 2.

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.

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1
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

Abstract

PURPOSE:

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.

PATIENTS AND 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.

CONCLUSION:

HD cytarabine produces higher remission and survival rates than SD cytarabine, especially in patients younger than age 46 years.

TRIAL REGISTRATION:

ClinicalTrials.gov NCT00004128.

PMID:
24297940
DOI:
10.1200/JCO.2013.51.8571
[Indexed for MEDLINE]
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