High-Dose Cytarabine Consolidation With or Without Additional Amsacrine and Mitoxantrone in Acute Myeloid Leukemia: Results of the Prospective Randomized AML2003 Trial Markus Schaich, Stefani Parmentier, Michael Kramer, Thomas Illmer, Friedrich Sto ¨lzel, Christoph Ro ¨llig, Christian Thiede, Mathias Ha ¨nel, Kerstin Scha ¨fer-Eckart, Walter Aulitzky, Hermann Einsele, Anthony D. Ho, Hubert Serve, Wolfgang E. Berdel, Jiri Mayer, Norbert Schmitz, Stefan W. Krause, Andreas Neubauer, Claudia D. Baldus, Johannes Schetelig, Martin Bornha ¨user, and Gerhard Ehninger See accompanying editorial on page 2067 Author affiliations appear at the end of this article. Published online ahead of print at www.jco.org on April 29, 2013. Written on behalf of the Study Alliance Leukemia. Presented in part at the 53rd Annual Meeting of the American Society of Hematology, San Diego, CA, December 10-13, 2011. Authors’ disclosures of potential con- flicts of interest and author contribu- tions are found at the end of this article. Clinical trial information: NCT00180102. Corresponding author: Markus Schaich, MD, Medizinische Klinik und Poliklinik I, Universita ¨ tsklinikum Dresden, Fetscher- straße 74, 01307 Dresden, Germany; e-mail: markus.schaich@uniklinikum- dresden.de. © 2013 by American Society of Clinical Oncology 0732-183X/13/3117w-2094w/$20.00 DOI: 10.1200/JCO.2012.46.4743 A B S T R A C T Purpose To assess the treatment outcome benefit of multiagent consolidation in young adults with acute myeloid leukemia (AML) in a prospective, randomized, multicenter trial. Patients and Methods Between December 2003 and November 2009, 1,179 patients (median age, 48 years; range, 16 to 60 years) with untreated AML were randomly assigned at diagnosis to receive either standard high-dose cytarabine consolidation with three cycles of 18 g/m 2 (3 HD-AraC) or multiagent consolidation with two cycles of mitoxantrone (30 mg/m 2 ) plus cytarabine (12 g/m 2 ) and one cycle of amsacrine (500 mg/m 2 ) plus cytarabine (10 g/m 2 ; MAC/MAMAC/MAC). Allogeneic and autologous hematopoietic stem-cell transplantations were performed in a risk-adapted and priority-based manner. Results After double induction therapy using a 3 + 7 regimen including standard-dose cytarabine and daunorubicin, complete remission was achieved in 65% of patients. In the primary efficacy population of patients evaluable for consolidation outcomes, consolidation with either 3 HD-AraC or MAC/MAMC/MAC did not result in any significant difference in 3-year overall (69% v 64%; P = .18) or disease-free survival (46% v 48%; P = .99) according to the intention-to-treat analysis. Furthermore, MAC/MAMAC/MAC led to additional GI and hepatic toxicity and a higher rate of infection and bleeding, resulting in significantly shorter 3-year overall survival in the per-protocol analysis compared with 3 HD-AraC (63% v 72%; P = .04). Conclusion In younger adults with AML, multiagent consolidation using mitoxantrone and amsacrine in combination with high-dose cytarabine does not improve treatment outcome and confers additional toxicity. J Clin Oncol 31:2094-2102. © 2013 by American Society of Clinical Oncology INTRODUCTION The standard treatment of acute myeloid leukemia (AML) comprises one or two cycles of chemothera- py to induce complete remission (CR) followed by postremission treatment to improve long-term re- mission duration. To date, mainly four approaches have been explored as postremission strategies, in- cluding allogeneic hematopoietic stem-cell trans- plantation (HSCT), 1 autologous HSCT, 2 low-dose maintenance therapy, 3 and intensive consolidation chemotherapy. The latter was established in the landmark study published by the Eastern Coopera- tive Oncology Group in 1992 4 and has since been regarded as standard therapy for younger patients with AML with favorable- or intermediate-risk cy- togenetics in first CR. Internationally accepted, the standard chemotherapy consolidation consists of repetitive cycles of high-dose cytarabine. 5 The higher efficacy of four repeated cycles of six doses of 3 g/m 2 compared with intermediate- or standard- dose cytarabine was demonstrated by the Cancer and Leukemia Group B (CALGB) in 1994. 6 How- ever, issues such as the optimal dosage of cytarabine, JOURNAL OF CLINICAL ONCOLOGY O R I G I N A L R E P O R T VOLUME 31  NUMBER 17  JUNE 10 2013 2094 © 2013 by American Society of Clinical Oncology Downloaded from ascopubs.org by 3.238.176.130 on June 17, 2022 from 003.238.176.130 Copyright © 2022 American Society of Clinical Oncology. All rights reserved.