title: Increasing intensity of therapies assigned at diagnosis does not improve survival of adults with acute myeloid leukemia.
abstract: We randomized 3375 adults with newly diagnosed acute myeloid leukemia (AML) or high-risk myelodysplastic syndrome to test whether increasingly intensive chemotherapies assigned at study-entry and analyzed on an intent-to-treat basis improved outcomes. In total, 1529 subjects <60 years were randomized to receive: (1) a first course of induction therapy with high-dose cytarabine and mitoxantrone (HAM) or with standard-dose cytarabine, daunorubicin and 6-thioguanine (TAD) followed by a second course of HAM; (2) granulocyte-colony stimulating factor (G-CSF) or no G-CSF before induction and consolidation courses; and (3) high-dose therapy and an autotransplant or maintenance chemotherapy. In total, 1846 subjects ⩾60 years were randomized to receive: (1) a first induction course of HAM or TAD and second induction course of HAM (if they had bone marrow blasts ⩾5% after the first course); and (2) G-CSF or no G-CSF as above. Median follow-up was 7.4 years (range, 1 day to 14.7 years). Five-year event-free survivals (EFSs) for subjects receiving a first induction course of HAM vs TAD were 17% (95% confidence interval, 15, 18%) vs 16% (95% confidence interval 14, 18%; P=0.719). Five-year EFSs for subjects randomized to receive or not receive G-CSF were 19% (95% confidence interval 16, 21%) vs 16% (95% confidence interval 14, 19%; P=0.266). Five-year relapse-free survivals (RFSs) for subjects <60 years receiving an autotransplant vs maintenance therapy were 43% (95% confidence interval 40, 47%) vs 40 (95% confidence interval 35, 44%; P=0.535). Many subjects never achieved pre-specified landmarks and consequently did not receive their assigned therapies. These data indicate the limited impact of more intensive therapies on outcomes of adults with AML. Moreover, none of the more intensive therapies we tested improved 5-year EFS, RFS or any other outcomes.
authors: Department of Medicine A, University Hospital, Muenster, Germany.
authors: U
authors: U
authors: Krug
authors: Department of Medicine A, University Hospital, Muenster, Germany.
authors: W E
authors: WE
authors: Berdel
authors: Celgene Inc., Summit, NJ, USA.
authors: R P
authors: RP
authors: Gale
authors: Munich Leukemia Laboratory, Munich, Germany.
authors: C
authors: C
authors: Haferlach
authors: Munich, Germany.
authors: S
authors: S
authors: Schnittger
authors: Department of Medicine A, University Hospital, Muenster, Germany.
authors: C
authors: C
authors: Müller-Tidow
authors: IIIrd Department of Medicine, University Hospital Großhadern, Munich, Germany.
authors: J
authors: J
authors: Braess
authors: IIIrd Department of Medicine, University Hospital Großhadern, Munich, Germany.
authors: K
authors: K
authors: Spiekermann
authors: Department of Medicine 1, University Hospital, Cologne, Germany.
authors: P
authors: P
authors: Staib
authors: Department of Bone Marrow Transplantation, University Hospital, Essen, Germany.
authors: D
authors: D
authors: Beelen
authors: Department of Medicine II, University Hospital, Frankfurt, Germany.
authors: H
authors: H
authors: Serve
authors: Department of Medicine A, University Hospital, Muenster, Germany.
authors: C
authors: C
authors: Schliemann
authors: Department of Medicine A, University Hospital, Muenster, Germany.
authors: M
authors: M
authors: Stelljes
authors: Evangelisches Krankenhaus, Department of Hematology, Oncology and Palliative Care, Hamm, Germany.
authors: L
authors: L
authors: Balleisen
authors: Klinikum Ernst von Bergmann, Department of Hematology, Oncology and Palliative Care, Berlin, Germany.
authors: G
authors: G
authors: Maschmeyer
authors: Vivantes Hospital Neukölln, Department of Hematology, Oncology and Palliative Care, Berlin, Germany.
authors: A
authors: A
authors: Grüneisen
authors: Allgemeines Krankenhaus, Department of Medicine and Oncology, Hagen, Germany.
authors: H
authors: H
authors: Eimermacher
authors: Helios Klinikum, Department of Oncology and Hematology, Duisburg, Germany.
authors: A
authors: A
authors: Giagounidis
authors: Klinikum Bremen Mitte, Department of Medicine I, Bremen, Germany.
authors: H
authors: H
authors: Rasche
authors: Department of Hematology and Oncology, University Hospital, Mannheim, Germany.
authors: R
authors: R
authors: Hehlmann
authors: Department of Hematology and Oncology, University Hospital, Mannheim, Germany.
authors: E
authors: E
authors: Lengfelder
authors: Department of Hematology, Oncology and Tumor Immunology, University Hospital Charité - Benjamin Franklin, Berlin, Germany.
authors: E
authors: E
authors: Thiel
authors: Department of Medicine III, University Hospital, Regensburg, Germany.
authors: A
authors: A
authors: Reichle
authors: Helios Klinikum, Department of Oncology and Hematology, Duisburg, Germany.
authors: C
authors: C
authors: Aul
authors: Helios Klinikum Berlin-Buch, Department of Hematology, Oncology, Tumor Immunology and Palliative Medicine, Berlin, Germany.
authors: W-D
authors: WD
authors: Ludwig
authors: Munich Leukemia Laboratory, Munich, Germany.
authors: W
authors: W
authors: Kern
authors: Munich Leukemia Laboratory, Munich, Germany.
authors: T
authors: T
authors: Haferlach
authors: University of Münster, Institute of Biostatistics and Clinical Research, Münster, Germany.
authors: W
authors: W
authors: Köpcke
authors: University of Münster, Institute of Biostatistics and Clinical Research, Münster, Germany.
authors: D
authors: D
authors: Görlich
authors: University of Münster, Institute of Biostatistics and Clinical Research, Münster, Germany.
authors: M C
authors: MC
authors: Sauerland
authors: University of Münster, Institute of Biostatistics and Clinical Research, Münster, Germany.
authors: A
authors: A
authors: Heinecke
authors: Klinikum Braunschweig, Department of Medicine III, Braunschweig, Germany.
authors: B J
authors: BJ
authors: Wörmann
authors: IIIrd Department of Medicine, University Hospital Großhadern, Munich, Germany.
authors: W
authors: W
authors: Hiddemann
authors: Department of Medicine A, University Hospital, Muenster, Germany.
authors: T
authors: T
authors: Büchner
mesh_terms: D000328:Adult; D000616:Aminoglutethimide / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D003561:Cytarabine / Q000627:therapeutic use; D003613:Danazol / Q000627:therapeutic use; D018572:Disease-Free Survival; D016179:Granulocyte Colony-Stimulating Factor; D006801:Humans; D060828:Induction Chemotherapy; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000401:mortality / Q000628:therapy; D008875:Middle Aged; D008942:Mitoxantrone / Q000627:therapeutic use; D033581:Stem Cell Transplantation; D015996:Survival Rate; D013629:Tamoxifen / Q000627:therapeutic use; D014182:Transplantation, Autologous; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D003561:Cytarabine; D013629:Tamoxifen; D000616:Aminoglutethimide; D016179:Granulocyte Colony-Stimulating Factor; D008942:Mitoxantrone; D003613:Danazol