title: Benefit of high-dose daunorubicin in AML induction extends across cytogenetic and molecular groups.
abstract: The initial report of the Eastern Cooperative Oncology Group-American College of Radiology Imaging Network Cancer Research Group trial E1900 (#NCT00049517) showed that induction therapy with high-dose (HD) daunorubicin (90 mg/m(2)) improved overall survival in adults <60 years old with acute myeloid leukemia (AML); however, at initial analysis, the benefit was restricted to younger patients (<50 years) and patients without unfavorable cytogenetics or aFLT3-ITD mutation. Here, we update the results of E1900 after longer follow-up (median, 80.1 months among survivors), focusing on the benefit of HD daunorubicin on common genetic subgroups. Compared with standard-dose daunorubicin (45 mg/m(2)), HD daunorubicin is associated with a hazard ratio (HR) for death of 0.74 (P= .001). Younger patients (<50 years) benefited from HD daunorubicin (HR, 0.66;P= .002), as did patients with favorable and intermediate cytogenetics (HR, 0.51;P= .03 and HR, 0.68;P= .01, respectively). Patients with unfavorable cytogenetics were shown to benefit from HD daunorubicin on multivariable analysis (adjusted HR, 0.66;P= .04). Patients with FLT3-ITD (24%),DNMT3A(24%), and NPM1(26%) mutant AML all benefited from HD daunorubicin (HR, 0.61,P= .009; HR, 0.62,P= .02; and HR, 0.50,P= .002; respectively). HD benefit was seen in the subgroup of older patients (50-60 years) with the FLT3-ITD or NPM1 mutation. Additionally, the presence of an NPM1 mutation confers a favorable prognosis only for patients receiving anthracycline dose intensification during induction.
authors.affiliation: Division of Hematology and Oncology, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA;
authors.forename: Marlise R
authors.initials: MR
authors.lastname: Luskin
authors.affiliation: Eastern Cooperative Oncology Group-American College of Radiology Imaging Network Biostatistics Center, Dana-Farber Cancer Institute, Boston, MA;
authors.forename: Ju-Whei
authors.initials: JW
authors.lastname: Lee
authors.affiliation: Department of Blood and Marrow Transplantation, Moffitt Cancer Center, Tampa, FL;
authors.forename: Hugo F
authors.initials: HF
authors.lastname: Fernandez
authors.affiliation: Human Oncology and Pathogenesis Program, and Leukemia Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY;
authors.forename: Omar
authors.initials: O
authors.lastname: Abdel-Wahab
authors.affiliation: Department of Pathology, University of Rochester, Rochester, NY;
authors.forename: John M
authors.initials: JM
authors.lastname: Bennett
authors.affiliation: Division of Hematopathology, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN;
authors.forename: Rhett P
authors.initials: RP
authors.lastname: Ketterling
authors.affiliation: Seidman Cancer Center, Case Western Reserve University, Cleveland, OH;
authors.forename: Hillard M
authors.initials: HM
authors.lastname: Lazarus
authors.affiliation: Human Oncology and Pathogenesis Program, and Leukemia Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY;
authors.forename: Ross L
authors.initials: RL
authors.lastname: Levine
authors.affiliation: Department of Hematology, Mayo Clinic, Rochester, MN;
authors.forename: Mark R
authors.initials: MR
authors.lastname: Litzow
authors.affiliation: Department of Oncology, Montefiore Medical Center, Bronx, NY; and.
authors.forename: Elisabeth M
authors.initials: EM
authors.lastname: Paietta
authors.affiliation: Human Oncology and Pathogenesis Program, and.
authors.forename: Jay P
authors.initials: JP
authors.lastname: Patel
authors.affiliation: Department of Oncology, Montefiore Medical Center, Bronx, NY; and.
authors.forename: Janis
authors.initials: J
authors.lastname: Racevskis
authors.affiliation: Rambam Medical Center, Haifa, Israel.
authors.forename: Jacob M
authors.initials: JM
authors.lastname: Rowe
authors.affiliation: Leukemia Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY;
authors.forename: Martin S
authors.initials: MS
authors.lastname: Tallman
authors.affiliation: Eastern Cooperative Oncology Group-American College of Radiology Imaging Network Biostatistics Center, Dana-Farber Cancer Institute, Boston, MA;
authors.forename: Zhuoxin
authors.initials: Z
authors.lastname: Sun
authors.affiliation: Division of Hematology and Oncology, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA;
authors.forename: Selina M
authors.initials: SM
authors.lastname: Luger
mesh_terms: D000293:Adolescent; D000328:Adult; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage / Q000627:therapeutic use*; D003582:Cytogenetics; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics*; D000090205:DNA Methyltransferase 3A; D003630:Daunorubicin / Q000008:administration & dosage / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D060828:Induction Chemotherapy / Q000379:methods; D015470:Leukemia, Myeloid, Acute / Q000175:diagnosis / Q000188:drug therapy* / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics*; D000090243:Nucleophosmin; D011379:Prognosis; D016019:Survival Analysis; D055815:Young Adult; D051941:fms-Like Tyrosine Kinase 3 / Q000235:genetics*
chemical_list: D000903:Antibiotics, Antineoplastic; C000717967:DNMT3A protein, human; C000716967:NPM1 protein, human; D009687:Nuclear Proteins; D000090243:Nucleophosmin; D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A; C497970:FLT3 protein, human; D051941:fms-Like Tyrosine Kinase 3; D003630:Daunorubicin