Anthracycline dose intensification in acute myeloid leukemia

N Engl J Med. 2009 Sep 24;361(13):1249-59. doi: 10.1056/NEJMoa0904544.

Abstract

Background: In young adults with acute myeloid leukemia (AML), intensification of the anthracycline dose during induction therapy has improved the rate of complete remission but not of overall survival. We evaluated the use of cytarabine plus either standard-dose or high-dose daunorubicin as induction therapy, followed by intensive consolidation therapy, in inducing complete remission to improve overall survival.

Methods: In this phase 3 randomized trial, we assigned 657 patients between the ages of 17 and 60 years who had untreated AML to receive three once-daily doses of daunorubicin at either the standard dose (45 mg per square meter of body-surface area) or a high dose (90 mg per square meter), combined with seven daily doses of cytarabine (100 mg per square meter) by continuous intravenous infusion. Patients who had a complete remission were offered either allogeneic hematopoietic stem-cell transplantation or high-dose cytarabine, with or without a single dose of the monoclonal antibody gemtuzumab ozogamicin, followed by autologous stem-cell transplantation. The primary end point was overall survival.

Results: In the intention-to-treat analysis, high-dose daunorubicin, as compared with a standard dose of the drug, resulted in a higher rate of complete remission (70.6% vs. 57.3%, P<0.001) and improved overall survival (median, 23.7 vs. 15.7 months; P=0.003). The rates of serious adverse events were similar in the two groups. Median follow-up was 25.2 months.

Conclusions: In young adults with AML, intensifying induction therapy with a high daily dose of daunorubicin improved the rate of complete remission and the duration of overall survival, as compared with the standard dose. (ClinicalTrials.gov number, NCT00049517.)

Publication types

  • Clinical Trial, Phase III
  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Age Factors
  • Antibiotics, Antineoplastic / administration & dosage*
  • Antibiotics, Antineoplastic / adverse effects
  • Antineoplastic Combined Chemotherapy Protocols / administration & dosage*
  • Antineoplastic Combined Chemotherapy Protocols / adverse effects
  • Combined Modality Therapy
  • Cytarabine / administration & dosage
  • Daunorubicin / administration & dosage*
  • Daunorubicin / adverse effects
  • Female
  • Histone-Lysine N-Methyltransferase
  • Humans
  • Infusions, Intravenous
  • Kaplan-Meier Estimate
  • Leukemia, Myelomonocytic, Acute / drug therapy*
  • Leukemia, Myelomonocytic, Acute / genetics
  • Leukemia, Myelomonocytic, Acute / mortality
  • Leukemia, Myelomonocytic, Acute / therapy
  • Male
  • Middle Aged
  • Mutation
  • Myeloid-Lymphoid Leukemia Protein / genetics
  • Proportional Hazards Models
  • Remission Induction / methods
  • Risk Factors
  • Stem Cell Transplantation
  • Young Adult
  • fms-Like Tyrosine Kinase 3 / genetics

Substances

  • Antibiotics, Antineoplastic
  • KMT2A protein, human
  • Cytarabine
  • Myeloid-Lymphoid Leukemia Protein
  • Histone-Lysine N-Methyltransferase
  • FLT3 protein, human
  • fms-Like Tyrosine Kinase 3
  • Daunorubicin

Associated data

  • ClinicalTrials.gov/NCT00049517