Anthracycline dose intensification in acute myeloid leukemia.
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.)
Fernandez
Hugo F
HF
Department of Blood and Marrow Transplantation, Moffitt Cancer Center and Research Institute, University of South Florida, Tampa, FL 33612, USA. hugo.fernandez@moffitt.org
Sun
Zhuoxin
Z
Yao
Xiaopan
X
Litzow
Mark R
MR
Luger
Selina M
SM
Paietta
Elisabeth M
EM
Racevskis
Janis
J
Dewald
Gordon W
GW
Ketterling
Rhett P
RP
Bennett
John M
JM
Rowe
Jacob M
JM
Lazarus
Hillard M
HM
Tallman
Martin S
MS
D000293:Adolescent; D000328:Adult; D000367:Age Factors; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage* / Q000009:adverse effects; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects; D003131:Combined Modality Therapy; D003561:Cytarabine / Q000008:administration & dosage; D003630:Daunorubicin / Q000008:administration & dosage* / Q000009:adverse effects; D005260:Female; D011495:Histone-Lysine N-Methyltransferase; D006801:Humans; D007262:Infusions, Intravenous; D053208:Kaplan-Meier Estimate; D015479:Leukemia, Myelomonocytic, Acute / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality / Q000628:therapy; D008297:Male; D008875:Middle Aged; D009154:Mutation; D051788:Myeloid-Lymphoid Leukemia Protein / Q000235:genetics; D016016:Proportional Hazards Models; D012074:Remission Induction / Q000379:methods; D012307:Risk Factors; D033581:Stem Cell Transplantation; D055815:Young Adult; D051941:fms-Like Tyrosine Kinase 3 / Q000235:genetics
D000903:Antibiotics, Antineoplastic; C497422:KMT2A protein, human; D003561:Cytarabine; D051788:Myeloid-Lymphoid Leukemia Protein; D011495:Histone-Lysine N-Methyltransferase; C497970:FLT3 protein, human; D051941:fms-Like Tyrosine Kinase 3; D003630:Daunorubicin