Optimization of chemotherapy for younger patients with acute myeloid leukemia: results of the medical research council AML15 trial.
OBJECTIVE
Treatment outcomes in younger patients with acute myeloid leukemia (AML) have improved, but optimization and new combinations are needed. We assess three combinations in induction and consolidation.


METHODS
Younger untreated patients with AML (median age, 49 years; range, 0 to 73 years) were randomly allocated to two induction courses of daunorubicin and cytarabine (DA) with or without etoposide (ADE; n = 1983) or ADE versus fludarabine, cytarabine, granulocyte colony-stimulating factor, and idarubicin (FLAG-Ida; n = 1268), and to amsacrine, cytarabine, etoposide, and then mitoxantrone/cytarabine (MACE-MidAC) or high-dose cytarabine (n = 1,445) 3 g/m(2) or 1.5 g/m(2) (n = 657) in consolidation, and finally to a fifth course (cytarabine) or not (n = 227).


RESULTS
Overall remission rates were similar for DA versus ADE (84% v 86%; P = .14) and ADE versus FLAG-Ida (86% v 85%; P = .7), with more course 1 remissions after FLAG-Ida (77%) reducing relapse (38% v 55%; P < .001) and improving relapse-free survival (45% v 34%; P = .01), overall and in subgroups, but with increased myelosuppression, reducing participation in the consolidation randomization. Overall outcomes were similar between MACE/MidAc and high-dose cytarabine (1.5/3.0 g/m(2)), but cytarabine required less supportive care. MACE/MidAc was superior for high-risk patients. A fifth course provided no benefit. The outcome for recipients of only two FLAG-Ida courses were not different from that with DA/ADE with consolidation.


CONCLUSIONS
FLAG-Ida is an effective remission induction treatment, with a high complete remission rate after course 1 and reduced relapse. Consolidation with MACE/MidAc is similar overall to high-dose cytarabine, but superior in high-risk patients. Cytarabine at 1.5 g/m(2) is equivalent to a 3 g/m(2) dose. A fifth course is unnecessary. In patients receiving FLAG-Ida (two courses) and cytarabine (two courses), 8-year survival was 63% for patients with intermediate-risk and 95% for those with favorable-risk disease.
Alan K. Burnett and Robert K. Hills, Cardiff University School of Medicine, Cardiff; Nigel H. Russell, Nottingham University Hospital National Health Service Trust, Nottingham; Ann E. Hunter, Leicester Royal Infirmary, Leicester; John Yin, Manchester Royal Infirmary, Manchester Brenda E.S. Gibson, Royal Hospital for Sick Children, Yorkhill, Glasgow; Keith Wheatley, Cancer Research UK Clinical Trials Unit, University of Birmingham; and Donald Milligan, Birmingham Heartlands Hospital, Birmingham, United Kingdom; and Lars Kjeldsen, Rigshopitalet, Copenhagen, Denmark.
Alan K
AK
Burnett
Nigel H
NH
Russell
Robert K
RK
Hills
Ann E
AE
Hunter
Lars
L
Kjeldsen
John
J
Yin
Brenda E S
BE
Gibson
Keith
K
Wheatley
Donald
D
Milligan
D000293:Adolescent; D000328:Adult; D000367:Age Factors; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D002648:Child; D002675:Child, Preschool; D060830:Consolidation Chemotherapy; D003561:Cytarabine / Q000008:administration & dosage; D005260:Female; D016179:Granulocyte Colony-Stimulating Factor / Q000008:administration & dosage; D006801:Humans; D015255:Idarubicin / Q000008:administration & dosage; D007223:Infant; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D016896:Treatment Outcome; D014740:Vidarabine / Q000008:administration & dosage / Q000031:analogs & derivatives; D055815:Young Adult
D003561:Cytarabine; D016179:Granulocyte Colony-Stimulating Factor; D014740:Vidarabine; D015255:Idarubicin