Minimal residual disease-directed therapy for childhood acute myeloid leukaemia: results of the AML02 multicentre trial.
BACKGROUND
We sought to improve outcome in patients with childhood acute myeloid leukaemia (AML) by applying risk-directed therapy that was based on genetic abnormalities of the leukaemic cells and measurements of minimal residual disease (MRD) done by flow cytometry during treatment.


METHODS
From Oct 13, 2002, to June 19, 2008, 232 patients with de-novo AML (n=206), therapy-related or myelodysplasia-related AML (n=12), or mixed-lineage leukaemia (n=14) were enrolled at eight centres. 230 patients were assigned by block, non-blinded randomisation, stratified by cytogenetic or morphological subtype, to high-dose (18 g/m(2), n=113) or low-dose (2 g/m(2), n=117) cytarabine given with daunorubicin and etoposide (ADE; induction 1). The primary aim of the study was to compare the incidence of MRD positivity of the high-dose group and the low-dose group at day 22 of induction 1. Induction 2 consisted of ADE with or without gemtuzumab ozogamicin (GO anti-CD33 monoclonal antibody); consolidation therapy included three additional courses of chemotherapy or haematopoietic stem-cell transplantation (HSCT). Levels of MRD were used to allocate GO and to determine the timing of induction 2. Both MRD and genetic abnormalities at diagnosis were used to determine the final risk classification. Low-risk patients (n=68) received five courses of chemotherapy, whereas high-risk patients (n=79), and standard-risk patients (n=69) with matched sibling donors, were eligible for HSCT (done for 48 high-risk and eight standard-risk patients). All 230 randomised patients were analysed for the primary endpoint. Other analyses were limited to the 216 patients with AML, excluding those with mixed-lineage leukaemia. This trial is closed to accrual and is registered with ClinicalTrials.gov, number NCT00136084.


RESULTS
Complete remission was achieved in 80% (173 of 216 patients) after induction 1 and 94% (203 of 216) after induction 2. Induction failures included two deaths from toxic effects and ten cases of resistant leukaemia. The introduction of high-dose versus low-dose cytarabine did not significantly lower the rate of MRD-positivity after induction 1 (34%vs 42%, p=0.17). The 6-month cumulative incidence of grade 3 or higher infection was 79.3% (SE 4.0) for patients in the high-dose group and 75.5% (4.2) for the low-dose group. 3-year event-free survival and overall survival were 63.0% (SE 4.1) and 71.1% (3.8), respectively. 80% (155 of 193) of patients achieved MRD of less than 0.1% after induction 2, and the cumulative incidence of relapse for this group was 17% (SE 3). MRD of 1% or higher after induction 1 was the only significant independent adverse prognostic factor for both event-free (hazard ratio 2.41, 95% CI 1.36-4.26; p=0.003) and overall survival (2.11, 1.09-4.11; p=0.028).


CONCLUSIONS
Our findings suggest that the use of targeted chemotherapy and HSCT, in the context of a comprehensive risk-stratification strategy based on genetic features and MRD findings, can improve outcome in patients with childhood AML.


BACKGROUND
National Institutes of Health and American Lebanese Syrian Associated Charities (ALSAC).
Rubnitz
Jeffrey E
JE
Department of Oncology, St Jude Children's Research Hospital and the University of Tennessee Health Science Center, Memphis, TN 38105-2794, USA. jeffrey.rubnitz@stjude.org
Inaba
Hiroto
H
Dahl
Gary
G
Ribeiro
Raul C
RC
Bowman
W Paul
WP
Taub
Jeffrey
J
Pounds
Stanley
S
Razzouk
Bassem I
BI
Lacayo
Norman J
NJ
Cao
Xueyuan
X
Meshinchi
Soheil
S
Degar
Barbara
B
Airewele
Gladstone
G
Raimondi
Susana C
SC
Onciu
Mihaela
M
Coustan-Smith
Elaine
E
Downing
James R
JR
Leung
Wing
W
Pui
Ching-Hon
CH
Campana
Dario
D
D000293:Adolescent; D000617:Aminoglycosides / Q000627:therapeutic use; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000627:therapeutic use; D002648:Child; D002675:Child, Preschool; D003561:Cytarabine / Q000008:administration & dosage; D020732:Cytogenetic Analysis; D003630:Daunorubicin / Q000008:administration & dosage; D018572:Disease-Free Survival; D005047:Etoposide / Q000008:administration & dosage; D005260:Female; D005434:Flow Cytometry; D000079982:Gemtuzumab; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality / Q000473:pathology*; D008297:Male; D018365:Neoplasm, Residual; D012074:Remission Induction; D015996:Survival Rate; D055815:Young Adult
D000617:Aminoglycosides; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D003561:Cytarabine; D005047:Etoposide; D000079982:Gemtuzumab; D003630:Daunorubicin
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