High WT1 expression after induction therapy predicts high risk of relapse and death in pediatric acute myeloid leukemia.
OBJECTIVE
To determine whether minimal residual disease (MRD) measured by Wilms' tumor gene 1 (WT1) expression is a prognostic marker in pediatric acute myeloid leukemia (AML), we quantified WT1 transcript by real-time quantitative-polymerase chain reaction in 92 AML at diagnosis and during follow-up.


METHODS
Patients (median age, 6 years; cytogenetics, favorable 27%, intermediate 59%, poor 13%) were treated between 1995 and 2002 and enrolled in Leucémie aiguë Myéloblastique Enfant (LAME) 89/91, LAME 99 pilot study and Acute Promyelocytic Leukemia French collaborative protocols. With a median follow-up of 26 months, event-free survival was 56% with a standard deviation (SD) of 5% and overall survival of 62.5% with an SD of 6%. WT1 copy number was normalized by TATA box binding protein gene transcripts and expressed as WT1/TBP x 1,000 ratio. Median WT1 ratio in normal patient controls was 12 (range, 0 to 57). A level over two SD than normal bone marrow controls (ie, WT1 ratio > 50), was considered as significant overexpression.


RESULTS
At diagnosis, WT1 overexpression was detected in 78% of patients (72 of 92 patients; median copy ratio, 2231). The WT1 values were significantly higher (P = .01) in favorable cytogenetics and lower (P < .0001) in M5-FAB subtype, 11q23 rearrangements (P < .001), and infants (P = .003) and demonstrate a strong correlation with fusion transcript AML1-ETO, PML-RARalpha expression. After induction treatment, WT1 ratio was analyzed in 46 of 72 patients and found above 50 in nine of 36 patients and five of 25 patients at D35-50 and 3 to 5 months, respectively. WT1 ratio > 50 after induction is an independent prognostic risk factor of relapse (P = .002) and death (P = .02).


CONCLUSIONS
WT1 quantification is an informative molecular marker for MRD in pediatric AML and is now performed as prospective analysis in ELAM02 protocol.
Lapillonne
Hélène
H
Laboratoire d'hématologie, Service d'hématologie et d'oncologie pédiatrique, hôpital Trousseau, Paris, France.
Renneville
Aline
A
Auvrignon
Anne
A
Flamant
Cyril
C
Blaise
Annick
A
Perot
Christine
C
Lai
Jean-Luc
JL
Ballerini
Paola
P
Mazingue
Françoise
F
Fasola
Sylvie
S
Dehée
Axelle
A
Bellman
Françoise
F
Adam
Mircéa
M
Labopin
Myriam
M
Douay
Luc
L
Leverger
Guy
G
Preudhomme
Claude
C
Landman-Parker
Judith
J
D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D050676:Core Binding Factor Alpha 2 Subunit / Q000235:genetics; D005260:Female; D018628:Gene Dosage; D016162:Genes, Wilms Tumor; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000235:genetics*; D008297:Male; D015999:Multivariate Analysis; D009363:Neoplasm Proteins / Q000235:genetics; D015514:Oncogene Proteins, Fusion / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis; D000075142:RUNX1 Translocation Partner 1 Protein; D012008:Recurrence; D020133:Reverse Transcriptase Polymerase Chain Reaction
C107844:AML1-ETO fusion protein, human; D050676:Core Binding Factor Alpha 2 Subunit; D009363:Neoplasm Proteins; D015514:Oncogene Proteins, Fusion; D012333:RNA, Messenger; D000075142:RUNX1 Translocation Partner 1 Protein; C093476:promyelocytic leukemia-retinoic acid receptor alpha fusion oncoprotein