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High WT1 Expression After Induction Therapy Predicts High Risk of Relapse and Death in Pediatric Acute Myeloid Leukemia

Hélène Lapillonne, Aline Renneville, Anne Auvrignon, Cyril Flamant, Annick Blaise, Christine Perot, Jean-Luc Lai, Paola Ballerini, Françoise Mazingue, Sylvie Fasola, Axelle Dehée, Françoise Bellman, Mircéa Adam, Myriam Labopin, Luc Douay, Guy Leverger, Claude Preudhomme, Judith Landman-Parker

From the Laboratoire d'hématologie, Service d'hématologie et d'oncologie pédiatrique, Service de réanimation pédiatrique, and Laboratoire de microbiologie, hôpital Trousseau; Laboratoire de cytogénétique, hôpital Saint-Antoine, Paris; Département d'hématologie et INSERM U524, hôpital Claude Huriez, Lille, France

Address reprint requests to Judith Landman-Parker, MD, Service d'hématologie et d'oncologie pédiatrique, hôpital Armand Trousseau, 26 avenue Arnold Netter, 75012 Paris, France; e-mail: judith.landman-parker{at}trs.ap-hop-paris.fr

PURPOSE: 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.

PATIENTS AND 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-RAR 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).

CONCLUSION: WT1 quantification is an informative molecular marker for MRD in pediatric AML and is now performed as prospective analysis in ELAM02 protocol.

Supported by the Association Pour La Recherche Dans Les Maladies Hématologiques De L'Enfant (ARMHE) and the Ligue Nationale Contre le Cancer (comité de Paris).

Presented in part at the Annual Meeting of the French Society of Hematology (SFH) Paris, March 7-9, 2004 and at the American Society of Hematology 46th Annual Meeting, San Diego, California, December 4-7, 2004.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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