Originally published as JCO Early Release 10.1200/JCO.2009.22.4865 on September 14 2009

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Real-Time Quantitative Polymerase Chain Reaction Detection of Minimal Residual Disease by Standardized WT1 Assay to Enhance Risk Stratification in Acute Myeloid Leukemia: A European LeukemiaNet Study

From the Department of Clinical & Biological Sciences, University of Turin, Turin; Department of Hematology, University Federico II, Naples, Italy; Department of Hematology, Biology and Pathology Center, University of Lille Medical School; Cancer Research Institute, Jean-Pierre Aubert Research Center, L'Institut National de la Santé et de la Recherche Médicale, U-837, Team 3, Lille; Research & Development, Ipsogen, Marseille, France; Department of Haematology, School of Medicine, Cardiff University, Cardiff; Department of Haematology, Manchester Royal Infirmary, Manchester; Department of Medical and Molecular Genetics, King's College London School of Medicine, London, United Kingdom; Munich Leukemia Laboratory, Munich, Germany; Department of Hematology, Hospital de Sant Pau, Barcelona, Spain; Central Hematology Laboratory, Radboud University Nijmegen Medical Centre, Nijmegen Centre for Molecular Life Sciences, Nijmegen; Department of Immunology, Erasmus MC University Medical Center, Rotterdam, the Netherlands; Laboratory of Immunohematology, Department of Hematology, Århus Sygehus, Tage-Hansens Gade, Århus University Hospital, Århus, Denmark.

Corresponding author: David Grimwade, PhD, FRCPath, Department of Medical and Molecular Genetics, King's College London School of Medicine, 8th Floor, Tower Wing, Guy's Hospital, London SE1 9RT, United Kingdom; e-mail: david.grimwade{at}genetics.kcl.ac.uk.

Purpose Risk stratification in acute myeloid leukemia (AML) is currently based on pretreatment characteristics. It remains to be established whether relapse risk can be better predicted through assessment of minimal residual disease (MRD). One proposed marker is the Wilms tumor gene WT1, which is overexpressed in most patients with AML, thus providing a putative target for immunotherapy, although in the absence of a standardized assay, its utility for MRD monitoring remains controversial.

Patients and Methods Nine published and in-house real-time quantitative polymerase chain reaction WT1 assays were systematically evaluated within the European LeukemiaNet; the best-performing assay was applied to diagnostic AML samples (n = 620), follow-up samples from 129 patients treated with intensive combination chemotherapy, and 204 normal peripheral blood (PB) and bone marrow (BM) controls.

Results Considering relative levels of expression detected in normal PB and BM, WT1 was sufficiently overexpressed to discriminate 2-log reduction in transcripts in 46% and 13% of AML patients, according to the respective follow-up sample source. In this informative group, greater WT1 transcript reduction after induction predicted reduced relapse risk (hazard ratio, 0.54 per log reduction; 95% CI, 0.36 to 0.83; P = .004) that remained significant when adjusted for age, WBC count, and cytogenetics. Failure to reduce WT1 transcripts below the threshold limits defined in normal controls by the end of consolidation also predicted increased relapse risk (P = .004).

Conclusion Application of a standardized WT1 assay provides independent prognostic information in AML, lending support to incorporation of early assessment of MRD to develop more robust risk scores, to enhance risk stratification, and to identify patients who may benefit from allogeneic transplantation.

Supported by Leukaemia Research of Great Britain and the European LeukemiaNet (J.V.J. and D.G.).

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

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