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.

Abstract

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 > or = 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.

• Authors: Daniela Cilloni, Aline Renneville, Fabienne Hermitte, Robert K Hills, Sarah Daly, Jelena V Jovanovic, Enrico Gottardi, Milena Fava, Susanne Schnittger, Tamara Weiss, Barbara Izzo, Josep Nomdedeu, Adrian van der Heijden, Bert A van der Reijden, Joop H Jansen, Vincent H J van der Velden, Hans Ommen, Claude Preudhomme, Giuseppe Saglio, David Grimwade
• Journal: Journal of clinical oncology : official journal of the American Society of Clinical Oncology (J Clin Oncol) Vol. 27 Issue 31 Pg. 5195-201 (Nov 01 2009) ISSN: 1527-7755 [Electronic] United States
• PMID: 19752335 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Biomarkers, Tumor

Topics

• Adolescent
• Adult
• Aged
• Antineoplastic Combined Chemotherapy Protocols (therapeutic use)
• Biomarkers, Tumor (genetics)
• Child
• Child, Preschool
• DNA Mutational Analysis
• Gene Expression (drug effects)
• Genes, Wilms Tumor
• Humans
• Leukemia, Myeloid, Acute (diagnosis, drug therapy, genetics)
• Middle Aged
• Neoplasm, Residual (genetics)
• Prognosis
• Reverse Transcriptase Polymerase Chain Reaction (methods)
• Risk Factors
• Young Adult