Relapse prediction in acute myeloid leukaemia patients in complete remission using WT1 as a molecular marker: development of a mathematical model to predict time from molecular to clinical relapse and define optimal sampling intervals

Abstract

Summary We hypothesized that Wilms tumour 1 gene (WT1) expression levels in acute myeloid leukaemia (AML) patients might have predictive value and reveal molecular relapse kinetics. WT1 level was determined at diagnosis, during therapy and post‐therapy follow‐up in 89 patients who reached first complete remission (CR1) (952 samples, median 8 samples/patient, range 2–38). CR1 bone marrow (BM) WT1 level above normal (based on 39 healthy donors) was an independent adverse prognostic factor regarding both disease‐free survival [hazard ratio (HR) 4·46, P = 0·001] and overall survival (HR 2·62, P = 0·019). By grouping 34 BM and 99 peripheral blood (PB) complete remission samples in monthly intervals prior to clinical relapse, disease development was delineated and a simple mathematical model constructed, that allowed for the prediction of relapse detection rates (RDRs) as well as median times [tms] from WT1 positivity to clinical relapse. BM sampling was required to obtain RDRs above 93% and tms above 67 d. Acceptable RDRs and tms (81% and 44 d, respectively) could be acquired by bimonthly PB sampling. In conclusion, CR1 WT1 expression is an independent prognostic factor in AML. According to our model, BM is superior for relapse prediction, but PB samples are useful when shorter sampling intervals are possible.

How and why minimal residual disease studies are necessary in leukemia: a review from WP10 and WP12 of the European LeukaemiaNet

“…59 Furthermore, the significance of normalized WT-1 expression levels post induction therapy was less clear, as 21 of 48 these patients relapsed. These findings are supported by Ommen et al 60 The available studies indicate that WT-1 levels above normal levels, which may be seen in normal regenerating marrow, are associated with subsequent relapse. These data are supported by finding them to correlate with disease-specific fusion gene transcript numbers.…”

WT1 mRNA Level in Peripheral Blood Is a Sensitive Biomarker for Monitoring Minimal Residual Disease in Acute Myeloid Leukemia

“…WT1 mRNA from PB detected MRD more sharply than the morphological findings of bone marrow aspiration. It has been reported that WT1 mRNA expression is a general molecular marker in leukemia (Inoue et al 1996;Cilloni et al 2002Cilloni et al , 2004Cilloni et al , 2008Lapillonne et al 2006;Ommen et al 2008). It is important to measure WT1 mRNA at any time, at diagnosis or in CR.…”

Protein expression and subcellular localization of familial acute myelogenous leukemia-related factor

“…This approach requires the selection of a specific peptide epitope. In general, to enhance antigen immunoreactivity, the peptide should have strong hydrophilicity and a stable conformation, and either end of the peptide should be linear to maximize its availability for antibody binding (5,7). Using this criterion, we selected a 14-amino acid sequence (CALWVSGIFVDEVI) at the N-terminus of the FAMLF protein that was predicted to have high hydrophilicity, be readily accessible to antibody, and be specific to FAMLF, thereby reducing the likelihood of non-specific binding.…”