Wilms' Tumor 1 Gene Expression Using a Standardized European LeukemiaNet-Certified Assay Compared to Other Methods for Detection of Minimal Residual Disease in Myelodysplastic Syndrome and Acute Myelogenous Leukemia after Allogeneic Blood Stem Cell Transplantation

Abstract

Overexpression of the Wilms' tumor 1 (WT1) gene is informative in many patients with acute myelogenous leukemia (AML) and myelodysplastic syndromes (MDS) and is measurable in peripheral blood (PB). Despite these advantages, WT1 has not broadly been established as a marker for minimal residual disease (MRD) monitoring after allogeneic hematopoietic stem cell transplantation (allo-HSCT) due to limited patient numbers, differing sample sources, and nonstandardized in-house methods. To estimate the value of WT1 as an MRD marker, we serially quantified PB WT1 expression using a standardized European LeukemiaNet-certified assay in 59 patients with AML and MDS after allo-HSCT. We compared its performance with routine methods such as chimerism, XY-fluorescence in situ hybridization (FISH), disease-specific cytogenetic, and molecular analyses, which were accessible in 100%, 34%, 68%, and 37%, respectively. Twenty-four patients (41%) relapsed within a median of 126 days after allo-HSCT, and 20 of them showed at least 1 elevated WT1 value above the validated cutoff. The other 35 patients (59%) remained in complete remission, and only 1 patient had a transient increase in WT1 expression. This reflects a sensitivity of 83% and a specificity of 97% for WT1 and appears to be favorable compared with the sensitivities and specificities observed for chimerism (33% and 91%), XY-FISH (67% and 73%), cytogenetic (33% and 77%), and molecular (78% and 85%) analyses. Further supporting its predictive impact, elevated WT1 expression prompted an earlier BM biopsy and consecutively the diagnosis of relapse in 62% of patients. The results of this real-life experience imply that PB WT1 expression is measurable by a standardized assay and predicts imminent relapse after allo-HSCT with high sensitivity and specificity in most patients with AML and MDS.

Novel Disease Risk Model for Patients with Acute Myeloid Leukemia Receiving Allogeneic Hematopoietic Cell Transplantation

“…Over the past several years other factors have been identified as important in prognosticating survival of patients with AML, such as molecular abnormalities and presence of minimal/measurable residual disease (MRD) before transplant [15][16][17][18][19]. Here we hypothesized that a prognostic model that includes molecular abnormalities and MRD would better stratify patients with AML undergoing AHCT and inform treatment decisions in the modern era.…”

Azacitidine as salvage therapy for relapsed acute myeloid leukemia/myelodysplastic syndrome after allogeneic hematopoietic stem cell transplantation

“…Molecular relapse (M‐Rel) was defined by the recurrence of MDS‐ or AML‐specific disease markers such as chromosomal aberrations or chimeric fusion genes. If patients didn't have any disease specific markers, we defined the elevated levels of Wilms tumor 1 (WT1) in PB to over 100 copies/µgRNA as M‐Rel. Molecular complete response (MCR) was defined as WT1 <50 copies/µgRNA and disappearance of MDS‐ or AML‐specific disease markers.…”

Pharmacologic Therapies to Prevent Relapse of Acute Myeloid Leukemia After Allogeneic Hematopoietic Stem Cell Transplantation

“…WT1 expression analysis in MRD assessment is recommended by ELN using a standardized and certified ELN assay (59). Several reports showed that persistent high bone marrow or continuous increase in peripheral blood WT1 transcripts at 3 months post-transplant are associated with higher risk of relapse (60,61). Conversely, patients with sustained low WT1 levels after transplant have excellent outcomes (62).…”