General AML|FLT3|NPM1

Is WT1 gene expression a biomarker for prognosis and MRD in NK-AML? – a Serbian study

Wilms Tumor 1 (WT1) is overexpressed in approximately 85% of Acute Myeloid Leukemia (AML) patients and it is associated with poor outcomes in this group of patients. There is a paucity of studies that have investigated WT1 as a marker for risk stratification especially in Normal Karyotype AML (NK-AML).

In an article published in Clinical Lymphoma, Myeloma & Leukemia, Irena Marjanovic and colleagues from the University of Belgrade, Serbia, aimed to investigate the use of WT1 as a biomarker and also evaluate its potential as a Measurable Residual Disease (MRD) marker in patients with NK-AML.

In total, 104 AML-NK patient bone marrow samples at diagnosis and disease relapse were analyzed for WT1 gene expression. At diagnosis, 98 patients had detectable WT1 gene expression.

The key results of the study were:
  • Using a cut-off value for WT1 expression, patients were divided into two groups; low WT1 (WT1low, n = 73) and high WT1 expression (WT1high, n = 25)
  • Complete Remission (CR) rates in patients with WT1low and WT1high status were 70% (49/71) and 36% (9/25), respectively; P = 0.004
  • WT1high status was found to be an independent adverse factor for achieving CR; P = 0.018
  • WT1high status at diagnosis associated with early death (P = 0.108) and resistance to therapy (P = 0.007)
  • Median Disease Free Survival (DFS) and Overall Survival (OS) was shorter in patients with WT1high status compared to WT1low; 9 vs 12 months (P = 0.794) and 4 vs 8 months (P = 0.160), respectively
  • WT1high status significantly associated with FLT3 (P = 0.001) and NPM1 mutations (P = 0.021)
  • Using the logarithmic reduction value of WT1 expression, measured in paired diagnosis/CR samples in 29 patients, 17 had a level reduction that was > 2 log and 12 had a log reduction value of < 2 log
  • Median OS in patients with > 2 log reduction and < 2 log reduction was 27 and 10 months, respectively; P = 0.166
  • Median DFS in patients with > 2 log reduction and < 2 log reduction was 18 and 9 months, respectively; P = 0.247

In summation, “WT1 expression status represents a good molecular marker of prognosis, response to treatment, and MRD monitoring”.

The authors concluded by suggesting that WT1 gene expression level should be used as an additional marker for “more precise risk stratification of AML-NK patients” as this could lead to a more “refined treatment protocol in which WT1 targeted therapy can be applied”.

Abstract
Background

Acute myeloid leukemia with normal karyotype (AML-NK) represents the largest group of AML patients classified with an intermediate prognosis. A constant need exists to introduce new molecular markers for more precise risk stratification and for minimal residual disease (MRD) monitoring.

Patients and Methods

Quantitative assessment of Wilms tumor 1 (WT1) gene transcripts was performed using real-time polymerase chain reaction. The bone marrow samples were collected at the diagnosis from 104 AML-NK patients and from 34 of these patients during follow-up or disease relapse.

Results

We found that overexpression of the WT1 gene (WT1 high status), present in 25.5% of patients, was an independent unfavorable factor for achieving complete remission. WT1 high status was also associated with resistance to therapy and shorter disease-free survival and overall survival. Assessment of the log reduction value of WT1 expression, measured in paired diagnosis/complete remission samples, revealed that patients with a log reduction of < 2 had a tendency toward shorter disease-free survival and overall survival and a greater incidence of disease relapse. Combining WT1 gene expression status with NPM1 and FLT3-ITD mutational status, we found that the tumor behavior of intermediate patients (FLT3-ITD − /NPM1 − double negative) with WT1 high status is almost the same as the tumor behavior of the adverse risk group.

Conclusion

WT1 expression status represents a good molecular marker of prognosis, response to treatment, and MRD monitoring. Above all, the usage of the WT1 expression level as an additional marker for more precise risk stratification of AML-NK patients could lead to more adapted, personalized treatment protocols.

References
  1. Marjanovic I. et al. Use of Wilms Tumor 1 Gene Expression as a Reliable Marker for Prognosis and Minimal Residual Disease Monitoring in Acute Myeloid Leukemia With Normal Karyotype Patients. Clin Lymphoma Myeloma Leuk. 2017 May; 17(5): 312–319. DOI: 10.1016/j.clml.2016.12.006. Epub 2017 Jan 11.