Serial Measurement of WT1 Expression and Decrement Ratio Until Hematopoietic Cell Transplantation as a Marker of Residual Disease in Patients with Cytogenetically Normal Acute Myelogenous Leukemia

Abstract

Using real-time quantitative PCR, we monitored Wilms tumor gene 1 (WT1) expression from diagnosis to hematopoietic stem cell transplantation (HSCT) in adult patients with cytogenetically normal acute myelogenous leukemia (CN-AML) and FLT3-ITD and NPM1 mutations. The values at diagnosis were evaluated in 104 patients. Data collected after induction chemotherapy were available for all patients, but only 68 patients were treated with HSCT. Significant WT1 expression cut-offs were determined by receiver operation characteristic curve analysis, and rates of overall survival (OS) and disease-free survival (DFS) were estimated. WT1 decrement ratios (DR) at postinduction chemotherapy and at pre- and post-HSCT compared with the diagnostic level were calculated. Higher WT1 expression at diagnosis, postinduction chemotherapy, and pre-HSCT showed inferior OS (P = .015, <.001, and .002) and DFS (P = .006, <.001, and .003). The cut-offs were determined at the median for diagnostic WT1 expression and at the 25% level from the top for other time points excluding post-HSCT. The WT1 DR ≥ 1-log after induction chemotherapy showed superior OS and DFS (P = .009 and .002) and WT1 DR ≥ 1-log preceding HSCT also showed superior OS and DFS (P = .009 and .003). Results of WT1 DR were consistently applicable in each subgroup with higher (≥ 1.0) and lower (<1.0) WT1 expression at diagnosis and also in NPM1-wild-type/FLT3-ITD-negative CN-AML. The WT1 DR therefore predicted survival outcomes after HSCT more accurately than did the diagnostic WT1 expression. WT1 expression may serve as a reliable marker for residual disease and WT1 DR as a prognostic indicator, particularly in NPM1-wild-type/FLT3-ITD-negative CN-AML. These measures may be applied throughout the course of treatment and even after HSCT.

Identification of molecular and cytogenetic risk factors for unfavorable core-binding factor-positive adult AML with post-remission treatment outcome analysis including transplantation

“…Previous reports have shown that WT1 expression in peripheral blood showed good correlation with BM, and higher WT1 expression without proper log-reduction after chemotherapy showed poor clinical outcomes in adult AML. 22,[31][32][33][34] Recently, we also reported the utility of WT1 in the CBF-AML. 19 Although the results of this study originated from the HSCT strategy, we expect that using CBF-MRD qPCR and WT1 can be similarly evaluated in the setting of chemotherapy alone.…”

“…The qPCR level represented the ratios of RUNX1/RUNX1T1, CBFβ/MYH11, BAALC and WT1 expression normalized to expression of the reference gene, ABL1 (1.0 × 10 4 ) as previously reported. 19,22 To determine the significant cutoff level, we used the receiver operation characteristic curve. The most significant cutoff level of both BAALC and WT1 expression was available at post HSCT, and the value was around the 65th percentile for BAALC expression (1.0, P = 0.016) and the 60th percentile for WT1 expression (0.015, P = 0.004).…”

Wilms Tumor Gene 1 Expression as a Predictive Marker for Relapse and Survival after Hematopoietic Stem Cell Transplantation for Myelodysplastic Syndromes

“…Several studies have reported that higher WT1 expression at diagnosis or after induction chemotherapy is a significant predictor for relapse and worse survival outcomes in acute myeloid leukemia (AML) [23][24][25], even after allo-HSCT [26,27]. Also, in MDS patients, several studies reported the utility of WT1 expression.…”

A Possible New Multiple Endocrine Neoplasia Mutation in a Patient with a Prototypic Multiple Endocrine Neoplasia Presentation

“…The apparent lack of a genotype/phenotype correlation as well as the wide diversity of mutations in the 1,830-bp coding region of the MEN-1 gene makes mutational analysis for definitive diagnosis of the MEN-1 syndrome more difficult [3]. Patients with truncating mutations in the N- or C-terminal region (exons 2, 9, or 10) of the MEN-1 gene have a significantly higher rate of malignant tumors (55 vs. 10%; p < 0.05) than those with other mutations [8]. However, in two prospective studies [8,9], none of the patients with germline mutation for MEN-1 developed RCC or thyroid cancer, as seen in the current case.…”

“…Patients with truncating mutations in the N- or C-terminal region (exons 2, 9, or 10) of the MEN-1 gene have a significantly higher rate of malignant tumors (55 vs. 10%; p < 0.05) than those with other mutations [8]. However, in two prospective studies [8,9], none of the patients with germline mutation for MEN-1 developed RCC or thyroid cancer, as seen in the current case.…”