Monitoring of minimal residual disease by quantitative WT1 gene expression following reduced intensity conditioning allogeneic stem cell transplantation in acute myeloid leukemia

Abstract

WT1 is well-known to be a panleukemic marker that is expressed in 90% of acute myeloid leukemias (AML). Quantification of WT gene expression in bone marrow (BM) samples may be useful as a marker of minimal residual disease (MRD) during and after treatment for early prediction of relapse. We evaluated the validity of this AML-MRD marker after reduced intensity conditioning (RIC) allogeneic stem cell transplantation (SCT). The quantitative assessment of WT1 expression by real-time quantitative PCR (RQ-PCR) was measured in 25 patients (pts) with AML at diagnosis, at the time of RIC-SCT and after transplant at precise time points. All pts showed high WT1 levels at diagnosis with a mean of 4895 (SD 4462) and a median of 3679 (range 454-16,853) copies WT1/10(4) ABL. At transplant, 18/25 pts (72%) were in complete cytologic remission (CcR) and 7/25 (28%) had refractory AML. At the pre-SCT evaluation, BM samples from pts transplanted in CcR showed significantly lower WT1 expression levels compared to the samples from pts with refractory AML (p = 0.002). Median follow-up after RIC-SCT was 18 months (range 2-54). On 18 pts transplanted in CcR, those (17/18) who maintained CcR after RIC-SCT displayed a WT1 copy number persistently low during all the follow-up period. In patients who received RIC-SCT with active disease obtaining a sustained CcR after transplant (3/25), WT1 levels decreased to normal range in the first two months after RIC-SCT and remained low through the entire study period. All pts who relapsed after RIC-SCT (4/25) had a high WT1 copy number before the cytologic relapse. In 50% of these cases, an increase in WT1 expression was documented before molecular chimerism decreasing. With this experience, taking into account the limited number of pts, we confirmed a concordance between WT1 expression levels (measured by RQ-PCR at precise and sequential time points) and status of AML before and after RIC-SCT and we found a concordance between WT1 expression levels and hematopoietic chimerism status. Our data suggest that, in the RIC-SCT setting, the sequential and quantitative analysis of WT1 may be useful as a leukemia marker for monitoring MRD and as a predictor of overt AML cytologic relapse.

Wilms’ tumor gene 1 expression: an independent acute leukemia prognostic indicator following allogeneic hematopoietic SCT

“…In addition, there are almost no large-scale studies evaluating WT1, and researchers still dispute whether WT1 should be regarded as an independent prognostic factor of clinical outcome following HSCT. [8][9][10][11] Despite the majority of studies conceding the predictive value of WT1, few decisions concerning therapeutic interventions are based on WT1 expression levels.…”

Prognostic and therapeutic implications of minimal residual disease at the time of transplantation in acute leukemia

“…The latter may be particularly warranted in the setting of persistent or newly developed MRD after transplantation, because numerous studies have established that post-HCT MRD detected by PCR, flow cytometry, or (as a surrogate) levels of mixed chimerism accurately identifies a subset of patients at high risk for relapse and poor outcome. 16,17,[33][34][35]40,63,[66][67][68][69][70][71][72][73] As there are no data available from controlled trials addressing these questions, inferences need to be made from observational studies that compare subgroups …”

Efficacy of Chemotherapy in Acute Leukemia Patients Resistant to Previous Standard Treatment According to the Series Measurement of WT1 Gene Expression

“…До настоящего времени такой подход чаще ис-пользовался для диагностики минимальной оста-точной болезни после трансплантации гемопоэтиче-ских стволовых клеток (ТГСК) [1,4,[8][9][10][11][12][13][14][15][16][17][18][19][20][21][22], а также для раннего распознавания рецидивов ОЛ [4,9,[23][24][25][26][27][28][29]. В то же время исследований, посвященных оценке эффективности индукционных курсов химиотерапии, недостаточно [4,14,[30][31][32][33][34][35][36][37].…”