Early prediction of treatment outcome in acute myeloid leukemia by measurement of WT1 transcript levels in peripheral blood samples collected after chemotherapy

Cilloni, Daniela; Messa, Francesca; Arruga, Francesca; Defilippi, Ilaria; Gottardi, Enrico; Fava, Milena; Carturan, Sonia; Catalano, Renata; Bracco, Enrico; Messa, Emanuela; Nicoli, Paolo; Diverio, Daniela; Sanz, Miguel Á.; Martinelli, Giovanni; Lo‐Coco, Francesco; Saglio, Giuseppe

doi:10.3324/haematol.12165

Cited by 87 publications

(89 citation statements)

References 22 publications

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“…WT1 expression has already been shown to be a helpful marker in patients with AML after chemotherapy, 19,[21][22][23] after autologous 24 and after conventional allogeneic HCT. [25][26][27] In this analysis, the ability of different markers to predict relapse following allogeneic HCT with RIC was analyzed both alone and in combination.…”

Section: Introductionmentioning

confidence: 99%

Monitoring of WT1 expression in PB and CD34+ donor chimerism of BM predicts early relapse in AML and MDS patients after hematopoietic cell transplantation with reduced-intensity conditioning

Lange¹,

Hubmann²,

Burkhardt

et al. 2010

Leukemia

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Relapse of malignant disease remains the major complication in patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) after hematopoietic cell transplantation (HCT) with reduced-intensity conditioning (RIC). In this study, we investigated the predictive value of disease-specific markers (DSMs), donor chimerism (DC) analysis of unsorted (UDC) or CD34 þ sorted cells and Wilms' tumor gene 1 (WT1) expression. Eighty-eight patients with AML or MDS were monitored after allogenic HCT following 2 Gy total-body irradiation with (n ¼ 84) or without (n ¼ 4) fludarabine 3 Â 30 mg/m 2 , followed by cyclosporin A and mycophenolate mofetil. DSMs were determined by fluorescence in situ hybridization (FISH) and WT1 expression by real-time polymerase chain reaction. Chimerism analysis was performed on unsorted or CD34 þ sorted cells, by FISH or short tandem repeat polymerase chain reaction. Twenty-one (24%) patients relapsed within 4 months after HCT. UDC, CD34 þ DC and WT1 expression were each significant predictors of relapse with sensitivities ranging from 53 to 79% and specificities of 82-91%. Relapse within 28 days was excluded almost entirely on the basis of WT1 expression combined with CD34 þ DC kinetics. Monitoring of WT1 expression and CD34 þ DC predict relapse of AML and MDS after RIC-HCT.

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Section: Introductionmentioning

confidence: 99%

Monitoring of WT1 expression in PB and CD34+ donor chimerism of BM predicts early relapse in AML and MDS patients after hematopoietic cell transplantation with reduced-intensity conditioning

Lange¹,

Hubmann²,

Burkhardt

et al. 2010

Leukemia

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“…52,53 Increased levels of WT1 detected by PCR have been shown to be a prognostically useful marker of MRD. [52][53][54] It has also been shown to be a predictor of relapse in AML patients who have undergone hematopoietic SCT. 55,56 A recent study showed that the combined use of MFC and WT1 monitoring could distinguish between patients with high and low risk of relapse after hematopoietic SCT.…”

Section: Future Directionsmentioning

confidence: 99%

Multi-color flow cytometric immunophenotyping for detection of minimal residual disease in AML: past, present and future

Jaso

Wang

Jorgensen

et al. 2014

Bone Marrow Transplant

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Current chemotherapeutic regimens achieve CR in a large percentage of patients with AML. However, relapse after CR remains a significant problem. The presence of leukemic cells at levels too low to be detected by conventional microscopy, termed minimal residual disease (MRD), has been associated with an increased risk of relapse and shortened survival. Detection of MRD requires the use of highly sensitive ancillary techniques. Multi-color flow cytometric immunophenotyping is a sensitive method for quick and accurate detection of MRD. Use of this method in patient management may result in lower rates of relapse and improved survival, and is an effective means of assessing novel therapeutic agents. This method can be used in the vast majority of patients with AML, regardless of the immunophenotypic, cytogenetic and molecular genetic abnormalities present. Unfortunately, conflicting data regarding optimum methods of measurement and reporting, as well as the expertize required to interpret results have limited broad application of this technique. We provide a broad overview of this technique, including its advantages and limitations, and discuss the methods employed at our institution. We also review several possible areas of future investigation. INTRODUCTION AML is characterized by clonal expansion of myeloid precursors in the BM, peripheral blood and/or extramedullary tissues. 1 Current treatment regimens achieve CR in the majority of adult patients; however, approximately 65% of patients develop relapsed disease. 2,3 Thus, there is a need to effectively identify which patients are at most risk for impending relapse. Low levels of leukemic cells, termed minimal residual disease (MRD), have been shown to correlate with an increased risk of relapse and shortened survival believed to be a major cause of relapse. 4 These cells are present at levels below the sensitivity of conventional microscopic examination and as such, their detection requires the use of sensitive ancillary techniques. Detection of MRD by multi-color flow cytometric immunophenotyping (MFC) has been shown to be useful in the detection and characterization of MRD. However, several important concepts must be understood in order to ensure optimal application of this technique in both the clinical and research settings so that the information provided can be translated into better patient outcomes.

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“…This means these patients can be treated with intensified chemotherapy protocols. 2 The major obstacle in MRD detection by RT-PCR or quantitative PCR (RQ-PCR) is represented by the limited percentage of AML patients presenting with detectable genetic aberrations. 3 The use of alternative markers for MRD detection suitable in the vast majority of AML patients, and in particular to test WT1 expression as a universal marker of leukemic cells.…”

Section: Introductionmentioning

confidence: 99%

“…Survival is highest for children with M3 sub-type. 2 After treatment of AML in children, either is in remission or in minimal residual disease (MRD). In general, children with detectable MRD during or after induction chemotherapy are more likely to develop relapse and may require more intense treatment 2 Evaluation of MRD in children with AML after induction therapy is important to predict prognosis and may improve selection of the type and intensity of post-remission treatment.…”

Section: Introductionmentioning

confidence: 99%

“…2 After treatment of AML in children, either is in remission or in minimal residual disease (MRD). In general, children with detectable MRD during or after induction chemotherapy are more likely to develop relapse and may require more intense treatment 2 Evaluation of MRD in children with AML after induction therapy is important to predict prognosis and may improve selection of the type and intensity of post-remission treatment. 1 One of the main goals of MRD monitoring is represented by the possibility of identifying as soon as possible after induction therapy the subset of patients who, although in complete morphologic remission (CR), present a high risk of relapse.…”

Section: Introductionmentioning

confidence: 99%

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New Insight Towards Prognosis in Pediatric Acute Myeloid Leukemia: Comparative Study.

Ibrahim¹

2015

UHOD

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Wilms tumor gene (WT1) is a reliable marker for minimal residual disease assessment in acute leukemia children. This study was designed to demonstrate the potential use of WT1 to establish quality of remission in acute leukemia children for early identification of children at high risk of relapse. This study based on a quantitative Real-Time polymerase chain reaction (PCR) (TaqMan) assay in bone marrow samples collected from 45 acute myeloid leukemia children at diagnosis and during follow-up was established. Our results revealed, there was no significant association between WT1expression,at diagnosis, and either of gender, organomegally, total leucocytic count (TLC), French-American-British system (FAB) subtypes, CD34 expression, cytogenetic studies, percentage of blast infiltration or response to induction therapy. By comparing the results obtained at day 14 and those obtained at day 28, we cannot depend on WT1gene expression or MRD detection at day14 in predicting resistance to treatment or predicting mortality (p= 0.12). In contrast WT1 gene expression or MRD detection values after induction therapy (at day28) is an independent prognostic risk factor of relapse (p= 0.001) and death (p= 0.001). The blast percentage was significantly correlated to the WT1expression levels at day 28.The presence of MRD or WT1gene expression at the end of induction therapy is an extremely powerful adverse prognostic factor.WT1 at presentation has no prognostic significance whereas a high WT1 expression after induction therapy is a predictor for poor outcome. A rise inWT1expression during treatment is a predictor for relapse. WT1 expression is a valuable and important tool for MRD study in AML and the presence of MRD value at the end of induction therapy is an extremely powerful adverse prognostic factor despite of achievement of morphological remission.Keywords: Wilms tumor gene 1, Acute myeloid leukemia, Minimal residual disease ÖZET Pediatrik Akut Miyeloid Lösemi Prognozunu Anlamada Yeni Görüşler: Karşılaştırmalı ÇalışmaAkut çocukluk dönemi lösemilerde minimal rezidüel hastalığı göstermede Wilms tümör geni (WT1) güvenli bir belirteçtir. Bu çalışma yüksek riskli akut lösemili çocuklarda remsiyon kalitesini ve erken relapsları göstermede WT1 kullanımının potansiyel yerini araştırmak için planlanmıştır. Bu çalışmada 45 akut myeloid lösemili çocuk hastanın Real-Time polimeraz zincir reaksiyonu (PCR) (TaqMan) testi kullanılarak tanı anı ve takip kemik iliği örnekleri incelenmiştir. Çalışmamızın sonuçlarında; tanı anında WT1 ekspresyonu ile cinsiyet, organomegali, toplam lökosit sayısı, FAB sınıflaması alt tipi, CD34 ekspresyonu, sitogenetik çalışmalar, tanı anındaki blast oranı ve indüksiyon tedavisine yanıt arasında herhangi bir ilişki saptanamamıştır. 14. gün ve 28. gün örnekleri değerlendrildiğinde; 14. gün örneklerinde bakılan WT1 gen ekspresyonunun veya minimal rezidüel hastalık (MRD) tedaviye direnç veya mortaliteyi saptamada güvenili bir yöntem olmadığı gösterilmiştir (p= 0.12). Ancak indüksiyon tedavisi sonrası (28....

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Early prediction of treatment outcome in acute myeloid leukemia by measurement of WT1 transcript levels in peripheral blood samples collected after chemotherapy

Cited by 87 publications

References 22 publications

Monitoring of WT1 expression in PB and CD34+ donor chimerism of BM predicts early relapse in AML and MDS patients after hematopoietic cell transplantation with reduced-intensity conditioning

Monitoring of WT1 expression in PB and CD34+ donor chimerism of BM predicts early relapse in AML and MDS patients after hematopoietic cell transplantation with reduced-intensity conditioning

Multi-color flow cytometric immunophenotyping for detection of minimal residual disease in AML: past, present and future

New Insight Towards Prognosis in Pediatric Acute Myeloid Leukemia: Comparative Study.

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