The use of receiver operating characteristic analysis for detection of minimal residual disease using five‐color multiparameter flow cytometry in acute myeloid leukemia identifies patients with high risk of relapse

Al-Mawali, Adhra; Gillis, David; Lewis, Ian D.

doi:10.1002/cyto.b.20444

Cited by 46 publications

(36 citation statements)

References 35 publications

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“…77,78 Al-Mawali et al found that a threshold of 0.15% residual leukemic cells discriminated MRD-negative from MRD-positive cases with optimal sensitivity and specificity, allowing impending relapse to be predicted at postinduction and postconsolidation time points. 75 Multivariate analysis showed that the postinduction MRD level affected independently RFS and OS. However, also diverging opinions have been published supporting the hypothesis that delayed time points may be even more informative compared with earlier ones.…”

Section: Timing Of Mpfc Assessmentmentioning

confidence: 99%

“…At least 4 manuscripts tried to address the issue of MRD "prognostically significant levels" applying specific statistical methods that would help selecting thresholds more appropriately. [72][73][74][75] In the paper by Al-Mawali et al, to determine the optimal cut-off yielding the best segregation of AML patients into categories of risk, a receiver operating characteristic analysis was carried out. 75 The threshold was established at the value of 0.15% residual leukemic cells; therefore, patients with MRD more than 0.15% qualified as MRD-positive, whereas those with MRD less than or equal to 0.15% as MRD-negative.…”

Section: Mrd Detection By Flow Cytometrymentioning

confidence: 99%

“…[72][73][74][75] In the paper by Al-Mawali et al, to determine the optimal cut-off yielding the best segregation of AML patients into categories of risk, a receiver operating characteristic analysis was carried out. 75 The threshold was established at the value of 0.15% residual leukemic cells; therefore, patients with MRD more than 0.15% qualified as MRD-positive, whereas those with MRD less than or equal to 0.15% as MRD-negative. We evaluated the trend of standardized log-rank statistics using relapse-free survival (RFS) and OS as dependent variables and the values of residual leukemic cells determined after induction and consolidation as independent variables (maximally selected log-rank statistics).…”

Section: Mrd Detection By Flow Cytometrymentioning

confidence: 99%

See 2 more Smart Citations

Prognostic and therapeutic implications of minimal residual disease detection in acute myeloid leukemia

Buccisano

Maurillo

Principe

et al. 2012

Blood

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168

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Section: Timing Of Mpfc Assessmentmentioning

confidence: 99%

Section: Mrd Detection By Flow Cytometrymentioning

confidence: 99%

Section: Mrd Detection By Flow Cytometrymentioning

confidence: 99%

See 1 more Smart Citation

Prognostic and therapeutic implications of minimal residual disease detection in acute myeloid leukemia

Buccisano

Maurillo

Principe

et al. 2012

Blood

234

168

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“…Lapillone et al (29) observed that WT1 higher than 50 × 10 4 ABL copies after induction was an independent prognostic risk factor of relapse (p = 0.002) and death (p = 0.02) in pediatric AML. Published results conferred to WT1 an important role in monitoring MRD and stratifying patients with AML, similarly to results obtained by MFC (30)(31)(32)(33)(34)(35)(36)(37). When the techniques were compared, a different role was addressed to each one on the basis of the timing of assessment and quantification of MRD or log reduction.…”

Section: Wt1 As a Minimal Residual Disease Marker After Conventional mentioning

confidence: 84%

Wilms’ Tumor Gene (WT1) Expression and Minimal Residual Disease in Acute Myeloid Leukemia

et al. 2016

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Copyright: The Authors.Licence: This open access article is licensed under Creative Commons Attribution 4.0 International (CC BY 4.0). http://creativecommons.org/licenses/by/4.0/ Users are allowed to share (copy and redistribute the material in any medium or format) and adapt (remix, transform, and build upon the material for any purpose, even commercially), as long as the authors and the publisher are explicitly identified and properly acknowledged as the original source. AbstractThe identification of minimal residual disease (MRD) has led to substantial improvements in early recognition of the recurrence of acute myeloid leukemia (AML). Flow cytometry (FC), real-time quantitative polymerase chain reaction (RQ-PCR) and fluorescence in situ hybridization are useful methods for the detection of MRD in AML patients although molecular monitoring of leukemia-specific rearranged (RUNX1-RUNX1T1 and CBFB-MYH11) or mutated genetic (NPM1, CEBPA) sequences represents the most sensitive methodology. Rossi et al. 274Besides, more than 50% of all AML patients lack one of these specific sequences, so it is crucial to identify molecular targets applicable for the majority of patients. WT1 is overexpressed at the mRNA level in 80-90% of AML cases at diagnosis in both peripheral blood and bone marrow, and is detectable in a consistent low range in normal donors. These features have led to its adoption for MRD detection using RQ-PCR. A European LeukemiaNet Study found the magnitude of WT1 log reduction after induction chemotherapy to be an independent predictor of relapse. Other studies showed a poorer outcome in patients having WT1 levels above reference thresholds at specific time points. WT1 expression was compared with other modalities of MRD assessment, such as RQ-PCR of specific fusion genes and FC, but no differences in terms of predictive value emerged. Finally, some authors translated the use of WT1 in the clinic giving donor lymphocytes infusions to patients with increasing WT1-mRNA levels after allogeneic stem cell transplantation and obtaining an improvement of survival in this subset. Data collected on WT1 expression over the past years provided evidence for the use of this molecular marker to stratify high-risk AML patients. It can also be used as a marker for early interventional therapy, but further studies are needed to demonstrate it.

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“…As previously mentioned, a receiver-operating characteristics-based threshold of 0.15% was recently used to characterize MRD positivity. 38 This threshold successfully divided patients into two groups with statistically significant differences in relapse and survival.…”

Section: Limitations Of Multi-color Flow Cytometry-based Mrd Detectionmentioning

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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The use of receiver operating characteristic analysis for detection of minimal residual disease using five‐color multiparameter flow cytometry in acute myeloid leukemia identifies patients with high risk of relapse

Cited by 46 publications

References 35 publications

Prognostic and therapeutic implications of minimal residual disease detection in acute myeloid leukemia

Prognostic and therapeutic implications of minimal residual disease detection in acute myeloid leukemia

Wilms’ Tumor Gene (WT1) Expression and Minimal Residual Disease in Acute Myeloid Leukemia

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

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