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New Molecular Technologies for Minimal Residual Disease Evaluation in B-Cell Lymphoid Malignancies.

ABSTRACT: The clearance of malignant clonal cells significantly correlates with clinical outcomes in many hematologic malignancies. Accurate and high throughput tools for minimal residual disease (MRD) detection are needed to overcome some drawbacks of standard molecular techniques; such novel tools have allowed for higher sensitivity analyses and more precise stratification of patients, based on molecular response to therapy. In this review, we depict the recently introduced digital PCR and next-generation sequencing technologies, describing their current application for MRD monitoring in lymphoproliferative disorders. Moreover, we illustrate the feasibility of these new technologies to test less invasive and more patient-friendly tissues sources, such as "liquid biopsy".

SUBMITTER: Dogliotti I

PROVIDER: S-EPMC6162632 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

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New Molecular Technologies for Minimal Residual Disease Evaluation in B-Cell Lymphoid Malignancies.

Dogliotti Irene I Drandi Daniela D Genuardi Elisa E Ferrero Simone S

Journal of clinical medicine 20180918 9

The clearance of malignant clonal cells significantly correlates with clinical outcomes in many hematologic malignancies. Accurate and high throughput tools for minimal residual disease (MRD) detection are needed to overcome some drawbacks of standard molecular techniques; such novel tools have allowed for higher sensitivity analyses and more precise stratification of patients, based on molecular response to therapy. In this review, we depict the recently introduced digital PCR and next-generati ...[more]

PMID: 30231510

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Project description:BackgroundMinimal residual disease (MRD) testing by higher performance techniques such as flow cytometry and polymerase chain reaction (PCR) can be used to detect the proportion of remaining leukemic cells in bone marrow or peripheral blood during and after the first phases of chemotherapy in children with acute lymphoblastic leukemia (ALL). The results of MRD testing are used to reclassify these patients and guide changes in treatment according to their future risk of relapse. We conducted a systematic review of the economic literature, cost-effectiveness analysis, and budget-impact analysis to ascertain the cost-effectiveness and economic impact of MRD testing by flow cytometry for management of childhood precursor B-cell ALL in Ontario.MethodsA systematic literature search (1998-2014) identified studies that examined the incremental cost-effectiveness of MRD testing by either flow cytometry or PCR. We developed a lifetime state-transition (Markov) microsimulation model to quantify the cost-effectiveness of MRD testing followed by risk-directed therapy to no MRD testing and to estimate its marginal effect on health outcomes and on costs. Model input parameters were based on the literature, expert opinion, and data from the Pediatric Oncology Group of Ontario Networked Information System. Using predictions from our Markov model, we estimated the 1-year cost burden of MRD testing versus no testing and forecasted its economic impact over 3 and 5 years.ResultsIn a base-case cost-effectiveness analysis, compared with no testing, MRD testing by flow cytometry at the end of induction and consolidation was associated with an increased discounted survival of 0.0958 quality-adjusted life-years (QALYs) and increased discounted costs of $4,180, yielding an incremental cost-effectiveness ratio (ICER) of $43,613/QALY gained. After accounting for parameter uncertainty, incremental cost-effectiveness of MRD testing was associated with an ICER of $50,249/QALY gained. In the budget-impact analysis, the 1-year cost expenditure for MRD testing by flow cytometry in newly diagnosed patients with precursor B-cell ALL was estimated at $340,760. We forecasted that the province would have to pay approximately $1.3 million over 3 years and $2.4 million over 5 years for MRD testing by flow cytometry in this population.ConclusionsCompared with no testing, MRD testing by flow cytometry in newly diagnosed patients with precursor B-cell ALL represents good value for money at commonly used willingness-to-pay thresholds of $50,000/QALY and $100,000/QALY.

Project description:Background: Papillary thyroid cancer (PTC) is the most common type of thyroid malignancy. Serum thyroglobulin (Tg) levels are used to monitor PTC treatment response and recurrences however, in about 25% of the cases the sensitivity of this method is compromised due to either the presence of neutralizing anti-Tg antibodies (TgAb) or the absence of Tg in less differentiated tumors. Up to 80% of PTC tumors harbor the c.1799T>A hotspot mutation in the BRAF gene (BRAFV600E). Here, we assessed the potential use of plasma cell-free BRAFV600E mutant tumor DNA (ctDNA) levels in determining the minimal residual tumor status of PTC patients. Methods: Patients were classified as either having persistent disease (PD) or no evidence of disease (NED) based on clinicopathological assessments. Tumor BRAFV600E status was determined by both direct sequencing and digital PCR. Plasma total cell-free BRAFV600 wild type DNA (cfDNA) and ctDNA fractions circulating in the plasma of PTC patients were determined by an emulsion based-digital PCR and total ctDNA was quantified by 3D digital PCR. The total ctDNA levels (copies/ml) were then compared to patients' clinicopathological features. Results: About 74% (28/38) of tumors harbored the BRAFV600E mutation. Percent plasma ctDNA fractions for PD patients with BRAFV600E tumors ranged from 0 to 2.07%, whereas absolute plasma ctDNA copies ranged from 0 to 62 copies. The ctDNA levels accurately detected tumor burden of PTC patients whose tumors harbored BRAFV600E; median plasma ctDNA copy numbers were significantly higher (Wilcoxon test, p = 0.03) in patients with metastasis (MET) (20 copies/ml) compared to patients with non-metastatic (non-MET) tumors (1 copy/ml). The plasma ctDNA levels (copies/ml) accurately determined the disease status of PTC patients with sensitivity of 86% and specificity of 90% as compared to 78% sensitivity and 65% specificity determined by serum Tg levels (ng/ml) with areas under the curves (AUC) of 0.88 and 0.71, respectively. Intriguingly, plasma total cfDNA levels were significantly higher in patients with no evidence of residual disease (NED) compared to persistent disease (PD) patients. Conclusions: Our study supports the clinical applicability of plasma ctDNA as biomarker to determine the residual tumor status and tumor burden of PTC patients.

Project description:Mantle Cell Lymphoma (MCL) is a B cell aggressive neoplasia accounting for about the 6% of all lymphomas. The most common molecular marker of clonality in MCL, as in other B lymphoproliferative disorders, is the ImmunoGlobulin Heavy chain (IGH) rearrangement, occurring in B-lymphocytes. The patient-specific IGH rearrangement is extensively used to monitor the Minimal Residual Disease (MRD) after treatment through the standardized Allele-Specific Oligonucleotides Quantitative Polymerase Chain Reaction based technique. Recently, several studies have suggested that the IGH monitoring through deep sequencing techniques can produce not only comparable results to Polymerase Chain Reaction-based methods, but also might overcome the classical technique in terms of feasibility and sensitivity. However, no standard bioinformatics tool is available at the moment for data analysis in this context.In this paper we present HashClone, an easy-to-use and reliable bioinformatics tool that provides B-cells clonality assessment and MRD monitoring over time analyzing data from Next-Generation Sequencing (NGS) technique. The HashClone strategy-based is composed of three steps: the first and second steps implement an alignment-free prediction method that identifies a set of putative clones belonging to the repertoire of the patient under study. In the third step the IGH variable region, diversity region, and joining region identification is obtained by the alignment of rearrangements with respect to the international ImMunoGenetics information system database. Moreover, a provided graphical user interface for HashClone execution and clonality visualization over time facilitate the tool use and the results interpretation. The HashClone performance was tested on the NGS data derived from MCL patients to assess the major B-cell clone in the diagnostic samples and to monitor the MRD in the real and artificial follow up samples.Our experiments show that in all the experimental settings, HashClone was able to correctly detect the major B-cell clones and to precisely follow them in several samples showing better accuracy than the state-of-art tool.

Dataset Information

New Molecular Technologies for Minimal Residual Disease Evaluation in B-Cell Lymphoid Malignancies.

Publications

New Molecular Technologies for Minimal Residual Disease Evaluation in B-Cell Lymphoid Malignancies.

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