Measurable Residual Diseases in Haematological Malignancies: Current Applications and Future Direction (original) (raw)
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Along with the evolution of immunophenotypic and molecular diagnostics, the assessment of Minimal Residual Disease (MRD) has progressively become a keystone in the clinical management of hematologic malignancies, enabling valuable post-therapy risk stratifications and guiding risk-adapted therapeutic approaches. However, specific prognostic values of MRD in different hematological settings, as well as its appropriate clinical uses (basically, when to measure it and how to deal with different MRD levels), still need further investigations, aiming to improve standardization and harmonization of MRD monitoring protocols and MRD-driven therapeutic strategies. Currently, MRD measurement in hematological neoplasms with bone marrow involvement is based on advanced highly sensitive methods, able to detect either specific genetic abnormalities (by PCR-based techniques and next-generation sequencing) or tumor-associated immunophenotypic profiles (by multiparametric flow cytometry, MFC). In th...
Detection of Minimal Residual Disease in Hematopoietic Tissues
Annals of the New York Academy of Sciences, 1995
Detection of minimal residual disease (MRD) has prognostic value in many hematologic malignancies, including acute lymphoblastic leukemia, acute myeloid leukemia, chronic myeloid leukemia, non-Hodgkin's lymphoma, and multiple myeloma. Quantitative MRD data can be obtained with realtime quantitative PCR (RQ-PCR) analysis of immunoglobulin and T-cell receptor gene rearrangements, breakpoint fusion regions of chromosome aberrations, fusion-gene transcripts, aberrant genes, or aberrantly expressed genes, their application being dependent on the type of disease. RQ-PCR analysis can be performed with SYBR Green I, hydrolysis (TaqMan) probes, or hybridization (LightCycler) probes, as detection system in several RQ-PCR instruments. Dependent on the type of MRD-PCR target, different types of oligonucleotides can be used for specific detection, such as an allele-specific oligonucleotide (ASO) probe, an ASO forward primer, an ASO reverse primer, or germline probe and primers. To assess the quantity and quality of the RNA/DNA, one or more control genes must be included. Finally, the interpretation of RQ-PCR MRD data needs standardized criteria and reporting of MRD data needs international uniformity. Several European networks have now been established and common guidelines for data analysis and for reporting of MRD data are being developed. These networks also include standardization of technology as well as regular quality control rounds, both being essential for the introduction of RQ-PCR-based MRD detection in multicenter clinical treatment protocols.
Depending on the tumour type and stage, considerable fractions of patients with cancer will have metastatic disease relapse within 5 years of primary tumour resec-tion despite initially being free of detectable meta stases. Hormone receptor-positive breast cancer is the pro-totypical cancer that is associated with late relapses, which can occur over a period of 20 years (and probably more): among the patients with stage T1 disease, the 20-year risk of distant recurrence is 13% in those with no nodal involvement (T1N0), 20% in those with 1-3 involved nodes (T1N1-3) and 34% in those with 4-9 involved nodes (T1N4-9); among patients with stage T2 disease, the risks are 19%, 26% and 41%, respectively 1. Thus, a considerable fraction of patients with seemingly successful treatment of early stage cancer have occult micrometastases or minimal residual disease (MRD) that persists after initial therapy as a potential source of subsequent metastatic relapse at distant sites. MRD detection and monitoring are established and widely used in patients with haematological malignancies but remain challenging in patients with solid tumours owing to difficulty in sampling the low concentrations of circulating tumour cells (CTCs) or factors shed from the cancer cells into the bloodstream. Over the past few years, considerable advances have been made in the development of technologies to detect blood-based, tumour-specific biomarkers, such as CTCs and circulating cell-free tumour DNA (ctDNA). The advent of real-time, high-sensitivity liquid biopsy assays has enabled the identification of MRD in individual patients with cancer. Herein, we outline the current CTC-based and ctDNA-based approaches for the detection and characterization MRD in patients with solid tumours and discuss the associated challenges. We also highlight the advances that might facilitate implementation of these technologies in future clinical trials designed to test the efficacy of anticancer agents in the neoadjuvant or adjuvant settings. In this context, liquid biopsy assays can be used to monitor MRD, thereby aiding the discovery of new drugs that effectively eliminate or control residual tumour cells in patients who have a high risk of disease relapse after primary therapy. Technologies for the assessment of MRD In the following sections, we provide a brief update focused on current technologies used for the enrichment , detection and characterization of CTCs in blood. Technologies for the analysis of ctDNA present in blood samples have been reviewed in detail elsewhere 2-4. Abstract | Liquid biopsy has been introduced as a new diagnostic concept predicated on the analysis of circulating tumour cells (CTCs) or circulating tumour-derived factors, in particular, cell-free tumour DNA (ctDNA). Highly sensitive liquid biopsy assays have been developed that can now be applied to detect and characterize minimal residual disease (MRD), which reflects the presence of tumour cells disseminated from the primary lesion to distant organs in patients who lack any clinical or radiological signs of metastasis or residual tumour cells left behind after local therapy that eventually lead to local recurrence. This application is the new frontier of liquid biopsy analyses, which are challenged by the very low concentrations of CTCs and ctDNA in blood samples. In this Review , we discuss the key technologies that can be used to detect and characterize CTCs in surveillance of MRD and provide a brief overview of similar roles of ctDNA analyses. We then focus on the current clinical data on the use of CTCs and ctDNA in the detection and monitoring of MRD and in obtaining information on therapeutic targets and resistance mechanisms relevant to the management of individual patients with cancer.
British Journal of Haematology, 2011
Minimal residual disease (MRD) has acquired a prominent role in the management of childhood and adult Acute Lymphoblastic Leukaemia (ALL) for its high prognostic value. Several studies have demonstrated the strong association between MRD and risk of relapse in childhood and adult ALL, irrespective of the methodology used. MRD is now used in clinical trials for risk assignment and to guide clinical management. Negativity at early time points may be considered to decrease treatment burden in patients who are likely to be cured with reduced intensity regimens. On the other hand, high MRD levels at late time points (end of consolidation) define ALL subgroups which deserve investigation of more effective treatments. The predictivity of MRD as a measurement of drug response in vivo opened new perspectives for its use in clinical decision, to deliver risk-based treatments, and possibly as a surrogate for efficacy in the evaluation of novel therapeutic approaches.
Minimal residual disease detection in lymphoma and multiple myeloma: impact on therapeutic paradigms
Hematological Oncology, 2011
Early identification of patients at high risk of relapse is a major goal of current translational research in oncohematology. Minimal residual disease (MRD) detection by polymerase chain reaction-based methods is currently part of the routine clinical management of patients with acute lymphoblastic leukemia. However, the current knowledge indicates that it is also a useful prognostic tool in several mature lymphoproliferative disorders. Its utility is currently well established in follicular lymphoma, mantle cell lymphoma, and multiple myeloma. In some of these entities, clinical trials employing MRD as a decision-making tool are currently ongoing. In the present review, we will discuss the 'state of the art' of MRD evaluation in these three neoplasms with the ultimate aim of providing critical take-home messages for clinicians working in the field. Moreover, we will outline the role of MRD detection in the design of future clinical trials.
Measurable residual disease in multiple myeloma and in acute myeloid leukemia, an evolving topic
PubMed, 2022
Minimal or measurable residual disease (MRD) is a term that refers to the submicroscopic tumor disease persisting after therapy. Sensitive immunophenotypic and molecular techniques are used to detect the small amount of residual tumor cells, conferring a detection capacity clearly more sensitive of common cytomorphologic techniques. MRD evaluation now represents an important tool in the study of solid tumors and of hematological malignancies. Concerning hematological malignancies, MRD evaluation was particularly developed in the study of multiple myeloma and acute myeloid leukemia, representing in these diseases a precious biomarker to quantify response to treatment, to evaluate the chemosensitivity/chemoresistance of the disease and to have a prognostic prediction on disease outcome. The finding that MRD evaluation may have a prognostic value, predicting the risk of relapse, stimulated interest in the introduction of MRD in clinical trials, either as a clinical endpoint or as a tool to guide treatment decisions. However, the clinical use of MRD requires a standardization of the techniques used for its detection, the use of multiple techniques and the development of a consistent accuracy and reproducibility. Finally, prospective clinical trials are required to assess the real clinical benefit potentially deriving from the introduction of MRD evaluation into clinical studies.
2020
Introduction: Advanced diagnostic methods give a huge advantage for identification of the abnormalities in myeloid malignancies. Researchers tried to show the potential importance of genetic tests both before the onset of the disease and during the remission. Large testing panels prevents false negative results in myeloid malignancies. But the important question is how can be merged with conventional cytogenetic and molecular cytogenetic techniques together with NGS technologies. Methods: In this paper, we draw an algorithm for evaluation of the malignancies. In order to evaluation of genetic abnormities we performed cytogenetics, molecular cytogenetics and NGS testing panels in hematologic malignancies. In this study, we analyzed 132 patients which are referred to Medical Genetics Laboratory within different type of hematologic malignancies. We highlighted possible algorithm for cytogenetically normal cases.Results: We analyzed cytogenetically normal patients by using NGS 141 gene ...
Detection of tumor-specific marker for minimal residual disease in multiple myeloma patients
Biomedical Papers, 2014
Aims. Multiple myeloma (MM), the second most common hematological cancer, is a lymphoproliferative disease of terminally differentiated B lymphocytes characterized by expansion of monoclonal plasma cells. With the introduction of new drugs, MM has become a hard-to-treat disease. The aim of treatment is clinical remission and eradication of clinical manifestations but most MM patients eventually relapse. For this reason, more accurate monitoring of remission and relapse using molecular biology techniques is at the center of attention. Methods. For monitoring, we used allele-specific PCR and quantitative real-time PCR based on specific detection of VDJ immunoglobulin heavy chain gene rearrangement of clonal cells for monitoring. The hypervariable region of IgH rearrangement is used for detection of minimal residual disease (MRD) in MM as this sequence is used for allele-specific primers and probe design. This technique is a complementary tool for flow cytometry in MRD detection; however, it has not been established in the Czech Republic so far. Results. Qualitative and quantitative MRD detection was performed in 50% (5/10) patients and qualitative MRD detection in another 3 oligoclonal patients. Conclusions. Next to flow cytometry, detection of MRD by qPCR is a viable option and has been introduced in the Czech Republic.