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Role of Minimal Residual Disease Assessment in Hematological Cancers
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Role of Minimal Residual Disease Assessment in Hematological Cancers

A special issue of Journal of Clinical Medicine (ISSN 2077-0383).

Deadline for manuscript submissions: closed (30 April 2017)

Special Issue Editor

Dr. Marco Ladetto

E-Mail Website
Guest Editor
Azienda Ospedaliera SS. Antonio e Biagio e Cesare Arrigo, Alessandria, Italy
Interests: diagnosis and treatment of non-Hodgkin lymphoma; hodgkin lymphoma; multiple myeloma and CLL; minimal residual disease in lymphoma; myeloma and CLL; prognostic factors in lymphoid malignancies; lymphomagenesis

Special Issue Information

Dear Colleagues,

Early identification of patients at high risk of relapse is a major goal of current translational research in oncohematology. Minimal residual disease (MRD) detection is increasingly employed in multiple different settings as additional tissue sources become useful targets for monitoring. Moreover, methods for MRD detection are rapidly evolving, thanks to substantial technical improvements of traditional approaches, such as real time polymerase chain reaction (PCR) and multiparameter flow cytometry and development of novel highly effective tools (digital droplet PCR and next generation sequencing). In the meantime, MRD diagnostics is applied to a number of novel clinical settings. In some entities, such as acute lymphoblastic leukemia, MRD detection by real time PCR using patient specific primers is already part of the routine clinical management of adult and pediatric patients. In other entities, such as follicular lymphoma, mantle cell lymphoma, chronic lymphocytic leukemia and multiple myeloma, MRD is a well-established prognostic tool and clinical trials employing MRD as a decision-making tool are currently ongoing. Finally in some entities, such as Hodgkin Lymphoma aggressive lymphoma and lymphoplasmacytic lymphoma, MRD diagnostics is highly promising but still in its infancy, In the present review, we shall discuss the 'state-of-the-art' of MRD evaluation in these 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.

Dr. Marco Ladetto
Gues Editor

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Keywords

  • real time PCR
  • multiparameter flow cytometry
  • next generation sequencing
  • digital droplet PCR
  • patient specific primers
  • acute lymphoblastic leukemia
  • lymphoma
  • multiple myeloma
  • chronic lymphocytic leukemia

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Published Papers (4 papers)

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Review

1844 KiB  
Review
Comparison of Minimal Residual Disease Detection by Multiparameter Flow Cytometry, ASO-qPCR, Droplet Digital PCR, and Deep Sequencing in Patients with Multiple Myeloma Who Underwent Autologous Stem Cell Transplantation
by Hiroyuki Takamatsu
J. Clin. Med. 2017, 6(10), 91; https://doi.org/10.3390/jcm6100091 - 25 Sep 2017
Cited by 31 | Viewed by 11311 | Correction
Abstract
Multiple myeloma (MM) is a hematological malignancy with a poor prognosis, characterized by clonal proliferation of plasma cells in the bone marrow (BM). Relapse due to undetected minimal residual disease (MRD) is the leading cause of death among patients with MM. This review [...] Read more.
Multiple myeloma (MM) is a hematological malignancy with a poor prognosis, characterized by clonal proliferation of plasma cells in the bone marrow (BM). Relapse due to undetected minimal residual disease (MRD) is the leading cause of death among patients with MM. This review summarizes the methods and prognostic value of MRD assessment in BM and autografts from MM patients who underwent autologous stem cell transplantation (ASCT) by multiparameter flow cytometry (MFC), allele-specific oligonucleotide real-time quantitative PCR (ASO-qPCR), droplet digital PCR (ddPCR), and next-generation sequencing (NGS)-based detection methods. MRD assessment using NGS-based approaches has clear prognostic value and better sensitivity compared to traditional methods. Full article
(This article belongs to the Special Issue Role of Minimal Residual Disease Assessment in Hematological Cancers)
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Figure 1

Figure 1
<p>An example of the Next-Generation Flow (NGF) method based on the analysis of (merged) data files corresponding to a bone marrow (BM) sample from multiple myeloma (MM) (&gt;10<sup>7</sup> cells) with low levels of minimal residual disease (MRD), stained with the NGF-MM MRD panel. The figure shows bivariate dot plot representations in which plasma cells (PCs; blue and red dots) were gated using a conventional manual analysis strategy. Normal PCs (blue dots) display characteristic normal patterns of expression for the surface membrane markers used with a cytoplasmic (Cy) Igκ vs. CyIgλ ratio of 1.3. In contrast, clonal/aberrant PCs (red dots) can be clearly discriminated from normal PCs based on their more homogeneous phenotypic profile, the presence of myeloma-associated phenotypes (CD138hi, CD38dim, CD19-, CD81-, CD117-, and CD27dim), and a restricted pattern of expression of CyIgκ. Other non-PC BM populations are depicted as gray dots. Please note that, in this sample, PCs corresponded to 0.06% of all nucleated BM cells; in turn, aberrant PCs corresponded to 0.0007% of the whole BM cellularity, with an assay sensitivity (in the quantitative range) of &lt;5 × 10<sup>−6</sup>.</p> Full article ">Figure 2
<p>Allele-specific oligonucleotide-quantitative PCR (ASO-qPCR) method to detect minimal residual disease (MRD), and design of ASO-qPCR primers and probes.</p> Full article ">Figure 3
<p>Next-generation sequencing method to detect minimal residual disease (MRD). (<b>A</b>) Schematic illustrations of LymphoSIGHT<sup>TM</sup> PCR primer strategy and sequencing assay. IgH V-J, IgH D-J, and IgK sequences were amplified from genomic DNA in a two-stage PCR (the first PCR using universal primer sets, and the second PCR using J primer and TAG primer). The amplified product was sequenced to obtain a high number of reads (e.g., 10<sup>6</sup> reads). The sequence reads were analyzed to determine similar sequences that form a clonotype. After clonotype determination, a standard quantitation scheme was used to calculate MRD level [<a href="#B43-jcm-06-00091" class="html-bibr">43</a>]. (<b>B</b>) Progression-free survival (PFS) and (<b>C</b>) overall survival (OS) of patients according to the MRD negativity in post-ASCT BM samples as determined by deep sequencing (threshold: 10<sup>−6</sup>). (<b>D</b>) PFS and (<b>E</b>) OS of the patients who did not receive post-ASCT treatment, according to MRD negativity in the autograft as determined by deep sequencing (threshold: 10<sup>−7</sup>).</p> Full article ">
427 KiB  
Review
Technical Advances in the Measurement of Residual Disease in Acute Myeloid Leukemia
by Gregory W. Roloff, Catherine Lai, Christopher S. Hourigan and Laura W. Dillon
J. Clin. Med. 2017, 6(9), 87; https://doi.org/10.3390/jcm6090087 - 19 Sep 2017
Cited by 29 | Viewed by 7614
Abstract
Outcomes for those diagnosed with acute myeloid leukemia (AML) remain poor. It has been widely established that persistent residual leukemic burden, often referred to as measurable or minimal residual disease (MRD), after induction therapy or at the time of hematopoietic stem cell transplant [...] Read more.
Outcomes for those diagnosed with acute myeloid leukemia (AML) remain poor. It has been widely established that persistent residual leukemic burden, often referred to as measurable or minimal residual disease (MRD), after induction therapy or at the time of hematopoietic stem cell transplant (HSCT) is highly predictive for adverse clinical outcomes and can be used to identify patients likely to experience clinically evident relapse. As a result of inherent genetic and molecular heterogeneity in AML, there is no uniform method or protocol for MRD measurement to encompass all cases. Several techniques focusing on identifying recurrent molecular and cytogenetic aberrations or leukemia-associated immunophenotypes have been described, each with their own strengths and weaknesses. Modern technologies enabling the digital quantification and tracking of individual DNA or RNA molecules, next-generation sequencing (NGS) platforms, and high-resolution imaging capabilities are among several new avenues under development to supplement or replace the current standard of flow cytometry. In this review, we outline emerging modalities positioned to enhance MRD detection and discuss factors surrounding their integration into clinical practice. Full article
(This article belongs to the Special Issue Role of Minimal Residual Disease Assessment in Hematological Cancers)
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Figure 1

Figure 1
<p>The use of unique molecular indexes (UMIs) in next-generation sequencing (NGS) libraries and droplet digital PCR (ddPCR) provide technical advances for measurable residual disease (MRD) detection. (<b>a</b>) Molecules consisting of three different nucleic acid targets (purple, green, and black lines) are individually tagged with UMIs. The UMI tags are maintained throughout amplification and library generation and are used to count the number of original target molecules present in the sample despite PCR amplification bias. (<b>b</b>) Alignment of read families (grey line) sorted by UMIs (blue or green line) allows for the discrimination of true mutations (blue asterisk) from sporadic errors introduced during PCR or sequencing procedures (pink asterisk). (<b>c</b>) A single PCR reaction is partitioned by ddPCR into thousands to millions of water–oil droplets for which no more than a single target sequence (red line) is present per droplet. PCR amplification is performed within the droplets and the fluorescent signal is measured as either positive or negative, allowing for absolute target copy number quantification.</p> Full article ">
228 KiB  
Review
When Less Is Good, Is None Better? The Prognostic and Therapeutic Significance of Peri-Transplant Minimal Residual Disease Assessment in Pediatric Acute Lymphoblastic Leukemia
by Adam Lamble, Rachel Phelan and Michael Burke
J. Clin. Med. 2017, 6(7), 66; https://doi.org/10.3390/jcm6070066 - 7 Jul 2017
Cited by 9 | Viewed by 5633
Abstract
The measurement of minimal residual disease (MRD) in pediatric acute lymphoblastic leukemia (ALL) has become the most important prognostic tool of, and the backbone to, upfront risk stratification. While MRD assessment is the standard of care for assessing response and predicting outcomes for [...] Read more.
The measurement of minimal residual disease (MRD) in pediatric acute lymphoblastic leukemia (ALL) has become the most important prognostic tool of, and the backbone to, upfront risk stratification. While MRD assessment is the standard of care for assessing response and predicting outcomes for pediatric patients with ALL receiving chemotherapy, its use in allogeneic hematopoietic stem cell transplant (HSCT) has been less clearly defined. Herein, we discuss the importance of MRD assessment during the peri-HSCT period and its role in prognostication and management. Full article
(This article belongs to the Special Issue Role of Minimal Residual Disease Assessment in Hematological Cancers)
585 KiB  
Review
Minimal Residual Disease in Acute Myeloid Leukemia: Still a Work in Progress?
by Federico Mosna, Debora Capelli and Michele Gottardi
J. Clin. Med. 2017, 6(6), 57; https://doi.org/10.3390/jcm6060057 - 3 Jun 2017
Cited by 27 | Viewed by 7586
Abstract
Minimal residual disease evaluation refers to a series of molecular and immunophenotypical techniques aimed at detecting submicroscopic disease after therapy. As such, its application in acute myeloid leukemia has greatly increased our ability to quantify treatment response, and to determine the chemosensitivity of [...] Read more.
Minimal residual disease evaluation refers to a series of molecular and immunophenotypical techniques aimed at detecting submicroscopic disease after therapy. As such, its application in acute myeloid leukemia has greatly increased our ability to quantify treatment response, and to determine the chemosensitivity of the disease, as the final product of the drug schedule, dose intensity, biodistribution, and the pharmakogenetic profile of the patient. There is now consistent evidence for the prognostic power of minimal residual disease evaluation in acute myeloid leukemia, which is complementary to the baseline prognostic assessment of the disease. The focus for its use is therefore shifting to individualize treatment based on a deeper evaluation of chemosensitivity and residual tumor burden. In this review, we will summarize the results of the major clinical studies evaluating minimal residual disease in acute myeloid leukemia in adults in recent years and address the technical and practical issues still hampering the spread of these techniques outside controlled clinical trials. We will also briefly speculate on future developments and offer our point of view, and a word of caution, on the present use of minimal residual disease measurements in “real-life” practice. Still, as final standardization and diffusion of the methods are sorted out, we believe that minimal residual disease will soon become the new standard for evaluating response in the treatment of acute myeloid leukemia. Full article
(This article belongs to the Special Issue Role of Minimal Residual Disease Assessment in Hematological Cancers)
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Graphical abstract

Graphical abstract
Full article ">Figure 1
<p>Paradigmatic scenarios of AML evolution after therapy considering MRD results. Nine paradigmatic scenarios (Cases 1 to 9) are displayed. Trends are simplified as compared to real life, for explicative reasons. Intermittent line at 1% represent the usual sensitivity limit of morphological examination; dotted line at 0.01% represents the usual sensitivity limit of MRD assessment. Vertical arrows represent chemotherapy cycles. Vertical lines represent common time-points for evaluation, i.e., after induction therapy and consolidation. (PANEL <b>A</b>): in Case 1, a quick response to chemotherapy cycles (white arrows) allows the patients to reach morphological CR after induction and the disappearance of measurable MRD after the first consolidation cycle. MRD remains undetectable during follow-up and the patient stays long-term in clinical remission. In Case 2, MRD negativity is reached within the end of consolidation therapy, so no further treatment (e.g., with allo-HSCT) is decided, and the patient remains in stable MRD negativity and clinical remission in the long term thereafter. In Case 3 the patient retains MRD-detectable disease at the end of consolidation, and allo-HSCT (lightning bolt) is decided; this enables us to obtain MRD negativity and long-term remission. (PANEL <b>B</b>): in Cases 4, 5 and 6 morphological remission is obtained following induction therapy, but no MRD is obtained by the end of consolidation in either cases. Case 4 is then consolidated by allo-HSCT, which enables the patient to reach MRD-negative leukemia levels briefly, but ultimately fails to eradicate the disease, with eventual relapse. In Case 5, no allo-HSCT is performed, and leukemia rapidly evolves from MRD persistence into overt clinical relapse. In Case 6, MRD identifies leukemia persistence just below the level of morphological detection (1%), and allo-HSCT, though inducing a brief reduction of residual disease, does not manage to obtain MRD negativity nor to prevent ultimate relapse. (PANEL <b>C</b>): in the scenario represented by Case 7 the patient never achieves a proper control over the disease, which results primary refractory; allo-HSCT is used with little efficacy, and ultimately clinical progression is unavoidable. Finally, Case 8 and 9 experience deep early response, achieving MRD negativity within the end of consolidation. In both cases reappearance of AML is detected by MRD monitoring during follow-up before clinical relapse: Case 9 is treated with additional therapy (either experimental treatments—i.e., grey arrow—or, less likely, allo-HSCT, lightning bolts) and restored to MRD negativity. Case 8 does not receive such treatment and ultimately relapse. In Case 9 the possibility of a molecular relapse spontaneously reverting to MRD-negativity also without the need for a clinical intervention, although increasingly rare with modern MRD measurement technique, cannot be ruled out, especially in the case of CBF AML.</p> Full article ">
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