Minimal Residual Disease Detection in Mantle Cell Lymphoma: Technical Aspects and Clinical Relevance
Section snippets
Techniques for MRD Detection in MCL
Principally clinical relevant MRD information can be obtained using two techniques: (1) flow cytometric immunophenotyping using aberrant or lymphoma-associated immunophenotypes, and (2) polymerase chain reaction (PCR) using chromosomal aberrations or clonally rearranged immune genes as targets.
PCR-Based MRD Detection
Currently, PCR-based methods are the most sensitive, specific, and broadly applicable techniques for MRD assessment in lymphoid malignancies. PCR-based approaches are mostly based on DNA while only few studies have used RNA and reverse transcriptase (RT)-PCR–based approaches.24 DNA as a source for MRD investigations has the great advantage of a high stability and is therefore suitable for multicenter clinical trials.
The most broadly applicable marker for MRD studies in malignant B-cell
Molecular Targets for MRD Detection in MCL
The most broadly applicable marker for MRD studies in MCL is the immunoglobulin heavy chain gene rearrangement that is detectable in about 80% to 85% of the cases.25, 28, 29, 30, 38, 39, 40, 41 The clonal IGH rearrangement represents an ideal target for MRD detection; the junctional regions represent fingerprint-like sequences, which vary enormously due to the fact that different variable (V), diversity (D), and joining (J) gene segments are combined and various numbers of nucleotides are
Work Flow for MRD Assessment in MCL
Pretherapeutic sample assessment is a prerequisite for identification of the clonal rearrangements and subsequent PCR-based MRD analysis. With respect to RQ-PCR, determination of the malignant clone and subsequent sequence analysis is mandatory for the design of allele-specific (ASO) primers.
Quantitative MRD assessment by RQ-PCR requires the establishment of a standard curve from serially diluted genomic DNA with known starting copy numbers, optimally from tumor samples with almost 100% tumor
Clinical Relevance of MRD in MCL
With the availability of new treatment strategies, including high-dose chemoradiotherapy followed by ASCT, the prognosis of MCL has changed substantially during the last 20 years and higher rates of clinical response and prolonged overall survival could be achieved.58 With the introduction of the monoclonal anti-CD20–chimeric antibody rituximab in treatment protocols, high response rates have been observed in MCL, particularly when it is given in combination with chemotherapy.59, 60, 61
However,
Pitfalls in MRD Detection
MRD assessment will be possible in about 80% to 85% of all patients with MCL. However, there are certain factors that limit the application of MRD to all MCL patients.
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Few patients (<5%) have no detectable circulating MCL in diagnostic PB or BM for determination of a clonal marker. In these cases, DNA from fresh frozen lymph node could serve as an alternative for clonality assessment, as well as diagnostic material for establishment of serial dilution to quantify MRD at follow-up. However, fresh
Future Role of MRD Assessment in MCL
Longitudinal MRD studies have led to a better understanding of disease kinetics and relapse patterns of hematologic malignancies. Furthermore, MRD assessment is highly suitable for investigating the potential of new treatment modalities, as well as the efficiency of new drugs as recent results from the European-MCL network have shown.75 With the availability of new potent drugs, MRD will be a highly valuable secondary study endpoint and, being a surrogate parameter for prognosis, results could
Summary
Sequential MRD analysis has provided novel insights into the behavior of residual neoplastic lymphoma cells and disease kinetics of different B-cell neoplasias, and has allowed the identification of different prognostic subgroups. A selection of the relevant literature is summarized in Table 3. With the improvement of complete and overall response rates due to more intensive treatment and newly available drugs, MRD investigations have attracted notice also in MCL.
From the currently available
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