Minimal Residual Disease Detection in Mantle Cell Lymphoma: Technical Aspects and Clinical Relevance

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The prognostic impact of minimal residual disease (MRD) has been demonstrated for several hematologic malignancies. While in acute lymphoblastic leukemias MRD assessment by polymerase chain reaction (PCR)-based methods has been established as an important tool for clinical risk assessment and is part of clinical management, data demonstrating a prognostic value of MRD in mantle cell lymphoma (MCL) were sparse and results from randomized trials have been published only recently. In the present review technical aspects of different MRD detection methods are discussed, as well as the prognostic relevance of MRD in the context of clinical trials in patients with MCL. Furthermore, recommendations are given for workflow and useful implication of MRD in future clinical trials design.

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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.

  • 1)

    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

References (81)

  • S.H. Walsh et al.

    Mutated VH genes and preferential VH3-21 use define new subsets of mantle cell lymphoma

    Blood

    (2003)
  • C. Pott et al.

    Molecular remission is an independent predictor of clinical outcome in patients with mantle cell lymphoma after combined immunochemotherapy: a European MCL intergroup study

    Blood

    (2010)
  • N.S. Andersen et al.

    Failure of immunologic purging in mantle cell lymphoma assessed by polymerase chain reaction detection of minimal residual disease

    Blood

    (1997)
  • N.S. Andersen et al.

    Real-time polymerase chain reaction estimation of bone marrow tumor burden using clonal immunoglobulin heavy chain gene and bcl-1/JH rearrangements in mantle cell lymphoma

    Exp Hematol

    (2002)
  • J.G. Gribben et al.

    Detection by polymerase chain reaction of residual cells with the bcl-2 translocation is associated with increased risk of relapse after autologous bone marrow transplantation for B-cell lymphoma

    Blood

    (1993)
  • R. Siebert et al.

    Application of interphase cytogenetics for the detection of t(11;14)(q13;q32) in mantle cell lymphomas

    Ann Oncol

    (1998)
  • M.E. Williams et al.

    Rearrangement of the chromosome 11 bcl-1 locus in centrocytic lymphoma: analysis with multiple breakpoint probes

    Blood

    (1991)
  • R. Rimokh et al.

    Detection of the chromosomal translocation t(11;14) by polymerase chain reaction in mantle cell lymphomas

    Blood

    (1994)
  • R. Rimokh et al.

    Rearrangement and overexpression of the BCL-1/PRAD-1 gene in intermediate lymphocytic lymphomas and in t(11q13)-bearing leukemias

    Blood

    (1993)
  • R. Rimokh et al.

    Rearrangement of CCND1 (BCL1/PRAD1) 3' untranslated region in mantle- cell lymphomas and t(11q13)-associated leukemias

    Blood

    (1994)
  • S.H. Swerdlow et al.

    From centrocytic to mantle cell lymphoma: a clinicopathologic and molecular review of 3 decades

    Hum Pathol

    (2002)
  • M. Ladetto et al.

    Prospective, multicenter randomized GITMO/IIL trial comparing intensive (R-HDS) versus conventional (CHOP-R) chemoimmunotherapy in high-risk follicular lymphoma at diagnosis: the superior disease control of R-HDS does not translate into an overall survival advantage

    Blood

    (2008)
  • M. Ladetto et al.

    High rate of clinical and molecular remissions in follicular lymphoma patients receiving high-dose sequential chemotherapy and autografting at diagnosis: a multicenter, prospective study by the Gruppo Italiano Trapianto Midollo Osseo (GITMO)

    Blood

    (2002)
  • P. Corradini et al.

    High-dose sequential chemoradiotherapy in multiple myeloma: residual tumor cells are detectable in bone marrow and peripheral blood cell harvests and after autografting

    Blood

    (1995)
  • P. Corradini et al.

    Molecular monitoring of minimal residual disease in follicular and mantle cell non-Hodgkin's lymphomas treated with high-dose chemotherapy and peripheral blood progenitor cell autografting

    Blood

    (1997)
  • M. Magni et al.

    Successful in vivo purging of CD34-containing peripheral blood harvests in mantle cell and indolent lymphoma: evidence for a role of both chemotherapy and rituximab infusion

    Blood

    (2000)
  • A.M. Gianni et al.

    Long-term remission in mantle cell lymphoma following high-dose sequential chemotherapy and in vivo rituximab-purged stem cell autografting (R-HDS regimen)

    Blood

    (2003)
  • M. Ladetto et al.

    Rituximab induces effective clearance of minimal residual disease in molecular relapses of mantle cell lymphoma [abstract]

    Biol Blood Marrow Transplant

    (2006)
  • B.D. Cheson et al.

    Revised response criteria for malignant lymphoma

    J Clin Oncol

    (2007)
  • N.S. Andersen et al.

    Primary treatment with autologous stem cell transplantation in mantle cell lymphoma: outcome related to remission pretransplant

    Eur J Haematol

    (2003)
  • E. Vandenberghe et al.

    Outcome of autologous transplantation for mantle cell lymphoma: a study by the European Blood and Bone Marrow Transplant and Autologous Blood and Marrow Transplant Registries

    Br J Haematol

    (2003)
  • F. Bosch et al.

    Fludarabine, cyclophosphamide, and mitoxantrone as initial therapy of chronic lymphocytic leukemia: high response rate and disease eradication

    Clin Cancer Res

    (2008)
  • M. Bruggemann et al.

    Significance of minimal residual disease in lymphoid malignancies

    Acta Haematol

    (2004)
  • L. Foroni et al.

    Molecular detection of minimal residual disease in adult and childhood acute lymphoblastic leukaemia reveals differences in treatment response

    Leukemia

    (1997)
  • F.Y. Mortuza et al.

    Minimal residual disease tests provide an independent predictor of clinical outcome in adult acute lymphoblastic leukemia

    J Clin Oncol

    (2002)
  • P. Moreton et al.

    Eradication of minimal residual disease in B-cell chronic lymphocytic leukemia after alemtuzumab therapy is associated with prolonged survival

    J Clin Oncol

    (2005)
  • G.A.M. Neale et al.

    Comparative analysis of flow cytometry and polymerase chain reaction for the detection of minimal residual disease in childhood acute lymphoblastic leukemia

    Leukemia

    (2004)
  • P. Moreton et al.

    Eradication of minimal residual disease in B-cell chronic lymphocytic leukemia after alemtuzumab therapy is associated with prolonged survival

    J Clin Oncol

    (2005)
  • S. Bottcher et al.

    Minimal residual disease detection in mantle cell lymphoma: methods and significance of four-color flow cytometry compared to consensus IGH-polymerase chain reaction at initial staging and for follow-up examinations

    Haematologica

    (2008)
  • S. Bottcher et al.

    Comparative analysis of minimal residual disease detection using four-color flow cytometry, consensus IgH-PCR, and quantitative IgH PCR in CLL after allogeneic and autologous stem cell transplantation

    Leukemia

    (2004)
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