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REVIEW Clinical Relevance of Minimal Residual Disease Monitoring in Non Leukemia (1999) 13, 1691–1695 1999 Stockton Press All rights reserved 0887-6924/99 $15.00 http://www.stockton-press.co.uk/leu REVIEW Clinical relevance of minimal residual disease monitoring in non-Hodgkin’s lymphomas: a critical reappraisal of molecular strategies P Corradini1, M Ladetto2, A Pileri2 and C Tarella2 1Bone Marrow Transplantation Unit, Istituto Scientifico HS Raffaele, Milan; and 2Divisione Universitaria di Ematologia–Azienda Ospedaliera S Giovanni Battista, Turin, Italy Although current treatments can induce clinical complete neoplasms. In the NHL setting, several studies have been pub- remissions in the vast majority of patients with indolent lym- lished on the prognostic significance of minimal residual dis- phoma, most of them actually relapse, because of the persist- ence of residual tumor cells which are undetectable using con- ease (MRD) detection. Most of these studies focus on indolent ventional diagnostic procedures. Polymerase chain reaction lymphomas: small lymphocytic lymphoma/chronic lympho- (PCR)-based methods are increasingly used for minimal cytic leukemia (SLL/CLL),17,18 follicular (FCL)19–21 and mantle residual disease detection (MRD), and provide useful prognos- cell lymphomas (MCL).20,22 This is mostly because these tic information. In this review, current approaches for MRD tumors, unlike more aggressive NHL histotypes, are dissemi- detection in indolent lymphomas are summarized. In addition, nated disorders with frequent microscopic or submicroscopic the prognostic aspects of molecular monitoring after transplan- tation procedures are discussed. The experience accumulated bone marrow (BM) and peripheral blood (PB) involvement, over the past decade shows that PCR analysis has a prognostic and thus they represent ideal targets for MRD evaluation with impact in several therapeutic programs including conventional PCR-based assays.23,24 and high-dose regimens. Major advantages coming from the In this review, we summarize the characteristics of the most introduction of molecular monitoring in clinical programs have frequently used strategies for PCR detection of residual disease been: (1) a rapid evaluation of the anti-tumor activity of innov- in lymphoma patients. The clinical relevance of molecular ative treatments; and (2) an early identification of patients with a high-risk of disease recurrence. monitoring after autologous or allogeneic transplantation will Keywords: minimal residual disease in lymphomas also be discussed. Introduction PCR strategies for monitoring residual disease in indolent lymphomas During the last 10 years, the treatment of non-Hodgkin’s lym- phoma (NHL) has dramatically changed.1,2 Major advances in The essential requirement for a PCR assay is the presence of the field have been the introduction of high-dose chemo- DNA sequences that are constantly detectable in the neoplas- therapy regimens followed by autologous or allogeneic trans- tic population and constantly undetectable in normal hemo- plantation of hematopoietic cells,3–8 the development of novel poietic cells. From these sequences primers and probes can drugs such as purine analogues9 and monoclonal anti- be designed and used for MRD detection. There are two bodies,10 and the use of innovative methods for ex vivo categories of tumor molecular markers: tumor-specific manipulation of autologous stem cells.11–19 Treatment evol- translocations, and antigen-receptor rearrangements. Tumor ution has been particularly remarkable in low grade subtypes, translocations have two major advantages: first, MRD detec- where palliative approaches have been progressively substi- tion is relatively simple since it involves only a PCR amplifi- tuted by treatments aimed at improving disease-free survival cation possibly followed by probe hybridization; second, and possibly curing at least patients younger than 60–65 these chromosonal aberrations are pathogenetically related to years. the neoplastic process, they represent a stable molecular Despite the introduction of these novel approaches, a size- marker, and they are usually not detected in normal cells. The able fraction of patients achieving clinical complete remission main disadvantage of translocation-based markers is that they actually relapse and die of their disease. The relapse is pre- provide a molecular marker only for a subset of patients. Such sumably caused by the persistence of small numbers of lym- a fraction is highly variable depending on the lymphoma sub- phoma cells that are below the limit of detection of standard type: FCLs harbor the t(14;18) translocation in approximately 60–80% of cases,19 whereas t(11;14) translocation is detect- diagnostic procedures. Therefore, considerable effort has been 22 made over the past decade to develop new techniques that able in 70–100% of MCL patients. Moreover, in several NHL allow the detection of extremely small numbers of tumor cells. subtypes no chromosomal translocation is presently available Among these techniques, the most sensitive and widely used for MRD evaluation. is the polymerase chain reaction (PCR). Its use has been exten- The rearrangement of immunoglobulin heavy-chain (IgH) sive in several hematological neoplasms, and the persistence and T cell receptor genes (TCR), has a wider applicability and of PCR detectable tumor cells has been correlated with can be used as molecular markers in the vast majority of increased likelihood of relapse in both myeloid and lymphoid lymphoid tumors. However, their use for PCR detection of MRD is somehow more complex than chromosomal translo- cations since it requires the sequencing analysis of rearranged variable region in order to design tumor-specific primers and Correspondence: P Corradini, Bone Marrow Transplantation Unit, Isti- 25,26 tuto Scientifico HS Raffaele, Via Olgettina 60, 20132 Milano, Italy; probes. In addition, clonal evolution is a potential prob- 27 Fax: 0039 02 26434760 lem associated with the use of IgH or TCR rearrangements. Received 5 May 1999; accepted 9 July 1999 Clonal evolution, however, is a phenomenon peculiar to more Review P Corradini et al 1692 immature disorders such as acute lymphoblastic leukemia, reproducible methods for quantitative analysis of MRD is and it does not take place in mature lymphoid tumors such required. This is of particular interest in evaluating the kinetic as indolent lymphomas and myelomas. of the tumor clone in those diseases in which the persistence So far, the three most widely used clonal markers in NHL of PCR detectable tumor cells is frequently observed with stan- patients are the t(14;18), the t(11;14) and the IgH gene dard qualitative methods. Traditional quantitative and semi- rearrangement. The t(14;18) was the first lesion routinely quantitative PCR approaches of end-product DNA analysis, employed for MRD analysis in NHL and it is detectable in limiting dilution strategies and competitive PCR are labour approximately 60–80% of FCL patients and in 20% of diffuse intensive, show a limited dynamic range and often give non- large cell lymphomas.28,29 In this translocation, the Bcl-2 reproducible results, and thus are of limited applicability in proto-oncogene on chromosome 18 is juxtaposed to the IgH the clinical setting.34 Recently, the introduction of the TaqMan locus on chromosome 14. Breakpoints are located at two technology and the development of analytical thermal cyclers main clusters 3Ј to the Bcl-2 coding region, named major have allowed the development of extremely powerful systems breakpoint region (MBR) and minor cluster region (mcr).30,31 for quantitative analysis. These methods are highly accurate, The t(14;18) translocation upregulates expression of the Bcl-2 mostly because they allow direct measurement of quantitative gene product that induces prolonged cell survival by blocking data at the beginning of the exponential phase of PCR ampli- programed cell death. The two breakpoint regions require dif- fication and thus eliminate biases taking place during late ferent sets of primers for PCR amplification. MRD evaluation post-exponential phases of the reaction and during post-PCR is performed by PCR amplification of the junctional region manipulation of samples. Several different tumor translo- using a 5Ј primer derived from the Bcl-2 locus and a 3Ј primer cations including the t(14;18) as well as the IgH rearrange- derived from the JH region of IgH genes. PCR products can ment35–37 have been used as targets for MRD detection using be hybridized to a Bcl-2 specific probe or, alternatively, TaqMan-based approaches. However, large studies, reamplified using a second set of internal primers: the so- investigating the prognostic relevance of quantitative called nested-PCR. Both hybridization and nested-PCR are evaluation of MRD in lymphoid tumours, are still awaited. extremely sensitive and specific techniques and can routinely detect one lymphoma cell in 105–106 normal cells.20,21 The t(11;14) fuses the Bcl-1 locus with the IgH locus and Molecular analysis as a tool to assess the efficacy of in is detected by cytogenetic or Southern blot analysis in the vast vitro purging procedures majority of MCL patients (70–100%). This translocation acti- vates the cyclin D1 (PRAD-1/CCND1) gene. Cyclin D1 is a High-dose chemotherapy regimens followed by autologous G1 cyclin that participates in the control of cell cycle pro- transplantation with BM or peripheral blood progenitor cells gression at the G1- to S-phase transition. Overexpression of (PBPC) are increasingly used for the treatment of indolent lym- this cyclin induces
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