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

Foroni, Letizia; Coyle, Luke; Papaioannou, M; Yaxley, John C.; Sinclair, Marie; Chim, Chor Sang; Cannell, Paul; Secker-Walker, LM; Mehta, Atul; Prentice, H. G.; Hoffbrand, A. V.

doi:10.1038/sj.leu.2400841

Cited by 75 publications

(43 citation statements)

References 2 publications

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“…2,3,5,6 The so-called real-time quantitative PCR (RQ-PCR) techniques offer the possibility for rapid and reproducible quantitation of MRD levels without post-PCR handling, thereby preventing contamination with PCR products. 133,192,193 The molecular laboratories of the BIOMED-1 Concerted Action have therefore now initiated a large study group of 25 laboratories from 10 European countries in order to standardize the RQ-PCR analyses of chromosome aberrations using the TaqMan technique.…”

Section: Resultsmentioning

confidence: 99%

“…[1][2][3][4][5][6] In particular the (semi-) quantitative measurement of the decrease of the leukemic cell load during the first phases of treatment has high prognostic value. In childhood acute lymphoblastic leukemia (ALL) this application of MRD measurement has been proven to identify an unprecedented large group of low-risk patients (40-45%) with a 4-year relapse rate of only 2%, and a high-risk group (15%) with a 4-year relapse rate of 80%.…”

Section: Prefacementioning

confidence: 99%

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1999

Leukemia

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Prospective studies on the detection of minimal residual disease (MRD) in acute leukemia patients have shown that largescale MRD studies are feasible and that clinically relevant MRDbased risk group classification can be achieved and can now be used for designing new treatment protocols. However, multicenter international treatment protocols with MRD-based stratification of treatment need careful standardization and quality control of the MRD techniques. This was the aim of the European BIOMED-1 Concerted Action 'Investigation of minimal residual disease in acute leukemia: international standardization and clinical evaluation' with participants of 14 laboratories in eight European countries (ES, NL, PT, IT, DE, FR, SE and AT). Standardization and quality control was performed for the three main types of MRD techniques, ie flow cytometric immunophenotyping, PCR analysis of antigen receptor genes, and RT-PCR analysis of well-defined chromosomal aberrations. This study focussed on the latter MRD technique. A total of nine well-defined chromosome aberrations with fusion gene transcripts were selected: t(1;19) with E2A-PBX1, t(4;11) with MLL-AF4, t(8;21) with AML1-ETO, t(9;22) with BCR-ABL p190 and BCR-ABL p210, t(12;21) with TEL-AML1, t(15;17) with PML-RARA, inv (16) with CBFB-MYH11, and microdeletion 1p32 with SIL-TAL1. PCR primers were designed according to predefined criteria for single PCR (external primers A ↔ B) and nested PCR (internal primers C ↔ D) as well as for 'shifted' PCR with a primer upstream (E5Ј primer) or downstream (E3Ј primer) of the external A ↔ B primers. The 'shifted' E primers were designed for performing an independent PCR together with one of the internal primers for confirmation (or exclusion) of positive results. Various local RT and PCR protocols were compared and subsequently a common protocol was designed, tested and adapted, resulting in a standardized RT-PCR protocol. After initial testing (with adaptations whenever necessary) and approval by two or three laboratories, the primers were tested by all participating laboratories, using 17 cell lines and patient samples as positive controls. This testing included comparison with local protocols and primers as well as sensitivity testing via dilution experiments. The collaborative efforts resulted in standardized primer sets with a minimal target sensitivity of 10 −2 for virtually all single PCR analyses, whereas the nested PCR analyses generally reached the minimal target sensitivity of 10 −4 . The standardized RT-PCR protocol and primer sets can now be used for molecular classification of acute leukemia at diagnosis and for MRD detection during follow-up to evaluate treatment effectiveness. Keywords: acute myeloid leukemia (AML); acute lymphoblastic leukemia (ALL); PCR; standardization; fusion genes; chromosome PrefaceMonitoring of acute leukemia patients during and after treatment for the presence of remaining leukemic cells ('minimal residual disease', MRD) has been shown to give major insight into the effectiveness of treatment. [1...

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Section: Resultsmentioning

confidence: 99%

Section: Prefacementioning

confidence: 99%

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1999

Leukemia

135

110

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“…With this approach, a detection limit of 5 × 10 −5 was reached in five cases and of 10 −3 in one case, which may not be sensitive enough for clinical application in ALL. 1,5,6,28,29 This problem has also been described in a recent paper by Pongers-Willemse et al, 13 who showed that this type of RQ PCR appeared to be comparable to quantification by dot-blotting but less sensitive than liquid hybridization. An additional disadvantage of this procedure is the expensive and time-consuming need for unique primer and probe sets for each individual patient.…”

Section: Design Of Primers and Probes For Rq Pcrmentioning

confidence: 87%

Improved assessment of minimal residual disease in B cell malignancies using fluorogenic consensus probes for real-time quantitative PCR

et al. 2000

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“…14,17,35 In precursor-B-ALL, this especially concerns junctional regions of IGH, IGK, TCRG and TCRD genes. 15 For this purpose the precise configuration of the gene rearrangements (ie the V(D), and J gene segments) has to be identified at diagnosis.…”

Section: Figurementioning

confidence: 99%

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1999

Leukemia

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The discrepancies could be assigned to the presence of 'atypical' TCRD gene rearrangements or translocations only detectable by SB, but also to efficient PCR-based detection of rearrangements derived from small subclones, which are difficult to detect with SB. Indications for oligoclonality were observed in 38% and 30% of patients with TCRG and TCRD gene rearrangements, respectively, which is comparable to the frequency of oligoclonality in IGH locus. Based on the combined data it was possible to reduce the broad panel of six TCRD and 12 TCRG primer combinations for MRD studies to two TCRD combinations (V␦2-D␦3 and D␦2-D␦3) and six TCRG combinations (V␥I, V␥II, V␥IV family-specific primers with J␥1.1/2.1 and J␥1.3/2.3 primers) resulting in the detection of 80% and 97% of all TCRD and TCRG gene rearrangements, respectively. Finally, the heteroduplex PCR data indicate that MRD monitoring with TCRG and/or TCRD targets is possible in approximately 80% of childhood precursor-B-ALL patients; ෂ55% of patients even have two TCRG and/or TCRD targets.

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

Cited by 75 publications

References 2 publications

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Improved assessment of minimal residual disease in B cell malignancies using fluorogenic consensus probes for real-time quantitative PCR

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