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Minimal Residual Disease

Minimal residual disease-directed risk stratification using real-time quantitative PCR analysis of immunoglobulin and T-cell receptor gene rearrangements in the international multicenter trial AIEOP-BFM ALL 2000 for childhood acute lymphoblastic leukemia

Leukemia volume 22, pages 771–782 (2008)Cite this article

Abstract

Detection of minimal residual disease (MRD) is the most sensitive method to evaluate treatment response and one of the strongest predictors of outcome in childhood acute lymphoblastic leukemia (ALL). The 10-year update on the I-BFM-SG MRD study 91 demonstrates stable results (event-free survival), that is, standard risk group (MRD-SR) 93%, intermediate risk group (MRD-IR) 74%, and high risk group (MRD-HR) 16%. In multicenter trial AIEOP-BFM ALL 2000, patients were stratified by MRD detection using quantitative PCR after induction (TP1) and consolidation treatment (TP2). From 1 July 2000 to 31 October 2004, PCR target identification was performed in 3341 patients: 2365 (71%) patients had two or more sensitive targets (⩽10−4), 671 (20%) patients revealed only one sensitive target, 217 (6%) patients had targets with lower sensitivity, and 88 (3%) patients had no targets. MRD-based risk group assignment was feasible in 2594 (78%) patients: 40% were classified as MRD-SR (two sensitive targets, MRD negativity at both time points), 8% as MRD-HR (MRD ⩾10−3 at TP2), and 52% as MRD-IR. The remaining 823 patients were stratified according to clinical risk features: HR (n=108) and IR (n=715). In conclusion, MRD-PCR-based stratification using stringent criteria is feasible in almost 80% of patients in an international multicenter trial.

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Acknowledgements

We thank Nicola Passow, Kirsten Linsmeier, Cornelia Rütz, Carmen Scherer, Heike Kuzan, Ivonne Schmitt, Daniela Mueller, Claudia Holzschuh, Yvonne Yeboah, and Anne Camminady (Heidelberg, Germany); Nicole Wittner and Annette Müller-Brechlin (Hannover, Germany); Lilia Corral, Elisabetta d'Aniello, Monica Manenti, Eugenia Mella, Antonella Musarò, Simona Songia, Tiziana Villa, and Giuseppe Gaipa (Monza, Italy); Giuseppe Germano, Laura Del Giudice, Emanuela Giarin, Monica Spinelli, and Marinella Veltroni (Padua, Italy); Marianne Konrad, Eva Csinadi, and Ulrike Monschein (Vienna, Austria); Rahel Schaub, Marco Thali, and Silvia van Essen (Zurich, Switzerland) for their excellent technical assistance and Anja Mörike and Gunnar Cario for their great help in preparing figures and tables and for critically reviewing the paper. We gratefully acknowledge the clinicians of the participating hospitals for their excellent cooperation and compliance and for sending bone marrow samples to the national study centers. We also thank the participants of the International BFM Study Group and all the centers of the Associazione Italiana Ematologia e Oncologia Pediatrica (AIEOP) for their close collaboration. The collaborative study was supported by the Deutsche Krebshilfe (Germany), the St Anna Kinderkrebsforschung, a grant from the FWF (P-13575-MED) to RP-G (Austria), the Associazione Italiana Ricerca Cancro (AIRC), Comitato ML Verga, Fondazione M Tettamanti (Monza, Italy), Fondazione Cariplo (Milano, Italy), Fondazione Città della Speranza (Padua, Italy), OncoSuisse (grant no. OCS01230-02-2002), Swiss Cancer League (grant no. SKL-01230-02-2002), and Swiss Research Foundation Child and Cancer (Switzerland). RS acknowledges support of NHMRC and TCCN Australia. The external quality control rounds were organized by the European Study Group on MRD detection in ALL (ESG-MRD-ALL; coordinated by JJM van Dongen and VHJ van der Velden), which was supported by Leukaemia Research Fund (LRF) and the European LeukemiaNet (ELN). From 2000 to 2006, the laboratory meetings of the MRD Task Force, which established the quality rounds, were supported by the German ‘Kind-Philipp-Foundation for Leukemia Research’.

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  1. T Flohr, A Schrauder and G Cazzaniga: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Pediatrics, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany

    T Flohr, A Schrauder & M Schrappe

  2. Institute of Human Genetics, Ruprecht-Karls University, Heidelberg, Germany

    T Flohr, R Koehler & C R Bartram

  3. Pediatric Clinic, University of Milano-Bicocca, Ospedale Nuovo San Gerardo, and Childhood Leukemia Research Center M. Tettamanti, Monza, Italy

    G Cazzaniga, M G Valsecchi, G Masera & A Biondi

  4. Children's Cancer Research Institute, Vienna, Austria

    R Panzer-Grümayer, S Fischer & H Gadner

  5. St Anna Children's Hospital, Vienna, Austria

    R Panzer-Grümayer & H Gadner

  6. Department of Immunology, Erasmus MC, University Medical Center, Rotterdam, The Netherlands

    V van der Velden & J J M van Dongen

  7. Department of Pediatric Hematology/Oncology, Hannover Medical School, Hannover, Germany

    M Stanulla & M Zimmermann

  8. Department of Pediatrics, University of Padova, Padova, Italy

    G Basso

  9. Department of Pediatric Hematology/Oncology and Oncology Laboratories, University Children's Hospital, Zurich, Switzerland

    F K Niggli & B W Schäfer

  10. Children's Cancer Institute Australia for Medical Research, University of New South Wales, Randwick, New South Wales, Australia

    R Sutton

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Flohr, T., Schrauder, A., Cazzaniga, G. et al. Minimal residual disease-directed risk stratification using real-time quantitative PCR analysis of immunoglobulin and T-cell receptor gene rearrangements in the international multicenter trial AIEOP-BFM ALL 2000 for childhood acute lymphoblastic leukemia. Leukemia 22, 771–782 (2008). https://doi.org/10.1038/leu.2008.5

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