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Standardized MRD quantification in European ALL trials: Proceedings of the Second International Symposium on MRD assessment in Kiel, Germany, 18–20 September 2008

Abstract

Assessment of minimal residual disease (MRD) has acquired a prominent position in European treatment protocols for patients with acute lymphoblastic leukemia (ALL), on the basis of its high prognostic value for predicting outcome and the possibilities for implementation of MRD diagnostics in treatment stratification. Therefore, there is an increasing need for standardization of methodologies and harmonization of terminology. For this purpose, a panel of representatives of all major European study groups on childhood and adult ALL and of international experts on PCR- and flow cytometry-based MRD assessment was built in the context of the Second International Symposium on MRD assessment in Kiel, Germany, 18–20 September 2008. The panel summarized the current state of MRD diagnostics in ALL and developed recommendations on the minimal technical requirements that should be fulfilled before implementation of MRD diagnostics into clinical trials. Finally, a common terminology for a standard description of MRD response and monitoring was established defining the terms ‘complete MRD response’, ‘MRD persistence’ and ‘MRD reappearance’. The proposed MRD terminology may allow a refined and standardized assessment of response to treatment in adult and childhood ALL, and provides a sound basis for the comparison of MRD results between different treatment protocols.

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References

  1. Bader P, Kreyenberg H, Henze GHR, Eckert C, Reising M, Willasch A et al. Prognostic value of minimal residual disease quantification before allogeneic stem-cell transplantation in relapsed childhood acute lymphoblastic leukemia: the ALL-REZ BFM study group. J Clin Oncol 2009; 27: 377–384.

    Google Scholar 

  2. Bassan R, Spinelli O, Oldani E, Intermesoli T, Tosi M, Peruta B et al. Improved risk classification for risk-specific therapy based on the molecular study of minimal residual disease (MRD) in adult acute lymphoblastic leukemia (ALL). Blood 2009; 113: 4153–4162.

    CAS  Google Scholar 

  3. Bjorklund E, Mazur J, Soderhall S, Porwit-MacDonald A . Flow cytometric follow-up of minimal residual disease in bone marrow gives prognostic information in children with acute lymphoblastic leukemia. Leukemia 2003; 17: 138–148.

    Article  CAS  Google Scholar 

  4. Borowitz MJ, Devidas M, Hunger SP, Bowman WP, Carroll AJ, Carroll WL et al. Clinical significance of minimal residual disease in childhood acute lymphoblastic leukemia and its relationship to other prognostic factors: a Children's Oncology Group Study. Blood 2008; 111: 5477–5485.

    CAS  Google Scholar 

  5. Brüggemann M, Raff T, Flohr T, Gokbuget N, Nakao M, Droese J et al. Clinical significance of minimal residual disease quantification in adult patients with standard-risk acute lymphoblastic leukemia. Blood 2006; 107: 1116–1123.

    Google Scholar 

  6. Cave H, van der Werff ten Bosch J, Suciu S, Guidal C, Waterkeyn C, Otten J et al. Clinical significance of minimal residual disease in childhood acute lymphoblastic leukemia. European Organization for Research and Treatment of Cancer—Childhood Leukemia Cooperative Group. N Engl J Med 1998; 339: 591–598.

    CAS  Google Scholar 

  7. Coustan-Smith E, Sancho J, Hancock ML, Boyett JM, Behm FG, Raimondi SC et al. Clinical importance of minimal residual disease in childhood acute lymphoblastic leukemia. Blood 2000; 96: 2691–2696.

    CAS  Google Scholar 

  8. Eckert C, Biondi A, Seeger K, Cazzaniga G, Hartmann R, Beyermann B et al. Prognostic value of minimal residual disease in relapsed childhood acute lymphoblastic leukaemia. Lancet 2001; 358: 1239–1241.

    CAS  Google Scholar 

  9. Fronkova E, Mejstrikova E, Avigad S, Chik KW, Castillo L, Manor S et al. Minimal residual disease (MRD) analysis in the non-MRD-based ALL IC-BFM 2002 protocol for childhood ALL: is it possible to avoid MRD testing? Leukemia 2008; 22: 989–997.

    CAS  Google Scholar 

  10. Goulden NJ, Knechtli CJ, Garland RJ, Langlands K, Hancock JP, Potter MN et al. Minimal residual disease analysis for the prediction of relapse in children with standard-risk acute lymphoblastic leukaemia. Br J Haematol 1998; 100: 235–244.

    CAS  Google Scholar 

  11. Huguet F, Leguay T, Raffoux E, Thomas X, Beldjord K, Delabesse E et al. Pediatric-inspired therapy in adults with Philadelphia chromosome-negative acute lymphoblastic leukemia: the GRAALL-2003 study. J Clin Oncol 2009; 27: 911–918.

    CAS  Google Scholar 

  12. Knechtli CJ, Goulden NJ, Hancock JP, Grandage VL, Harris EL, Garland RJ et al. Minimal residual disease status before allogeneic bone marrow transplantation is an important determinant of successful outcome for children and adolescents with acute lymphoblastic leukemia. Blood 1998; 92: 4072–4079.

    CAS  Google Scholar 

  13. Knechtli CJ, Goulden NJ, Hancock JP, Harris EL, Garland RJ, Jones CG et al. Minimal residual disease status as a predictor of relapse after allogeneic bone marrow transplantation for children with acute lymphoblastic leukaemia. Br J Haematol 1998; 102: 860–871.

    CAS  Google Scholar 

  14. Lee S, Kim DW, Cho B, Kim YJ, Kim YL, Hwang JY et al. Risk factors for adults with Philadelphia-chromosome-positive acute lymphoblastic leukaemia in remission treated with allogeneic bone marrow transplantation: the potential of real-time quantitative reverse-transcription polymerase chain reaction. Br J Haematol 2003; 120: 145–153.

    CAS  Google Scholar 

  15. Lee S, Kim DW, Kim YJ, Chung NG, Kim YL, Hwang JY et al. Minimal residual disease-based role of imatinib as a first-line interim therapy prior to allogeneic stem cell transplantation in Philadelphia chromosome-positive acute lymphoblastic leukemia. Blood 2003; 102: 3068–3070.

    CAS  Google Scholar 

  16. Mortuza FY, Papaioannou M, Moreira IM, Coyle LA, Gameiro P, Gandini D et al. Minimal residual disease tests provide an independent predictor of clinical outcome in adult acute lymphoblastic leukemia. J Clin Oncol 2002; 20: 1094–1104.

    Google Scholar 

  17. Nyvold C, Madsen HO, Ryder LP, Seyfarth J, Svejgaard A, Clausen N et al. Precise quantification of minimal residual disease at day 29 allows identification of children with acute lymphoblastic leukemia and an excellent outcome. Blood 2002; 99: 1253–1258.

    CAS  Google Scholar 

  18. Pane F, Cimino G, Izzo B, Camera A, Vitale A, Quintarelli C et al. Significant reduction of the hybrid BCR/ABL transcripts after induction and consolidation therapy is a powerful predictor of treatment response in adult Philadelphia-positive acute lymphoblastic leukemia. Leukemia 2005; 19: 628–635.

    CAS  Google Scholar 

  19. Raff T, Gökbuget N, Lüschen S, Reutzel R, Ritgen M, Irmer S et al. Molecular relapse in adult standard-risk ALL patients detected by prospective MRD monitoring during and after maintenance treatment: data from the GMALL 06/99 and 07/03 trials. Blood 2007; 109: 910–915.

    CAS  Google Scholar 

  20. Ribera JM, Oriol A, Gonzalez M, Vidriales B, Brunet S, Esteve J et al. Concurrent intensive chemotherapy and imatinib before and after stem cell transplantation in newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia. Final results of the CSTIBES02 trial. Haematologica 2009; (e-pub ahead of print).

  21. Scheuring UJ, Pfeifer H, Wassmann B, Bruck P, Atta J, Petershofen EK et al. Early minimal residual disease (MRD) analysis during treatment of Philadelphia chromosome/Bcr-Abl-positive acute lymphoblastic leukemia with the Abl-tyrosine kinase inhibitor imatinib (STI571). Blood 2003; 101: 85–90.

    CAS  Google Scholar 

  22. Schmiegelow K, Nyvold C, Seyfarth J, Pieters R, Rottier MM, Knabe N et al. Post-induction residual leukemia in childhood acute lymphoblastic leukemia quantified by PCR correlates with in vitro prednisolone resistance. Leukemia 2001; 15: 1066–1071.

    CAS  Google Scholar 

  23. Seyfarth J, Madsen HO, Nyvold C, Ryder LP, Clausen N, Jonmundsson GK et al. Post-induction residual disease in translocation t(12;21)-positive childhood ALL. Med Pediatr Oncol 2003; 40: 82–87.

    Google Scholar 

  24. Spinelli O, Peruta B, Tosi M, Guerini V, Salvi A, Zanotti MC et al. Clearance of minimal residual disease after allogeneic stem cell transplantation and the prediction of the clinical outcome of adult patients with high-risk acute lymphoblastic leukemia. Haematologica 2007; 92: 612–618.

    Google Scholar 

  25. Thomas X, Boiron JM, Huguet F, Dombret H, Bradstock K, Vey N et al. Outcome of treatment in adults with acute lymphoblastic leukemia: analysis of the LALA-94 trial. J Clin Oncol 2004; 22: 4075–4086.

    CAS  Google Scholar 

  26. van Dongen JJM, Seriu T, Panzer-Grumayer ER, Biondi A, Pongers-Willemse MJ, Corral L et al. Prognostic value of minimal residual disease in acute lymphoblastic leukaemia in childhood. Lancet 1998; 352: 1731–1738.

    CAS  Google Scholar 

  27. Wassmann B, Pfeifer H, Goekbuget N, Beelen DW, Beck J, Stelljes M et al. Alternating versus concurrent schedules of imatinib and chemotherapy as front-line therapy for Philadelphia-positive acute lymphoblastic leukemia (Ph+ ALL). Blood 2006; 108: 1469–1477.

    CAS  Google Scholar 

  28. Brüggemann M, van der Velden VHJ, Raff T, Droese J, Ritgen M, Pott C et al. Rearranged T-cell receptor beta genes represent powerful targets for quantification of minimal residual disease in childhood and adult T-cell acute lymphoblastic leukemia. Leukemia 2004; 18: 709–719.

    Google Scholar 

  29. Campana D, Coustan-Smith E . Minimal residual disease studies by flow cytometry in acute leukemia. Acta Haematol 2004; 112: 8–15.

    Google Scholar 

  30. Cave H, Guidal C, Rohrlich P, Delfau MH, Broyart A, Lescoeur B et al. Prospective monitoring and quantitation of residual blasts in childhood acute lymphoblastic leukemia by polymerase chain reaction study of delta and gamma T-cell receptor genes. Blood 1994; 83: 1892–1902.

    CAS  Google Scholar 

  31. Coustan-Smith E, Behm FG, Sanchez J, Boyett JM, Hancock ML, Raimondi SC et al. Immunological detection of minimal residual disease in children with acute lymphoblastic leukaemia. Lancet 1998; 351: 550–554.

    CAS  Google Scholar 

  32. Dworzak MN, Froschl G, Printz D, Mann G, Potschger U, Muhlegger N et al. Prognostic significance and modalities of flow cytometric minimal residual disease detection in childhood acute lymphoblastic leukemia. Blood 2002; 99: 1952–1958.

    CAS  Google Scholar 

  33. Dworzak MN, Gaipa G, Ratei R, Veltroni M, Schumich A, Maglia O et al. Standardization of flow cytometric minimal residual disease evaluation in acute lymphoblastic leukemia: multicentric assessment is feasible. Cytometry B Clin Cytom 2008; 74: 331–340.

    Google Scholar 

  34. Gleissner B, Rieder H, Thiel E, Fonatsch C, Janssen LA, Heinze B et al. Prospective BCR-ABL analysis by polymerase chain reaction (RT-PCR) in adult acute B-lineage lymphoblastic leukemia: reliability of RT-nested-PCR and comparison to cytogenetic data. Leukemia 2001; 15: 1834–1840.

    CAS  Google Scholar 

  35. Irving J, Jesson J, Virgo P, Case M, Minto L, Eyre L et al. Establishment and validation of a standard protocol for the detection of minimal residual disease in B lineage childhood acute lymphoblastic leukemia by flow cytometry in a multi-center setting. Haematologica 2009; 94: 870–874.

    Google Scholar 

  36. Mitterbauer G, Nemeth P, Wacha S, Cross NC, Schwarzinger I, Jaeger U et al. Quantification of minimal residual disease in patients with BCR-ABL-positive acute lymphoblastic leukaemia using quantitative competitive polymerase chain reaction. Br J Haematol 1999; 106: 634–643.

    CAS  Google Scholar 

  37. Radich J, Gehly G, Lee A, Avery R, Bryant E, Edmands S et al. Detection of bcr-abl transcripts in Philadelphia chromosome-positive acute lymphoblastic leukemia after marrow transplantation. Blood 1997; 89: 2602–2609.

    CAS  Google Scholar 

  38. Van der Velden VHJ, Cazzaniga G, Schrauder A, Hancock J, Bader P, Panzer-Grumayer ER et al. Analysis of minimal residual disease by Ig/TCR gene rearrangements: guidelines for interpretation of real-time quantitative PCR data. Leukemia 2007; 21: 604–611.

    CAS  Google Scholar 

  39. van der Velden VHJ, Wijkhuijs JM, Jacobs DC, van Wering ER, van Dongen JJM . T cell receptor gamma gene rearrangements as targets for detection of minimal residual disease in acute lymphoblastic leukemia by real-time quantitative PCR analysis. Leukemia 2002; 16: 1372–1380.

    CAS  Google Scholar 

  40. van der Velden VHJ, Willemse MJ, van der Schoot CE, Hahlen K, van Wering ER, van Dongen JJM . Immunoglobulin kappa deleting element rearrangements in precursor-B acute lymphoblastic leukemia are stable targets for detection of minimal residual disease by real-time quantitative PCR. Leukemia 2002; 16: 928–936.

    CAS  Google Scholar 

  41. Breit TM, Beishuizen A, Ludwig WD, Mol EJ, Adriaansen HJ, van Wering ER et al. tal-1 deletions in T-cell acute lymphoblastic leukemia as PCR target for detection of minimal residual disease. Leukemia 1993; 7: 2004–2011.

    CAS  Google Scholar 

  42. Van der Velden VH, Corral L, Valsecchi MG, Jansen MW, De LP, Cazzaniga G et al. Prognostic significance of minimal residual disease in infants with acute lymphoblastic leukemia treated within the Interfant-99 protocol. Leukemia 2009; 23: 1073–1079.

    CAS  Google Scholar 

  43. Szczepanski T, Flohr T, van der Velden VH, Bartram CR, van Dongen JJM . Molecular monitoring of residual disease using antigen receptor genes in childhood acute lymphoblastic leukaemia. Best Pract Res Clin Haematol 2002; 15: 37–57.

    CAS  Google Scholar 

  44. van der Velden VHJ, Hochhaus A, Cazzaniga G, Szczepanski T, Gabert J, van Dongen JJM . Detection of minimal residual disease in hematologic malignancies by real-time quantitative PCR: principles, approaches, and laboratory aspects. Leukemia 2003; 17: 1013–1034.

    CAS  Google Scholar 

  45. Guidal C, Vilmer E, Grandchamp B, Cave H . A competitive PCR-based method using TCRD, TCRG and IGH rearrangements for rapid detection of patients with high levels of minimal residual disease in acute lymphoblastic leukemia. Leukemia 2002; 16: 762–764.

    CAS  Google Scholar 

  46. Van der Velden VH, Bruggemann M, Hoogeveen PG, de BM, Hart PG, Raff T et al. TCRB gene rearrangements in childhood and adult precursor-B-ALL: frequency, applicability as MRD-PCR target, and stability between diagnosis and relapse. Leukemia 2004; 18: 1971–1980.

    CAS  Google Scholar 

  47. Van der Velden VHJ, van Dongen JJM . MRD detection in acute lymphoblastic leukemia patients using Ig/TCR gene rearrangements as targets for real-time quantitative PCR. Methods Mol Biol 2009; 538: 115–150.

    CAS  Google Scholar 

  48. Gaipa G, Cazzaniga G, Panzer-Grumayer RE, Veltroni M, Karawajew L, Silvestri D et al. Time point-dependent concordance of flow cytometry and RQ-PCR in the MRD detection in childhood ALL: the experience of the AIEOP-BFM- ALL MRD study group. ASH Annual Meeting Abstracts 2008; 112: 700.

    Google Scholar 

  49. Malec M, van der Velden VHJ, Bjorklund E, Wijkhuijs JM, Soderhall S, Mazur J et al. Analysis of minimal residual disease in childhood acute lymphoblastic leukemia: comparison between RQ-PCR analysis of Ig/TcR gene rearrangements and multicolor flow cytometric immunophenotyping. Leukemia 2004; 18: 1630–1636.

    CAS  Google Scholar 

  50. Neale GA, Coustan-Smith E, Stow P, Pan Q, Chen X, Pui CH 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; 18: 934–938.

    CAS  Google Scholar 

  51. Beishuizen A, Verhoeven MA, van Wering ER, Hahlen K, Hooijkaas H, van Dongen JJM . Analysis of Ig and T-cell receptor genes in 40 childhood acute lymphoblastic leukemias at diagnosis and subsequent relapse: implications for the detection of minimal residual disease by polymerase chain reaction analysis. Blood 1994; 83: 2238–2247.

    CAS  Google Scholar 

  52. Szczepanski T, Van der Velden VH, Raff T, Jacobs DC, van Wering ER, Bruggemann M et al. Comparative analysis of T-cell receptor gene rearrangements at diagnosis and relapse of T-cell acute lymphoblastic leukemia (T-ALL) shows high stability of clonal markers for monitoring of minimal residual disease and reveals the occurrence of second T-ALL. Leukemia 2003; 17: 2149–2156.

    CAS  Google Scholar 

  53. Szczepanski T, Willemse MJ, Brinkhof B, van Wering ER, van der Burg M, van Dongen JJM . Comparative analysis of Ig and TCR gene rearrangements at diagnosis and at relapse of childhood precursor-B-ALL provides improved strategies for selection of stable PCR targets for monitoring of minimal residual disease. Blood 2002; 99: 2315–2323.

    CAS  Google Scholar 

  54. Fronkova E, Muzikova K, Mejstrikova E, Kovac M, Formankova R, Sedlacek P et al. B-cell reconstitution after allogeneic SCT impairs minimal residual disease monitoring in children with ALL. Bone Marrow Transplant 2008; 42: 187–196.

    CAS  Google Scholar 

  55. van der Velden VHJ, Wijkhuijs JM, van Dongen JJM . Non-specific amplification of patient-specific Ig//TCR gene rearrangements depends on the time point during therapy: implications for minimal residual disease monitoring. Leukemia 2007; 22: 641–644.

    Google Scholar 

  56. Preudhomme C, Henic N, Cazin B, Lai JL, Bertheas MF, Vanrumbeke M et al. Good correlation between RT-PCR analysis and relapse in Philadelphia (Ph1)-positive acute lymphoblastic leukemia (ALL). Leukemia 1997; 11: 294–298.

    CAS  Google Scholar 

  57. Zaliova M, Fronkova E, Krejcikova K, Muzikova K, Mejstrikova E, Stary J et al. Quantification of fusion transcript reveals a subgroup with distinct biological properties and predicts relapse in BCR/ABL-positive ALL: implications for residual disease monitoring. Leukemia 2009; 23: 944–951.

    CAS  Google Scholar 

  58. Campana D . Determination of minimal residual disease in leukaemia patients. Br J Haematol 2003; 121: 823–838.

    Google Scholar 

  59. Coustan-Smith E, Sancho J, Behm FG, Hancock ML, Razzouk BI, Ribeiro RC et al. Prognostic importance of measuring early clearance of leukemic cells by flow cytometry in childhood acute lymphoblastic leukemia. Blood 2002; 100: 52–58.

    CAS  Google Scholar 

  60. Dworzak MN, Froschl G, Printz D, Zen LD, Gaipa G, Ratei R et al. CD99 expression in T-lineage ALL: implications for flow cytometric detection of minimal residual disease. Leukemia 2004; 18: 703–708.

    CAS  Google Scholar 

  61. van Wering ER, Beishuizen A, Roeffen ET, van der Linden-Schrever BE, Verhoeven MA, Hahlen K et al. Immunophenotypic changes between diagnosis and relapse in childhood acute lymphoblastic leukemia. Leukemia 1995; 9: 1523–1533.

    CAS  Google Scholar 

  62. Veltroni M, De Zen L, Sanzari MC, Maglia O, Dworzak MN, Ratei R et al. Expression of CD58 in normal, regenerating and leukemic bone marrow B cells: implications for the detection of minimal residual disease in acute lymphocytic leukemia. Haematologica 2003; 88: 1245–1252.

    Google Scholar 

  63. Vidriales MB, Perez JJ, Lopez-Berges MC, Gutierrez N, Ciudad J, Lucio P et al. Minimal residual disease in adolescent (older than 14 years) and adult acute lymphoblastic leukemias: early immunophenotypic evaluation has high clinical value. Blood 2003; 101: 4695–4700.

    CAS  Google Scholar 

  64. Basso G, Veltroni M, Valsecchi MG, Dworzak MN, Ratei R, Silvetri D et al. Risk of relapse of childhood acute lymphoblastic leukemia is predicted by flow cytometric measurement of residual disease on day 15 bone marrow. J Clin Oncol 2009; 27: 5168–5174.

    Google Scholar 

  65. da Costa ES, Peres RT, Almeida J, Lecrevisse Q, Arroyo ME, Teodosio C ; et al. Harmonization of light scatter and fluorescence flow cytometry profiles obtained after staining peripheral blood leucocytes for cell surface-only versus intracellular antigens with the Fix & Perm reagent. Cytometry B Clin Cytom 2009; (e-pub ahead of print).

  66. Pedreira CE, Costa ES, Almeida J, Fernandez C, Quijano S, Flores J et al. A probabilistic approach for the evaluation of minimal residual disease by multiparameter flow cytometry in leukemic B-cell chronic lymphoproliferative disorders. Cytometry A 2008; 73A: 1141–1150.

    CAS  Google Scholar 

  67. Pedreira CE, Costa ES, Barrena S, Lecrevisse Q, Almeida J, van Dongen JJM et al. Generation of flow cytometry data files with a potentially infinite number of dimensions. Cytometry A 2008; 73: 834–846.

    Google Scholar 

  68. Dworzak MN, Schumich A, Printz D, Potschger U, Husak Z, Attarbaschi A et al. CD20 up-regulation in pediatric B-cell precursor acute lymphoblastic leukemia during induction treatment: setting the stage for anti-CD20 directed immunotherapy. Blood 2008; 112: 3982–3988.

    CAS  Google Scholar 

  69. Gaipa G, Basso G, Maglia O, Leoni V, Faini A, Cazzaniga G et al. Drug-induced immunophenotypic modulation in childhood ALL: implications for minimal residual disease detection. Leukemia 2005; 19: 49–56.

    CAS  Google Scholar 

  70. van der Sluijs-Gelling AJ, Van der Velden VH, Roeffen ET, Veerman AJ, van Wering ER . Immunophenotypic modulation in childhood precursor-B-ALL can be mimicked in vitro and is related to the induction of cell death. Leukemia 2005; 19: 1845–1847.

    CAS  Google Scholar 

  71. Stams WA, Den Boer ML, Beverloo HB, Kazemier KM, van Wering ER, Janka-Schaub GE et al. Effect of the histone deacetylase inhibitor depsipeptide on B-cell differentiation in both TEL-AML1-positive and negative childhood acute lymphoblastic leukemia. Haematologica 2005; 90: 1697–1699.

    CAS  Google Scholar 

  72. van der Velden VHJ, Jacobs C, Wijkhuijs J, Comans-Bitter WM, Willemse MJ, Hählen K et al. Minimal residual disease levels in bone marrow and peripheral blood are comparable in children with T cell acute lymphoblastic leukemia (ALL), but not in precursor-B-ALL. Leukemia 2002; 16: 1432–1436.

    CAS  Google Scholar 

  73. Coustan-Smith E, Sancho J, Hancock ML, Razzouk BI, Ribeiro RC, Rivera GK et al. Use of peripheral blood instead of bone marrow to monitor residual disease in children with acute lymphoblastic leukemia. Blood 2002; 100: 2399–2402.

    CAS  Google Scholar 

  74. Beillard E, Pallisgaard N, van der Velden VHJ, Bi W, Dee R, van der SE et al. Evaluation of candidate control genes for diagnosis and residual disease detection in leukemic patients using ‘real-time’ quantitative reverse-transcriptase polymerase chain reaction (RQ-PCR)—a Europe against cancer program. Leukemia 2003; 17: 2474–2486.

    CAS  Google Scholar 

  75. Davis BH, Holden JT, Bene MC, Borowitz MJ, Braylan RC, Cornfield D et al. 2006 Bethesda International Consensus recommendations on the flow cytometric immunophenotypic analysis of hematolymphoid neoplasia: medical indications. Cytometry B Clin Cytom 2007; 72 (Suppl 1): S5–S13.

    Google Scholar 

  76. Escribano L, Diaz-Agustin B, Lopez A, Nunez LR, Garcia-Montero A, Almeida J et al. Immunophenotypic analysis of mast cells in mastocytosis: when and how to do it. Proposals of the Spanish Network on Mastocytosis (REMA). Cytometry B Clin Cytom 2004; 58: 1–8.

    Google Scholar 

  77. Subira D, Castanon S, Aceituno E, Hernandez J, Jimenez-Garofano C, Jimenez A et al. Flow cytometric analysis of cerebrospinal fluid samples and its usefulness in routine clinical practice. Am J Clin Pathol 2002; 117: 952–958.

    Google Scholar 

  78. Rawstron AC, Orfao A, Beksac M, Bezdickova L, Brooimans RA, Bumbea H et al. Report of the European Myeloma Network on multiparametric flow cytometry in multiple myeloma and related disorders. Haematologica 2008; 93: 431–438.

    Google Scholar 

  79. Baccarani M, Saglio G, Goldman J, Hochhaus A, Simonsson B, Appelbaum F et al. Evolving concepts in the management of chronic myeloid leukemia: recommendations from an expert panel on behalf of the European LeukemiaNet. Blood 2006; 108: 1809–1820.

    CAS  Google Scholar 

  80. Diverio D, Rossi V, Avvisati G, DeSantis S, Pistilli A, Pane F et al. Early detection of relapse by prospective reverse transcriptase-polymerase chain reaction analysis of the PML/RARalpha fusion gene in patients with acute promyelocytic leukemia enrolled in the GIMEMA-AIEOP multicenter ‘AIDA’ trial. Blood 1998; 92: 784–789.

    CAS  Google Scholar 

  81. Grimwade D, Lo CF . Acute promyelocytic leukemia: a model for the role of molecular diagnosis and residual disease monitoring in directing treatment approach in acute myeloid leukemia. Leukemia 2002; 16: 1959–1973.

    CAS  Google Scholar 

  82. Lo Coco F, Diverio D, Avvisati G, Petti MC, Meloni G, Pogliani EM et al. Therapy of molecular relapse in acute promyelocytic leukemia. Blood 1999; 94: 2225–2229.

    CAS  Google Scholar 

  83. Sanz MA, Grimwade D, Tallman MS, Lowenberg B, Fenaux P, Estey EH et al. Management of acute promyelocytic leukemia: recommendations from an expert panel on behalf of the European LeukemiaNet. Blood 2009; 113: 1875–1891.

    CAS  Google Scholar 

  84. Zur SU, Harms DO, Schluter S, Schrappe M, Goebel U, Spaar H et al. MRD at the end of induction therapy in childhood acute lymphoblastic leukemia: outcome prediction strongly depends on the therapeutic regimen. Leukemia 2001; 15: 283–285.

    Google Scholar 

  85. Willemse MJ, Seriu T, Hettinger K, d’Aniello E, Hop WC, Panzer-Grumayer ER et al. Detection of minimal residual disease identifies differences in treatment response between T-ALL and precursor B-ALL. Blood 2002; 99: 4386–4393.

    CAS  Google Scholar 

  86. Cayuela JM, Beljord K, Preudhomme C, Cave H, Eliahou JF, Auclerc MF et al. Minimal residual disease (MRD) at the end of induction (EOI) after a three or four-drug induction regimen for childhood standard-risk B-cell precursor acute lymphoblastic leukemia (SR-BCP-ALL): interim results of the FRALLE 2000-A protocol. ASH Annual Meeting Abstracts 2004; 104: 1105.

    Google Scholar 

  87. Cayuela JM, Ballerini P, Romeo M, Asnafi V, Auclerc MF, Fund X et al. Evaluation of minimal residual disease (MRD) by quantification of TEL-AML1 transcripts is a powerful prognostic tool in children with T(12;21) positive acute lymphoblastic leukemia (ALL). ASH Annual Meeting Abstracts 2004; 104: 322.

    Google Scholar 

  88. Cimino G, Elia L, Rapanotti MC, Sprovieri T, Mancini M, Cuneo A et al. A prospective study of residual-disease monitoring of the ALL1/AF4 transcript in patients with t(4;11) acute lymphoblastic leukemia. Blood 2000; 95: 96–101.

    CAS  Google Scholar 

  89. Krampera M, Vitale A, Vincenzi C, Perbellini O, Guarini A, Annino L et al. Outcome prediction by immunophenotypic minimal residual disease detection in adult T-cell acute lymphoblastic leukaemia. Br J Haematol 2003; 120: 74–79.

    Google Scholar 

  90. Krampera M, Perbellini O, Vincenzi C, Zampieri F, Pasini A, Scupoli MT et al. Methodological approach to minimal residual disease detection by flow cytometry in adult B-lineage acute lymphoblastic leukemia. Haematologica 2006; 91: 1109–1112.

    Google Scholar 

  91. Vignetti M, Fazi P, Cimino G, Martinelli G, Di RF, Ferrara F et al. Imatinib plus steroids induces complete remissions and prolonged survival in elderly Philadelphia chromosome-positive patients with acute lymphoblastic leukemia without additional chemotherapy: results of the Gruppo Italiano Malattie Ematologiche dell’Adulto (GIMEMA) LAL0201-B protocol. Blood 2007; 109: 3676–3678.

    CAS  Google Scholar 

  92. Björklund E, Matinlauri I, Tierens A, Axelsson S, Forestier E, Jacobsson S et al. Quality control of flow cytometry data analysis for evaluation of minimal residual disease in bone marrow from acute leukemia patients during treatment. J Pediatr Hematol Oncol 2009; 31: 406–415.

    Google Scholar 

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This study was supported in part by the European LeukemiaNet.

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Brüggemann, M., Schrauder, A., Raff, T. et al. Standardized MRD quantification in European ALL trials: Proceedings of the Second International Symposium on MRD assessment in Kiel, Germany, 18–20 September 2008. Leukemia 24, 521–535 (2010). https://doi.org/10.1038/leu.2009.268

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  • DOI: https://doi.org/10.1038/leu.2009.268

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