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Minimal Residual Disease (MRD) Diagnostics: Methodology and Prognostic Significance

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Book cover Childhood Acute Lymphoblastic Leukemia

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Abstract

Monitoring of minimal residual disease (MRD) has become part of routine clinical practice in treatment of childhood acute lymphoblastic leukemia (ALL). MRD measurements have proven to be the strongest independent prognostic factor, allowing for risk-group assignment into different treatment arms, ranging from treatment reduction or intensification. MRD measurements are also guiding treatment decisions in relapsed ALL patients and patients undergoing stem cell transplantation. MRD may also become a surrogate measure of efficacy in new drug studies. And phase III clinical trials, thereby requiring shorter follow-up to answer the study question. MRD techniques need to be sensitive (≤10−4, preferably ≤10−5), broadly applicable, accurate, reliable, fast, and affordable. So far, flow cytometry and PCR analysis of rearranged immunoglobulin and T-cell receptor genes (ASO-PCR) meet these criteria, but standard flow cytometry often does not reliably detect MRD levels below 10−4, whereas ASO-PCR is time-consuming and labor intensive. Therefore two high throughput technologies are being explored; high throughput sequencing and next generation (multidimensional) flow cytometry, both evaluating millions of sequences or cells, respectively. Both have specific advantages and disadvantages, but standardization, external quality assessment, and world-wide availability will become decisive criteria for acceptance.

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References

  1. van Dongen JJ, 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;352:1731–8.

    Article  PubMed  Google Scholar 

  2. 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;339:591–8.

    Article  CAS  PubMed  Google Scholar 

  3. 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;351:550–4.

    Article  CAS  PubMed  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;111:5477–85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Raff T, Gokbuget N, Luschen 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;109:910–5.

    Article  CAS  PubMed  Google Scholar 

  6. Gokbuget N, Kneba M, Raff T, Trautmann H, Bartram CR, Arnold R, et al. Adult patients with acute lymphoblastic leukemia and molecular failure display a poor prognosis and are candidates for stem cell transplantation and targeted therapies. Blood. 2012;120:1868–76.

    Article  PubMed  CAS  Google Scholar 

  7. Ribera JM, Oriol A, Morgades M, Montesinos P, Sarra J, Gonzalez-Campos J, et al. Treatment of high-risk Philadelphia chromosome-negative acute lymphoblastic leukemia in adolescents and adults according to early cytologic response and minimal residual disease after consolidation assessed by flow cytometry: final results of the PETHEMA ALL-AR-03 trial. J Clin Oncol. 2014;32:1595–604.

    Article  CAS  PubMed  Google Scholar 

  8. 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;99:1952–8.

    Article  CAS  PubMed  Google Scholar 

  9. Bruggemann M, Schrauder A, Raff T, Pfeifer H, Dworzak M, Ottmann OG, 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. 2010;24:521–35.

    Article  CAS  PubMed  Google Scholar 

  10. van Dongen JJ, Breit TM, Adriaansen HJ, Beishuizen A, Hooijkaas H. Detection of minimal residual disease in acute leukemia by immunological marker analysis and polymerase chain reaction. Leukemia. 1992;6(Suppl 1):47–59.

    PubMed  Google Scholar 

  11. Szczepanski T, Orfao A, van der Velden VH, San Miguel JF, van Dongen JJ. Minimal residual disease in leukaemia patients. Lancet Oncol. 2001;2:409–17.

    Article  CAS  PubMed  Google Scholar 

  12. van Dongen JJ, van der Velden VH, Bruggemann M, Orfao A. Minimal residual disease diagnostics in acute lymphoblastic leukemia: need for sensitive, fast, and standardized technologies. Blood 2015;125:3996–4009. doi: 10.1182/blood-2015-03-580027. Epub 2015 May 21.

  13. Lucio P, Parreira A, van den Beemd MW, van Lochem EG, van Wering ER, Baars E, et al. Flow cytometric analysis of normal B cell differentiation: a frame of reference for the detection of minimal residual disease in precursor-B-ALL. Leukemia. 1999;13:419–27.

    Article  CAS  PubMed  Google Scholar 

  14. van der Velden VH, 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;21:604–11.

    PubMed  Google Scholar 

  15. 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;74:331–40.

    Article  PubMed  Google Scholar 

  16. Fossat C, Roussel M, Arnoux I, Asnafi V, Brouzes C, Garnache-Ottou F, et al. Methodological aspects of minimal residual disease assessment by flow cytometry in acute lymphoblastic leukemia: a French multicenter study. Cytometry B Clin Cytom. 2015;88:21–9.

    Article  PubMed  Google Scholar 

  17. Yeoh AE, Ariffin H, Chai EL, Kwok CS, Chan YH, Ponnudurai K, et al. Minimal residual disease-guided treatment deintensification for children with acute lymphoblastic leukemia: results from the Malaysia-Singapore acute lymphoblastic leukemia 2003 study. J Clin Oncol. 2012;30:2384–92.

    Article  CAS  PubMed  Google Scholar 

  18. Weng XQ, Shen Y, Sheng Y, Chen B, Wang JH, Li JM, et al. Prognostic significance of monitoring leukemia-associated immunophenotypes by eight-color flow cytometry in adult B-acute lymphoblastic leukemia. Blood Cancer J. 2013;3:e133.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Basso G, Veltroni M, Valsecchi MG, Dworzak MN, Ratei R, Silvestri 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;27:5168–74.

    Article  PubMed  Google Scholar 

  20. Ratei R, Basso G, Dworzak M, Gaipa G, Veltroni M, Rhein P, et al. Monitoring treatment response of childhood precursor B-cell acute lymphoblastic leukemia in the AIEOP-BFM-ALL 2000 protocol with multiparameter flow cytometry: predictive impact of early blast reduction on the remission status after induction. Leukemia. 2009;23:528–34.

    Article  CAS  PubMed  Google Scholar 

  21. Coustan-Smith E, Sandlund JT, Perkins SL, Chen H, Chang M, Abromowitch M, et al. Minimal disseminated disease in childhood T-cell lymphoblastic lymphoma: a report from the children's oncology group. J Clin Oncol. 2009;27:3533–9.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Flohr T, Schrauder A, Cazzaniga G, Panzer-Grumayer R, van der Velden V, Fischer S, 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. 2008;22:771–82.

    Article  CAS  PubMed  Google Scholar 

  23. 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;91:1109–12.

    PubMed  Google Scholar 

  24. d'Auriol L, Macintyre E, Galibert F, Sigaux F. In vitro amplification of T cell gamma gene rearrangements: a new tool for the assessment of minimal residual disease in acute lymphoblastic leukemias. Leukemia. 1989;3:155–8.

    PubMed  Google Scholar 

  25. Yamada M, Hudson S, Tournay O, Bittenbender S, Shane SS, Lange B, et al. Detection of minimal disease in hematopoietic malignancies of the B-cell lineage by using third-complementarity-determining region (CDR-III)-specific probes. Proc Natl Acad Sci U S A. 1989;86:5123–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Hansen-Hagge TE, Yokota S, Bartram CR. Detection of minimal residual disease in acute lymphoblastic leukemia by in vitro amplification of rearranged T-cell receptor delta chain sequences. Blood. 1989;74:1762–7.

    CAS  PubMed  Google Scholar 

  27. Breit TM, Wolvers-Tettero IL, Hahlen K, van Wering ER, van Dongen JJ. Extensive junctional diversity of gamma delta T-cell receptors expressed by T-cell acute lymphoblastic leukemias: implications for the detection of minimal residual disease. Leukemia. 1991;5:1076–86.

    CAS  PubMed  Google Scholar 

  28. Pongers-Willemse MJ, Verhagen OJ, Tibbe GJ, Wijkhuijs AJ, de Haas V, Roovers E, et al. Real-time quantitative PCR for the detection of minimal residual disease in acute lymphoblastic leukemia using junctional region specific TaqMan probes. Leukemia. 1998;12:2006–14.

    Article  CAS  PubMed  Google Scholar 

  29. Brüggemann M, Droese J, Bolz I, Lüth P, Pott C, Von Neuhoff N, et al. Improved assessment of minimal residual disease in B cell malignancies using fluorogenic consensus probes for real-time quantitative PCR. Leukemia. 2000;14:1419–25.

    Article  PubMed  Google Scholar 

  30. Verhagen OJHM, Willemse MJ, Breunis WB, Wijkhuijs AJM, Jacobs DCH, Joosten SA, et al. Application of germline IGH probes in real-time quantitative PCR for the detection of minimal residual disease in acute lymphoblastic leukemia. Leukemia. 2000;14:1426–35.

    Article  CAS  PubMed  Google Scholar 

  31. van der Velden VH, Szczepanski T, Wijkhuijs JM, Hart PG, Hoogeveen PG, Hop WC, et al. Age-related patterns of immunoglobulin and T-cell receptor gene rearrangements in precursor-B-ALL: implications for detection of minimal residual disease. Leukemia. 2003;17:1834–44.

    Article  PubMed  CAS  Google Scholar 

  32. van der Velden VH, Hochhaus A, Cazzaniga G, Szczepanski T, Gabert J, van Dongen JJ. Detection of minimal residual disease in hematologic malignancies by real-time quantitative PCR: principles, approaches, and laboratory aspects. Leukemia. 2003;17:1013–34.

    Article  PubMed  CAS  Google Scholar 

  33. Beishuizen A, Hahlen K, Hagemeijer A, Verhoeven MA, Hooijkaas H, Adriaansen HJ, et al. Multiple rearranged immunoglobulin genes in childhood acute lymphoblastic leukemia of precursor B-cell origin. Leukemia. 1991;5:657–67.

    CAS  PubMed  Google Scholar 

  34. 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;99:2315–23.

    Article  CAS  PubMed  Google Scholar 

  35. 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;17:2149–56.

    Article  CAS  PubMed  Google Scholar 

  36. Beishuizen A, de Bruijn MA, Pongers-Willemse MJ, Verhoeven MA, van Wering ER, Hahlen K, et al. Heterogeneity in junctional regions of immunoglobulin kappa deleting element rearrangements in B cell leukemias: a new molecular target for detection of minimal residual disease. Leukemia. 1997;11:2200–7.

    Article  CAS  PubMed  Google Scholar 

  37. van Dongen JJ, Langerak AW, Bruggemann M, Evans PA, Hummel M, Lavender FL, et al. Design and standardization of PCR primers and protocols for detection of clonal immunoglobulin and T-cell receptor gene recombinations in suspect lymphoproliferations: report of the BIOMED-2 Concerted Action BMH4-CT98-3936. Leukemia. 2003;17:2257–317.

    Article  PubMed  Google Scholar 

  38. Bruggemann M, van der Velden VH, 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;18:709–19.

    Article  CAS  PubMed  Google Scholar 

  39. Szczepanski T, van der Velden VH, Hoogeveen PG, de Bie M, Jacobs DC, van Wering ER, et al. Vdelta2-Jalpha rearrangements are frequent in precursor-B-acute lymphoblastic leukemia but rare in normal lymphoid cells. Blood. 2004;103:3798–804.

    Article  CAS  PubMed  Google Scholar 

  40. van der Velden VH, de Bie M, van Wering ER, van Dongen JJ. Immunoglobulin light chain gene rearrangements in precursor-B-acute lymphoblastic leukemia: characteristics and applicability for the detection of minimal residual disease. Haematologica. 2006;91:679–82.

    PubMed  Google Scholar 

  41. Ciudad J, San Miguel JF, Lopez-Berges MC, Vidriales B, Valverde B, Ocqueteau M, et al. Prognostic value of immunophenotypic detection of minimal residual disease in acute lymphoblastic leukemia. J Clin Oncol. 1998;16:3774–81.

    Article  CAS  PubMed  Google Scholar 

  42. 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;96:2691–6.

    CAS  PubMed  Google Scholar 

  43. Ciudad J, San Miguel JF, Lopez-Berges MC, Garcia Marcos MA, Gonzalez M, Vazquez L, et al. Detection of abnormalities in B-cell differentiation pattern is a useful tool to predict relapse in precursor-B-ALL. Br J Haematol. 1999;104:695–705.

    Article  CAS  PubMed  Google Scholar 

  44. Porwit-MacDonald A, Bjorklund E, Lucio P, van Lochem EG, Mazur J, Parreira A, et al. BIOMED-1 concerted action report: flow cytometric characterization of CD7+ cell subsets in normal bone marrow as a basis for the diagnosis and follow-up of T cell acute lymphoblastic leukemia (T-ALL). Leukemia. 2000;14:816–25.

    Article  CAS  PubMed  Google Scholar 

  45. Ryan J, Quinn F, Meunier A, Boublikova L, Crampe M, Tewari P, et al. Minimal residual disease detection in childhood acute lymphoblastic leukaemia patients at multiple time-points reveals high levels of concordance between molecular and immunophenotypic approaches. Br J Haematol. 2009;144:107–15.

    Article  PubMed  Google Scholar 

  46. Thorn I, Forestier E, Botling J, Thuresson B, Wasslavik C, Bjorklund E, et al. Minimal residual disease assessment in childhood acute lymphoblastic leukaemia: a Swedish multi-centre study comparing real-time polymerase chain reaction and multicolour flow cytometry. Br J Haematol. 2011;152:743–53.

    Article  PubMed  Google Scholar 

  47. Gaipa G, Cazzaniga G, Valsecchi MG, Panzer-Grumayer R, Buldini B, Silvestri D, et al. Time point-dependent concordance of flow cytometry and real-time quantitative polymerase chain reaction for minimal residual disease detection in childhood acute lymphoblastic leukemia. Haematologica. 2012;97:1582–93.

    Article  PubMed  PubMed Central  Google Scholar 

  48. Denys B, van der Sluijs-Gelling AJ, Homburg C, van der Schoot CE, de Haas V, Philippe J, et al. Improved flow cytometric detection of minimal residual disease in childhood acute lymphoblastic leukemia. Leukemia. 2013;27:635–41.

    Article  CAS  PubMed  Google Scholar 

  49. van Lochem EG, Wiegers YM, van den Beemd R, Hahlen K, van Dongen JJ, Hooijkaas H. Regeneration pattern of precursor-B-cells in bone marrow of acute lymphoblastic leukemia patients depends on the type of preceding chemotherapy. Leukemia. 2000;14:688–95.

    Article  PubMed  Google Scholar 

  50. van Wering ER, van der Linden-Schrever BE, Szczepanski T, Willemse MJ, Baars EA, van Wijngaarde-Schmitz HM, et al. Regenerating normal B-cell precursors during and after treatment of acute lymphoblastic leukaemia: implications for monitoring of minimal residual disease. Br J Haematol. 2000;110:139–46.

    Article  PubMed  Google Scholar 

  51. Gabert J, Beillard E, van der Velden VH, Bi W, Grimwade D, Pallisgaard N, et al. Standardization and quality control studies of 'real-time' quantitative reverse transcriptase polymerase chain reaction of fusion gene transcripts for residual disease detection in leukemia – a Europe Against Cancer program. Leukemia. 2003;17:2318–57.

    Article  CAS  PubMed  Google Scholar 

  52. Van Dongen JJM, Macintyre EA, Gabert JA, Delabesse E, Rossi V, Saglio G, et al. Standardized RT-PCR analysis of fusion gene transcripts from chromosome aberrations in acute leukemia for detection of minimal residual disease. Report of the BIOMED-1 Concerted Action: Investigation of minimal residual disease in acute leukemia. Leukemia. 1999;13:1901–28.

    Article  CAS  PubMed  Google Scholar 

  53. Grimwade D, Jovanovic JV, Hills RK, Nugent EA, Patel Y, Flora R, et al. Prospective minimal residual disease monitoring to predict relapse of acute promyelocytic leukemia and to direct pre-emptive arsenic trioxide therapy. J Clin Oncol. 2009;27:3650–8.

    Article  CAS  PubMed  Google Scholar 

  54. Beillard E, Pallisgaard N, van der Velden VH, Bi W, Dee R, van der Schoot E, 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;17:2474–86.

    Article  CAS  PubMed  Google Scholar 

  55. Brisco MJ, Sykes PJ, Hughes E, Dolman G, Neoh SH, Peng LM, et al. Monitoring minimal residual disease in peripheral blood in B-lineage acute lymphoblastic leukaemia. Br J Haematol. 1997;99:314–9.

    Article  CAS  PubMed  Google Scholar 

  56. van der Velden VH, Jacobs DC, Wijkhuijs AJ, Comans-Bitter WM, Willemse MJ, Hahlen 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;16:1432–6.

    Article  PubMed  Google Scholar 

  57. 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;100:2399–402.

    Article  CAS  PubMed  Google Scholar 

  58. van der Velden VH, Hoogeveen PG, Pieters R, van Dongen JJ. Impact of two independent bone marrow samples on minimal residual disease monitoring in childhood acute lymphoblastic leukaemia. Br J Haematol. 2006;133:382–8.

    Article  PubMed  Google Scholar 

  59. van der Velden VH, Panzer-Grumayer ER, Cazzaniga G, Flohr T, Sutton R, Schrauder A, et al. Optimization of PCR-based minimal residual disease diagnostics for childhood acute lymphoblastic leukemia in a multi-center setting. Leukemia. 2007;21:706–13.

    PubMed  Google Scholar 

  60. Panzer-Grumayer ER, Schneider M, Panzer S, Fasching K, Gadner H. Rapid molecular response during early induction chemotherapy predicts a good outcome in childhood acute lymphoblastic leukemia. Blood. 2000;95:790–4.

    CAS  PubMed  Google Scholar 

  61. Sutton R, Venn NC, Tolisano J, Bahar AY, Giles JE, Ashton LJ, et al. Clinical significance of minimal residual disease at day 15 and at the end of therapy in childhood acute lymphoblastic leukaemia. Br J Haematol. 2009;146:292–9.

    Article  CAS  PubMed  Google Scholar 

  62. Conter V, Bartram CR, Valsecchi MG, Schrauder A, Panzer-Grumayer R, Moricke A, et al. Molecular response to treatment redefines all prognostic factors in children and adolescents with B-cell precursor acute lymphoblastic leukemia: results in 3184 patients of the AIEOP-BFM ALL 2000 study. Blood. 2010;115:3206–14.

    Article  CAS  PubMed  Google Scholar 

  63. Schrappe M, Valsecchi MG, Bartram CR, Schrauder A, Panzer-Grumayer R, Moricke A, et al. Late MRD response determines relapse risk overall and in subsets of childhood T-cell ALL: results of the AIEOP-BFM-ALL 2000 study. Blood. 2011;118:2077–84.

    Article  CAS  PubMed  Google Scholar 

  64. Vora A, Goulden N, Wade R, Mitchell C, Hancock J, Hough R, et al. Treatment reduction for children and young adults with low-risk acute lymphoblastic leukaemia defined by minimal residual disease (UKALL 2003): a randomised controlled trial. Lancet Oncol. 2013;14:199–209.

    Article  CAS  PubMed  Google Scholar 

  65. Vora A, Goulden N, Mitchell C, Hancock J, Hough R, Rowntree C, et al. Augmented post-remission therapy for a minimal residual disease-defined high-risk subgroup of children and young people with clinical standard-risk and intermediate-risk acute lymphoblastic leukaemia (UKALL 2003): a randomised controlled trial. Lancet Oncol. 2014;15:809–18.

    Article  PubMed  Google Scholar 

  66. Van der Velden VH, Corral L, Valsecchi MG, Jansen MW, De Lorenzo P, Cazzaniga G, et al. Prognostic significance of minimal residual disease in infants with acute lymphoblastic leukemia treated within the Interfant-99 protocol. Leukemia. 2009;23:1073–9.

    Article  CAS  PubMed  Google Scholar 

  67. Roberts KG, Pei D, Campana D, Payne-Turner D, Li Y, Cheng C, et al. Outcomes of children with BCR-ABL1-like acute lymphoblastic leukemia treated with risk-directed therapy based on the levels of minimal residual disease. J Clin Oncol. 2014;32:3012–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Ravandi F, Jorgensen JL, Thomas DA, O'Brien S, Garris R, Faderl S, et al. Detection of MRD may predict the outcome of patients with Philadelphia chromosome-positive ALL treated with tyrosine kinase inhibitors plus chemotherapy. Blood. 2013;122:1214–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Attarbaschi A, Mann G, Panzer-Grumayer R, Rottgers S, Steiner M, Konig M, et al. Minimal residual disease values discriminate between low and high relapse risk in children with B-cell precursor acute lymphoblastic leukemia and an intrachromosomal amplification of chromosome 21: the Austrian and German acute lymphoblastic leukemia Berlin-Frankfurt-Munster (ALL-BFM) trials. J Clin Oncol. 2008;26:3046–50.

    Article  CAS  PubMed  Google Scholar 

  70. Waanders E, van der Velden VH, van der Schoot CE, van Leeuwen FN, van Reijmersdal SV, de Haas V, et al. Integrated use of minimal residual disease classification and IKZF1 alteration status accurately predicts 79% of relapses in pediatric acute lymphoblastic leukemia. Leukemia. 2011;25:254–8.

    Article  CAS  PubMed  Google Scholar 

  71. van der Velden VH, van Dongen JJMRD. detection in acute lymphoblastic leukemia patients using Ig/TCR gene rearrangements as targets for real-time quantitative PCR. Methods Mol Biol. 2009;538:115–50.

    Article  PubMed  CAS  Google Scholar 

  72. Pieters R, de Groot-Kruseman H, Van der Velden V, Fiocco M, van den Berg H, de Bont E, et al. Successful therapy reduction and intensification for childhood acute lymphoblastic leukemia based on minimal residual disease monitoring: study ALL10 from the Dutch Childhood Oncology Group. J Clin Oncol. 2016.

    Google Scholar 

  73. 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;358:1239–41.

    Article  CAS  PubMed  Google Scholar 

  74. 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;102:860–71.

    Article  CAS  PubMed  Google Scholar 

  75. Krejci O, van der Velden VH, Bader P, Kreyenberg H, Goulden N, Hancock J, et al. Level of minimal residual disease prior to haematopoietic stem cell transplantation predicts prognosis in paediatric patients with acute lymphoblastic leukaemia: a report of the Pre-BMT MRD Study Group. Bone Marrow Transplant. 2003;32:849–51.

    Article  CAS  PubMed  Google Scholar 

  76. Schlegel P, Lang P, Zugmaier G, Ebinger M, Kreyenberg H, Witte KE, et al. Pediatric posttransplant relapsed/refractory B-precursor acute lymphoblastic leukemia shows durable remission by therapy with the T-cell engaging bispecific antibody blinatumomab. Haematologica. 2014;99:1212–9.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  77. Bader P, Kreyenberg H, Henze GH, 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;27:377–84.

    Article  PubMed  Google Scholar 

  78. Bader P, Kreyenberg H, von Stackelberg A, Eckert C, Salzmann-Manrique E, Meisel R, et al. Monitoring of minimal residual disease after allogeneic stem-cell transplantation in relapsed childhood acute lymphoblastic leukemia allows for the identification of impending relapse: results of the ALL-BFM-SCT 2003 trial. J Clin Oncol. 2015;33:1275–84.

    Article  CAS  PubMed  Google Scholar 

  79. Lankester AC, Bierings MB, van Wering ER, Wijkhuijs AJ, de Weger RA, Wijnen JT, et al. Preemptive alloimmune intervention in high-risk pediatric acute lymphoblastic leukemia patients guided by minimal residual disease level before stem cell transplantation. Leukemia. 2010;24:1462–9.

    Article  CAS  PubMed  Google Scholar 

  80. Eckert C, Hagedorn N, Sramkova L, Mann G, Panzer-Grumayer R, Peters C, et al. Monitoring minimal residual disease in children with high-risk relapses of acute lymphoblastic leukemia: Prognostic relevance of early and late assessment. Leukemia. 2015:epub ahead of print.

    Google Scholar 

  81. Eckert C, Henze G, Seeger K, Hagedorn N, Mann G, Panzer-Grumayer R, et al. Use of allogeneic hematopoietic stem-cell transplantation based on minimal residual disease response improves outcomes for children with relapsed acute lymphoblastic leukemia in the intermediate-risk group. J Clin Oncol. 2013;31:2736–42.

    Article  PubMed  Google Scholar 

  82. Grupp SA, Kalos M, Barrett D, Aplenc R, Porter DL, Rheingold SR, et al. Chimeric antigen receptor-modified T cells for acute lymphoid leukemia. N Engl J Med. 2013;368:1509–18.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Topp MS, Kufer P, Gokbuget N, Goebeler M, Klinger M, Neumann S, et al. Targeted therapy with the T-cell-engaging antibody blinatumomab of chemotherapy-refractory minimal residual disease in B-lineage acute lymphoblastic leukemia patients results in high response rate and prolonged leukemia-free survival. J Clin Oncol. 2011;29:2493–8.

    Article  CAS  PubMed  Google Scholar 

  84. Kebriaei P, Wilhelm K, Ravandi F, Brandt M, de Lima M, Ciurea S, et al. Feasibility of allografting in patients with advanced acute lymphoblastic leukemia after salvage therapy with inotuzumab ozogamicin. Clin Lymphoma Myeloma Leuk. 2013;13:296–301.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Topp MS, Gokbuget N, Stein AS, Zugmaier G, O'Brien S, Bargou RC, et al. Safety and activity of blinatumomab for adult patients with relapsed or refractory B-precursor acute lymphoblastic leukaemia: a multicentre, single-arm, phase 2 study. Lancet Oncol. 2015;16:57–66.

    Article  CAS  PubMed  Google Scholar 

  86. Jabbour E, O’Brien S, Ravandi F, Kantarjian H. Monoclonal antibodies in acute lymphoblastic leukemia. Blood 2015;125:4010–4016. doi: 10.1182/blood-2014-08-596403. Epub 2015 May 21.

  87. Maus MV, Grupp SA, Porter DL, June CH. Antibody-modified T cells: CARs take the front seat for hematologic malignancies. Blood 2014;123:2625–2635. doi: 10.1182/blood-2013-11-492231. Epub 2014 Feb 27.

  88. Appelbaum FR, Rosenblum D, Arceci RJ, Carroll WL, Breitfeld PP, Forman SJ, et al. End points to establish the efficacy of new agents in the treatment of acute leukemia. Blood. 2007;109:1810–6.

    Article  CAS  PubMed  Google Scholar 

  89. Schultz FW, van Dongen JJM, Hählen K, Hagenbeek A. Time-history of the malignant population in the peripheral blood of a child with T-cell acute lymphoblastic leukemia. A pilot study. Comput Math Appl. 1989;18:929–36.

    Article  Google Scholar 

  90. Costa ES, Pedreira CE, Barrena S, Lecrevisse Q, Flores J, Quijano S, et al. Automated pattern-guided principal component analysis vs expert-based immunophenotypic classification of B-cell chronic lymphoproliferative disorders: a step forward in the standardization of clinical immunophenotyping. Leukemia. 2010;24:1927–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Pedreira CE, Costa ES, Lecrevisse Q, van Dongen JJ, Orfao A, EuroFlow C. Overview of clinical flow cytometry data analysis: recent advances and future challenges. Trends Biotechnol. 2013;31:415–25.

    Article  CAS  PubMed  Google Scholar 

  92. van Dongen JJ, Lhermitte L, Bottcher S, Almeida J, van der Velden VH, Flores-Montero J, et al. EuroFlow antibody panels for standardized n-dimensional flow cytometric immunophenotyping of normal, reactive and malignant leukocytes. Leukemia. 2012;26:1908–75.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  93. Kalina T, Flores-Montero J, van der Velden VH, Martin-Ayuso M, Bottcher S, Ritgen M, et al. EuroFlow standardization of flow cytometer instrument settings and immunophenotyping protocols. Leukemia. 2012;26:1986–2010.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Kalina T, Flores-Montero J, Lecrevisse Q, Pedreira CE, van der Velden VH, Novakova M, et al. Quality assessment program for EuroFlow protocols: summary results of four-year (2010–2013) quality assurance rounds. Cytometry A. 2015;87:145–56.

    Article  PubMed  Google Scholar 

  95. 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  PubMed  Google Scholar 

  96. 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;19:1845–7.

    Article  PubMed  Google Scholar 

  97. Dworzak MN, Gaipa G, Schumich A, Maglia O, Ratei R, Veltroni M, et al. Modulation of antigen expression in B-cell precursor acute lymphoblastic leukemia during induction therapy is partly transient: evidence for a drug-induced regulatory phenomenon. Results of the AIEOP-BFM-ALL-FLOW-MRD-Study Group. Cytometry B Clin Cytom. 2010;78:147–53.

    PubMed  Google Scholar 

  98. Slamova L, Starkova J, Fronkova E, Zaliova M, Reznickova L, van Delft FW, et al. CD2-positive B-cell precursor acute lymphoblastic leukemia with an early switch to the monocytic lineage. Leukemia. 2014;28:609–20.

    Article  CAS  PubMed  Google Scholar 

  99. Gardner R, Wu D, Cherian S, Fang M, Hanafi LA, Finney O, et al. Acquisition of a CD19-negative myeloid phenotype allows immune escape of MLL-rearranged B-ALL from CD19 CAR-T-cell therapy. Blood 2016;127:2406–2410. doi: 10.1182/blood-2015-08-665547. Epub 2016 Feb 23.

  100. Oliveira E, Bacelar TS, Ciudad J, Ribeiro MC, Garcia DR, Sedek L, et al. Altered neutrophil immunophenotypes in childhood Bcell precursor acute lymphoblastic leukemia. Oncotarget. 2016;25.

    Google Scholar 

  101. Boyd SD, Marshall EL, Merker JD, Maniar JM, Zhang LN, Sahaf B, et al. Measurement and clinical monitoring of human lymphocyte clonality by massively parallel VDJ pyrosequencing. Sci Transl Med. 2009;1:12ra23.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  102. Faham M, Zheng J, Moorhead M, Carlton VE, Stow P, Coustan-Smith E, et al. Deep-sequencing approach for minimal residual disease detection in acute lymphoblastic leukemia. Blood. 2012;120:5173–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Robins HS, Campregher PV, Srivastava SK, Wacher A, Turtle CJ, Kahsai O, et al. Comprehensive assessment of T-cell receptor beta-chain diversity in alphabeta T cells. Blood. 2009;114:4099–107.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. 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;42:187–96.

    Article  CAS  PubMed  Google Scholar 

  105. van der Velden VH, Wijkhuijs JM, van Dongen JJ. Non-specific amplification of patient-specific Ig/TCR gene rearrangements depends on the time point during therapy: implications for minimal residual disease monitoring. Leukemia. 2008;22:641–4.

    Article  PubMed  CAS  Google Scholar 

  106. Gawad C, Pepin F, Carlton VE, Klinger M, Logan AC, Miklos DB, et al. Massive evolution of the immunoglobulin heavy chain locus in children with B precursor acute lymphoblastic leukemia. Blood. 2012;120:4407–17.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Kotrova M, Muzikova K, Mejstrikova E, Novakova M, Bakardjieva-Mihaylova V, Fiser K, et al. The predictive strength of next-generation sequencing MRD detection for relapse compared with current methods in childhood ALL. Blood. 2015;126:1045–7. doi:10.1182/blood-2015-07-655159.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Ladetto M, Bruggemann M, Monitillo L, Ferrero S, Pepin F, Drandi D, et al. Next-generation sequencing and real-time quantitative PCR for minimal residual disease detection in B-cell disorders. Leukemia. 2014;28:1299–307.

    Article  CAS  PubMed  Google Scholar 

  109. Logan AC, Vashi N, Faham M, Carlton V, Kong K, Buno I, et al. Immunoglobulin and T cell receptor gene high-throughput sequencing quantifies minimal residual disease in acute lymphoblastic leukemia and predicts post-transplantation relapse and survival. Biol Blood Marrow Transplant. 2014;20:1307–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Wu D, Sherwood A, Fromm JR, Winter SS, Dunsmore KP, Loh ML, et al. High-throughput sequencing detects minimal residual disease in acute T lymphoblastic leukemia. Sci Transl Med. 2012;4:134ra63.

    Article  PubMed  CAS  Google Scholar 

  111. van Dongen JJM, Hooijkaas H, Adriaansen HJ, Hahlen K, van Zanen GE. Detection of minimal residual acute lymphoblastic leukemia by immunological marker analysis: possibilities and limitations. In: Hagenbeek A, Löwenberg B, editors. Minimal residual disease in acute leukemia. Dordrecht: Springer; 1986. p. 113–33.

    Google Scholar 

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Acknowledgments

The authors thank their colleagues of the EuroClonality, EuroMRD, and EuroFlow consortia for their fruitful collaboration and collective actions to innovate, standardize and disseminate the collective achievements in the field of MRD diagnostics. These achievements form the basis for this review. Marieke Bitter is thanked for the design of the figures and Bibi van Bodegom for her secretarial support.

Authorship

All four authors (JJMvD, VHJvdV, MB, and AO) have contributed to the writing of the invited review and to the design of the figures and the tables.

Conflict-of-Interest

The authors are members of EuroMRD (JJMvD, VHJvdV, and MB), EuroFlow (JJMvD, AO, and VHJvdV) and EuroClonality (JJMvD and MB). These consortia are scientifically independent organizations, which collectively own intellectual property (IP), including patents. Revenues from licensed IP and patents are collectively owned by the three above mentioned consortia and are fully used for sustainability of these consortia, such as for covering costs for scientific meetings, reagents, and management support as well as for educational materials, which are distributed upon request free-of-charge. BD Biosciences provides support for part of the external EuroFlow educational meetings and workshops, including part of the travelling costs (JJMvD and AO).

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Authors and Affiliations

  1. Department of Immunohematology and Blood Transfusion, Leiden University Medical Center LUMC, Albinusdreef 2, 2333, ZA, Leiden, The Netherlands

    J. J. M. van Dongen MD, PhD

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

    J. J. M. van Dongen MD, PhD & V. H. J. van der Velden

  3. Department of Hematology, University Hospital Schleswig Holstein, Campus Kiel (UNIKIEL), Kiel, DE, Germany

    M. Brüggemann

  4. Department of Medicine, Cancer Research Center (IBMCC-CSIC-USAL) and Cytometry Service (NUCLEUS), University of Salamanca (USAL) and IBSAL, Salamanca, ES, Spain

    A. Orfao

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  1. J. J. M. van Dongen MD, PhD
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  2. V. H. J. van der Velden
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  3. M. Brüggemann
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  4. A. Orfao
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Corresponding author

Correspondence to J. J. M. van Dongen MD, PhD .

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Editors and Affiliations

  1. Department of Paediatric Haemotology, Sheffield Children’s Hospital NHS Trust, University of Sheffield, Sheffield, South Yorkshire, United Kingdom

    Ajay Vora

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van Dongen, J.J.M., van der Velden, V.H.J., Brüggemann, M., Orfao, A. (2017). Minimal Residual Disease (MRD) Diagnostics: Methodology and Prognostic Significance. In: Vora, A. (eds) Childhood Acute Lymphoblastic Leukemia. Springer, Cham. https://doi.org/10.1007/978-3-319-39708-5_6

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