Skip to main content
SpringerLink
Log in

Minimal residual disease in acute lymphoblastic leukemia: optimal methods and clinical relevance, pitfalls and recent approaches

  • Review
  • Published:
Medical Oncology Aims and scope Submit manuscript

Abstract

After advances in experimental and clinical testing, minimal residual disease (MRD) assay results are considered a determining factor in treatment of acute lymphoblastic leukemia patients. According to MRD assay results, bone marrow (BM) leukemic burden and the rate of its decline after treatment can be directly evaluated. Detailed knowledge of the leukemic burden in BM can minimize toxicity and treatment complications in patients by tailoring the therapeutic dose based on patients’ conditions. In addition, reduction of MRD before allo-HSCT is an important prerequisite for reception of transplant by the patient. In direct examination of MRD by morphological methods (even by a professional hematologist), leukemic cells can be under- or over-estimated due to similarity with hematopoietic precursor cells. As a result, considering the importance of MRD, it is necessary to use other methods including flow cytometry, polymerase chain reaction (PCR) amplification and RQ-PCR to detect MRD. Each of these methods has its own advantages and disadvantages in terms of accuracy and sensitivity. In this review article, different MRD assay methods and their sensitivity, correlation of MRD assay results with clinical symptoms of the patient as well as pitfalls in results of these methods are evaluated. In the final section, recent advances in MRD have been addressed.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. 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(4):1253–8.

    Article  PubMed  CAS  Google Scholar 

  2. Campana D. Determination of minimal residual disease in leukaemia patients. Br J Haematol. 2003;121(6):823–38.

    Article  PubMed  Google Scholar 

  3. Szczepański T, van der Velden VH, van Dongen JJ. Flow-cytometric immunophenotyping of normal and malignant lymphocytes. Clin Chem Lab Med. 2006;44(7):775–96.

    PubMed  Google Scholar 

  4. Cazzaniga G, Biondi A. Molecular monitoring of childhood acute lymphoblastic leukemia using antigen receptor gene rearrangements and quantitative polymerase chain reaction technology. Haematologica. 2005;90(3):382–90.

    PubMed  CAS  Google Scholar 

  5. Hoelzer D, Gokbuget N, Ottmann O, Pui C-H, Relling MV, Appelbaum FR, et al. Acute lymphoblastic leukemia. Hematology. 2002;2002(1):162–92.

    Article  Google Scholar 

  6. Bunin N, Johnston DA, Roberts WM, Ouspenskaia MV, Papusha VZ, Brandt MA, et al. Residual leukaemia after bone marrow transplant in children with acute lymphoblastic leukaemia after first haematological relapse or with poor initial presenting features. Br J Haematol. 2003;120(4):711–5.

    Article  PubMed  Google Scholar 

  7. Cazzaniga G, Gaipa G, Rossi V, Biondi A. Minimal residual disease as a surrogate marker for risk assignment to ALL patients. Rev Clin Exp Hematol. 2003;7(3):292–323.

    PubMed  CAS  Google Scholar 

  8. Hoelzer D. Monitoring and managing minimal residual disease in acute lymphoblastic leukemia. Am Soc Clin Oncol Educ Book. 2013;33:290–3.

    Article  Google Scholar 

  9. Van der Velden V, Joosten S, Willemse M, Van Wering E, Lankester A, Van Dongen J, et al. Real-time quantitative PCR for detection of minimal residual disease before allogeneic stem cell transplantation predicts outcome in children with acute lymphoblastic leukemia. Leukemia. 2001;15(9):1485.

    Article  PubMed  Google Scholar 

  10. Bader P, Hancock J, Kreyenberg H, Goulde N, Niethammer D, Oakhill A, et al. Minimal residual disease (MRD) status prior to allogeneic stem cell transplantation is a powerful predictor for post-transplant outcome in children with ALL. Leukemia (08876924). 2002;16(9):1668–72.

    Article  CAS  Google Scholar 

  11. Lankester AC, Bierings M, Van Wering E, Wijkhuijs A, de Weger R, Wijnen J, 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(8):1462–9.

    Article  PubMed  CAS  Google Scholar 

  12. Yeoh AEJ, Ariffin H, Chai ELL, Kwok CSN, 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(19):2384–92.

    Article  PubMed  CAS  Google Scholar 

  13. Van der Velden V, Hochhaus A, Cazzaniga G, Szczepanski T, Gabert J, Van Dongen J. Detection of minimal residual disease in hematologic malignancies by real-time quantitative PCR: principles, approaches, and laboratory aspects. Leukemia. 2003;17(6):1013–34.

    Article  PubMed  Google Scholar 

  14. van Dongen J. 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 

  15. Lankester A, Bierings M, van Wering E, Wijkhuijs A, de Weger R, Wijnen J, et al. Preemptive alloimmune intervention in high-risk pediatric acute lymphoblastic leukemia patients guided by minimal residual disease level before stem cell transplantation. Leukemia (08876924). 2010;24(8):1462–9.

    Article  CAS  Google Scholar 

  16. Flohr T, Schrauder A, Cazzaniga G, Panzer-Grümayer 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(4):771–82.

    Article  PubMed  CAS  Google Scholar 

  17. 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(18):4153–62.

    Article  PubMed  CAS  Google Scholar 

  18. Brüggemann M, Schrauder A, Raff T, Pfeifer H, Dworzak M, Ottmann O, 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(3):521–35.

    Article  PubMed  Google Scholar 

  19. Caye A, Beldjord K, Mass-Malo K, Drunat S, Soulier J, Gandemer V, et al. Breakpoint-specific multiplex polymerase chain reaction allows the detection of IKZF1 intragenic deletions and minimal residual disease monitoring in B-cell precursor acute lymphoblastic leukemia. Haematologica. 2013;98(4):597–601.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  20. Van der Velden V, Cazzaniga G, Schrauder A, Hancock J, Bader P, Panzer-Grumayer E, et al. Analysis of minimal residual disease by Ig/TCR gene rearrangements: guidelines for interpretation of real-time quantitative PCR data. Leukemia. 2007;21(4):604–11.

    PubMed  CAS  Google Scholar 

  21. 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. Cytom Part B Clin Cytom. 2008;74(6):331–40.

    Article  Google Scholar 

  22. 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 (08876924). 2000;14(8):1419–25.

    Article  Google Scholar 

  23. Szczepański T. WillemseM, Van Wering E, Van Weerden J, Kamps W, Van Dongen J. Precursor-B-ALL with D H-J H gene rearrangements have an immature immunogenotype with a high frequency of oligoclonality and hyperdiploidy of chromosome 14. Leukemia (08876924). 2001;15(9):1415–23.

    Article  Google Scholar 

  24. Peham M, Panzer S, Fasching K, Haas OA, Fischer S, Marschalek R, et al. Low frequency of clonotypic Ig and T‐cell receptor gene rearrangements in t (4; 11) infant acute lymphoblastic leukaemia and its implication for the detection of minimal residual disease. Br J Haematol. 2002;117(2):315–21.

    Article  PubMed  CAS  Google Scholar 

  25. Szczepański T, Flohr T, van der Velden VH, Bartram CR, van Dongen JJ. Molecular monitoring of residual disease using antigen receptor genes in childhood acute lymphoblastic leukaemia. Best Pract Res Clin Haematol. 2002;15(1):37–57.

    Article  PubMed  Google Scholar 

  26. Van der Velden V, Willemse M, Van der Schoot C, Hählen K, Van Wering E, Van Dongen J. Immunoglobulin kappa deleting element rearrangements in precursor-B acute lymphoblastic leukemia are stable targetsfor detection of minimal residual disease by real-time quantitative PCR. Leukemia (08876924). 2002;16(5):928–36.

    Article  Google Scholar 

  27. Beishuizen A, Verhoeven MA, Mol EJ, van Dongen JJ. Detection of immunoglobulin kappa light-chain gene rearrangement patterns by Southern blot analysis. Leukemia. 1994; 8(12):2228–36; discussion 37–9.

  28. Van der Velden V, Wijkhujis J, Jacobs D, Van Wering E, Van Dongen J. 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 (08876924). 2002;16(7):1372–80.

    Article  Google Scholar 

  29. Meleshko A, Lipay N, Stasevich I, Potapnev M. Rearrangements of IgH, TCRD and TCRG genes as clonality marker of childhood acute lymphoblastic leukemia. Exp Oncol. 2005;27(4):319–24.

    PubMed  CAS  Google Scholar 

  30. Szczepański T, Langerak A, Willemse M, Wolvers-Tettero I, Van Wering E, Van Dongen J. T cell receptor gamma (TCRG) gene rearrangements in T cell acute lymphoblastic leukemia reflect ‘end-stage’recombinations: implications for minimal residual disease monitoring. Leukemia (08876924). 2000;14(7):1208–14.

    Article  Google Scholar 

  31. Moreau E, Langerak A, van Gastel-Mol E, Wolvers-Tettero I, Zhan M, Zhou Q, et al. Easy detection of all T cell receptor gamma (TCRG) gene rearrangements by Southern blot analysis: recommendations for optimal results. Leukemia (08876924). 1999;13(10):1620–6.

    Article  CAS  Google Scholar 

  32. Van Dongen J, Langerak A, Brüggemann M, Evans P, Hummel M, Lavender F, 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(12):2257–317.

    Article  PubMed  Google Scholar 

  33. 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(8):1109–12.

    PubMed  Google Scholar 

  34. 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(12):5477–85.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  35. 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(31):5168–74.

    Article  PubMed  Google Scholar 

  36. Dworzak M. Prognostic significance and modalities of flow cytometric minimal residual disease detection in childhood acute lymphoblastic leukemia. Blood. 2002;99:1952–8.

    Article  PubMed  CAS  Google Scholar 

  37. Lucio P, Gaipa G, Van Lochem E, Van Wering E, Porwit-MacDonald A, Faria T, et al. BIOMED-1 concerted action report: flow cytometric immunophenotyping of precursor B-ALL with standardized triple-stainings. Leukemia (08876924). 2001;15(8):1185–92.

    Article  CAS  Google Scholar 

  38. Dworzak M, Fröschl G, Printz D, De Zen L, Gaipa G, Ratei R, et al. CD99 expression in T-lineage ALL: implications for flow cytometric detection of minimal residual disease. Leukemia. 2004;18(4):703–8.

    Article  PubMed  CAS  Google Scholar 

  39. Dworzak M, Fritsch G, Fleischer C, Printz D, Fröschl G, Buchinger P, et al. Comparative phenotype mapping of normal vs. malignant pediatric B-lymphopoiesis unveils leukemia-associated aberrations. Exp Hematol. 1998;26(4):305–13.

    PubMed  CAS  Google Scholar 

  40. Campana D, Coustan-Smith E. Detection of minimal residual disease in acute leukemia by flow cytometry. Cytometry. 1999;38(4):139–52.

    Article  PubMed  CAS  Google Scholar 

  41. Weir E, Cowan K, LeBeau P, Borowitz M. A limited antibody panel can distinguish B-precursor acute lymphoblastic leukemia from normal B precursors with four color flow cytometry: implications for residual disease detection. Leukemia (08876924). 1999;13(4):558–67.

    Article  CAS  Google Scholar 

  42. 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(11):1245–52.

    PubMed  Google Scholar 

  43. 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(8):2691–6.

    PubMed  CAS  Google Scholar 

  44. Assumpcao JG, Paula FDF, Xavier SG, Murao M, Aguirre Neto JCd, Dutra AP, et al. Gene rearrangement study for minimal residual disease monitoring in children with acute lymphocytic leukemia. Revist Brasileira De Hematol E Hemoter. 2013;35(5):337–42.

    Article  Google Scholar 

  45. Dworzak MN, Panzer-Grümayer ER. Flow cytometric detection of minimal residual disease in acute lymphoblastic leukemia. Leuk Lymphoma. 2003;44(9):1445–55.

    Article  PubMed  Google Scholar 

  46. De Haas V, Verhagen O, von dem Borne A, Kroes W, Van Den Berg H, Van Der Schoot C. Quantification of minimal residual disease in children with oligoclonal B-precursor acute lymphoblastic leukemia indicates that the clones that grow out during relapse already have the slowest rate of reduction during induction therapy. Leukemia. 2001;15(1):134–40.

  47. 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(1):52–8.

    Article  PubMed  CAS  Google Scholar 

  48. Conter V, Bartram CR, Valsecchi MG, Schrauder A, Panzer-Grümayer R, Möricke 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(16):3206–14.

    Article  PubMed  CAS  Google Scholar 

  49. Schrappe M, Valsecchi MG, Bartram CR, Schrauder A, Panzer-Grümayer R, Möricke 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(8):2077–84.

    Article  PubMed  CAS  Google Scholar 

  50. Zhou J, Goldwasser MA, Li A, Dahlberg SE, Neuberg D, Wang H, et al. Quantitative analysis of minimal residual disease predicts relapse in children with B-lineage acute lymphoblastic leukemia in DFCI ALL Consortium Protocol 95-01. Blood. 2007;110(5):1607–11.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  51. 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(7):2399–402.

    Article  PubMed  CAS  Google Scholar 

  52. Borowitz MJ, Pullen DJ, Winick N, Martin PL, Bowman WP, Camitta B. Comparison of diagnostic and relapse flow cytometry phenotypes in childhood acute lymphoblastic leukemia: implications for residual disease detection: a report from the children’s oncology group. Cytom Part B Clin Cytom. 2005;68(1):18–24.

    Article  Google Scholar 

  53. 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(1):49–56.

    PubMed  CAS  Google Scholar 

  54. Pui C-H, Evans WE. Treatment of acute lymphoblastic leukemia. N Engl J Med. 2006;354(2):166–78.

    Article  PubMed  CAS  Google Scholar 

  55. 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 Jun 15;111(12):5477-85.

  56. Flohr T, Schrauder A, Cazzaniga G, Panzer-Grümayer 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(4):771–82.

    Article  PubMed  CAS  Google Scholar 

  57. van Dongen JJ, Seriu T, Panzer-Grümayer ER, Biondi A, Pongers-Willemse MJ, Corral L, et al. Prognostic value of minimal residual disease in acute lymphoblastic leukaemia in childhood. The Lancet. 1998;352(9142):1731–8.

    Article  Google Scholar 

  58. 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(1):107–15.

    Article  PubMed  Google Scholar 

  59. Basso G, Veltroni M, Grazia Valsecchi M, Dworzak MN, Ratei R, D Silvestri, 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(31):5168–74.

    Article  PubMed  Google Scholar 

  60. Guggemos A, Eckert C, Szczepanski T, Hanel C, Taube T, van der Velden V, et al. Assessment of clonal stability of minimal residual disease targets between 1st and 2nd relapse of childhood precursor B-cell acute lymphoblastic leukemia. Haematologica. 2003;88(7):737–46.

    PubMed  CAS  Google Scholar 

  61. 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(22):4407–17.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  62. Nyvold C. Precise quantification of minimal residual disease at day 29 allows identification of children with acute lymphoblastic leukemia and anexcellent outcome. Blood. 2002;99:1253–8.

    Article  PubMed  CAS  Google Scholar 

  63. Cazzaniga G, Biondi A. Molecular monitoring of minimal residual disease. Treatment of acute leukemias. Berlin: Springer; 2003. p. 537–47.

    Google Scholar 

  64. Borowitz M, Pullen D, Winick N, Martin P, Bowman W, Camitta B. Comparisonof diagnostic and relapse flow cytometry phenotypes in childhood acute lymphoblastic leukemia: implications for residual disease detection: a report from the children’s oncology group. Cytom Part B Clin Cytom. 2005;68(1):18–24.

    Article  Google Scholar 

  65. Dworzak M, Fritsch G, Fleischer C, Printz D, Fröschl G, Buchinger P, et al. Multiparameter phenotype mapping of normal and post-chemotherapy B lymphopoiesis in pediatric bone marrow. Leukemia (08876924). 1997;11(8):1266–73.

    Article  CAS  Google Scholar 

  66. McKenna RW, Washington LT, Aquino DB, Picker LJ, Kroft SH. Immunophenotypic analysis of hematogones (B-lymphocyte precursors) in 662 consecutive bone marrow specimens by 4-color flow cytometry. Blood. 2001;98(8):2498–507.

    Article  PubMed  CAS  Google Scholar 

  67. Rhein P, Mitlohner R, Basso G, Gaipa G, Dworzak MN, Kirschner-Schwabe R, et al. CD11b is a therapy resistance-and minimal residual disease—specific marker in precursor B-cell acute lymphoblastic leukemia. Blood. 2010;115(18):3763–71.

    Article  PubMed  CAS  Google Scholar 

  68. DiGiuseppe JA, Fuller SG, Borowitz MJ. Overexpression of CD49f in precursor B-cell acute lymphoblastic leukemia: Potential usefulness in minimal residual disease detection. Cytom Part B Clin Cytom. 2009;76(2):150–5.

    Article  Google Scholar 

  69. Muzzafar T, Medeiros LJ, Wang SA, Brahmandam A, Thomas DA, Jorgensen JL. Aberrant underexpression of CD81 in precursor B-cell acute lymphoblastic leukemia utility in detection of minimal residual disease by flow cytometry. Am J Clin Pathol. 2009;132(5):692–8.

    Article  PubMed  Google Scholar 

  70. Neale G, Coustan-Smith E, Stow P, Pan Q, Chen X, Pui C, 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(5):934–8.

    Article  PubMed  CAS  Google Scholar 

  71. Van der Velden V, Szczepanski T, Wijkhuijs J, Hart P, Hoogeveen P, Hop W, 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(9):1834–44.

    Article  PubMed  Google Scholar 

  72. Malec M, Van der Velden V, Björklund E, Wijkhuijs J, Söderhäll 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(10):1630–6.

    Article  PubMed  CAS  Google Scholar 

  73. Van der Velden V, Panzer-Grümayer E, 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(4):706–13.

    PubMed  Google Scholar 

  74. Aricò M, Valsecchi MG, Rizzari C, Barisone E, Biondi A, Casale F, et al. Long-term results of the AIEOP-ALL-95 trial for childhood acute lymphoblastic leukemia: insight on the prognostic value of DNA index in the framework of berlin-frankfurt-muenster-based chemotherapy. J Clin Oncol. 2008;26(2):283–9.

    Article  PubMed  Google Scholar 

  75. 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(6):870–4.

    Article  PubMed  PubMed Central  Google Scholar 

  76. Klein O, Schmidt C, Knights A, Davis ID, Chen W, Cebon J. Melanoma vaccines: developments over the past 10 years. Expert Rev Vaccines. 2011;10(6):853–73.

  77. Van Dongen J, Macintyre E, Gabert J, 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. Leukemia (08876924). 1999;13(12):1901–28.

    Article  Google Scholar 

  78. Luria D, Rosenthal E, Steinberg D, Kodman Y, Safanaiev M, Amariglio N, et al. Prospective comparison of two flow cytometry methodologies for monitoring minimal residual disease in a multicenter treatment protocol of childhood acute lymphoblastic leukemia. Cytom Part B Clin Cytom. 2010;78(6):365–71.

    Article  Google Scholar 

  79. Robillard N, Cavé H, Méchinaud F, Guidal C, Garnache-Ottou F, Rohrlich PS, et al. Four-color flow cytometry bypasses limitations of IG/TCR polymerase chain reaction for minimal residual disease detection in certain subsets of children with acute lymphoblastic leukemia. Haematologica. 2005;90(11):1516–23.

    PubMed  CAS  Google Scholar 

  80. Gaipa G, Cazzaniga G, Valsecchi MG, Panzer-Grümayer R, Buldini B, Silvestri D, et al. Time point-dependent concordance of flow cytometry and RQ-PCR in minimal residual disease detection in childhood acute lymphoblastic leukemia. Haematologica. 2012: Haematologica. 2011.060426

  81. Van der Velden V, Wijkhuijs J, Van Dongen J. 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(3):641–4.

    Article  PubMed  Google Scholar 

  82. Campana D, Neale G, Coustan-Smith E, Pui C. Detection of minimal residual disease in acute lymphoblastic leukemia: the St Jude experience. Leukemia. 2001;15(2):278–9.

    Article  PubMed  CAS  Google Scholar 

  83. Poopak B, Saki N, Purfatholah AA, Najmabadi H, Mortazavi Y, Arzanian MT, et al. Pattern of immunoglobulin and T-cell receptor-δ/γ gene rearrangements in Iranian children with B-precursor acute lymphoblastic leukemia. Hematology. 2013.

  84. Germano GD, Del Giudice L, Palatron S, Giarin E, Cazzaniga G, Biondi A, et al. Clonality profile in relapsed precursor-B-ALL children by genescan and sequencing analyses. Consequences on minimal residual disease monitoring. Leukemia. 2003;17(8):1573–82.

    Article  PubMed  CAS  Google Scholar 

  85. 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(26):5173–80.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  86. 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(12):12ra23.

  87. Orfao A, Schmitz G, Brando B, Ruiz-Arguelles A, Basso G, Braylan R, et al. Clinically useful information provided by the flow cytometric immunophenotyping of hematological malignancies: current status and future directions. Clin Chem. 1999;45(10):1709.

    Google Scholar 

Download references

Acknowledgments

We wish to thank all our colleagues in Shafa Hospital and Allied Health Sciences School, Ahvaz Jundishapur University of Medical Sciences.

Conflict of interest

The authors declare no conflict of interest.

Author information

Authors and Affiliations

  1. Health Research Institute, Research Center of Thalassemia and Hemoglobinopathy, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran

    Fatemeh Salari, Mohammad Shahjahani & Najmaldin Saki

  2. Department of Biochemistry and Hematology, Faculty of Medicine, Semnan University of Medical Sciences, Semnan, Iran

    Saeid Shahrabi

Authors
  1. Fatemeh Salari
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Mohammad Shahjahani
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Saeid Shahrabi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Najmaldin Saki
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Najmaldin Saki.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Salari, F., Shahjahani, M., Shahrabi, S. et al. Minimal residual disease in acute lymphoblastic leukemia: optimal methods and clinical relevance, pitfalls and recent approaches. Med Oncol 31, 266 (2014). https://doi.org/10.1007/s12032-014-0266-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s12032-014-0266-3

Keywords

Search

Navigation