Minimal Residual Disease in Acute Lymphoblastic Leukemia

  • Richa Chauhan
  • Richa Juneja
  • Rahul Sharma
  • Renu Saxena


Once patient of acute lymphoblastic leukemia (ALL) is in clinical remission, more sensitive tools than morphology are required to assess minimal residual disease (MRD), to guide clinicians in management of the disease. In the present time, MRD assessment by flow cytometry and molecular methods has emerged as the single most useful prognostic factor in ALL. The chapter deals with definition, technique, utility, and prognostic implications of MRD measurement in ALL.


Acute lymphoblastic leukemia Minimal residual disease Morphological remission Relapse Hematogones Leukemia associated immunophenotype Polymerase chain reaction 


  1. 1.
    Thomas A. How can we improve on the already impressive results in pediatric ALL? Hematology Am Soc Hematol Educ Program. 2015;2015(1):414–9.CrossRefGoogle Scholar
  2. 2.
    Campana D, Coustan-Smith E. Detection of minimal residual disease in acute leukemia by flow cytometry. Cytometry. 1999;38(4):139–52.CrossRefGoogle Scholar
  3. 3.
    Bradstock KF, Janossy G, Tidman N, Papageorgiou ES, Prentice HG, Willoughby M, et al. Immunological monitoring of residual disease in treated thymic acute lymphoblastic leukaemia. Leuk Res. 1981;5(4–5):301–9.CrossRefGoogle Scholar
  4. 4.
    Gaipa G, Basso G, Biondi A, Campana D. Detection of minimal residual disease in pediatric acute lymphoblastic leukemia: MRD in pediatric ALL. Cytometry B Clin Cytom. 2013;84(6):359–69.CrossRefGoogle Scholar
  5. 5.
    van Dongen JJM, van der Velden VHJ, Bruggemann M, Orfao A. Minimal residual disease diagnostics in acute lymphoblastic leukemia: need for sensitive, fast, and standardized technologies. Blood. 2015;125(26):3996–4009.CrossRefGoogle Scholar
  6. 6.
    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.CrossRefGoogle Scholar
  7. 7.
    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(3):292–9.CrossRefGoogle Scholar
  8. 8.
    Borowitz MJ, Wood BL, Devidas M, Loh ML, Raetz EA, Salzer WL, et al. Prognostic significance of minimal residual disease in high risk B-ALL: a report from Children’s Oncology Group study AALL0232. Blood. 2015;126(8):964–71.CrossRefGoogle Scholar
  9. 9.
    Ikoma MRV, Beltrame MP, Ferreira SIACP, Souto EX, Malvezzi M, Yamamoto M. Proposal for the standardization of flow cytometry protocols to detect minimal residual disease in acute lymphoblastic leukemia. Rev Bras Hematol Hemoter. 2015;37(6):406–13.CrossRefGoogle Scholar
  10. 10.
    Bradstock K, Papageorgiou ES, Janossy G, Hoffbrand AV, Willoughby M, Roberts P, et al. Detection of leukæmic lymphoblasts in CSF by immunofluorescence for terminal transferase. Lancet. 1980;315(8178):1144.CrossRefGoogle Scholar
  11. 11.
    Pedreira CE, Costa ES, Lecrevisse Q, van Dongen JJM, Orfao A, EuroFlow Consortium. Overview of clinical flow cytometry data analysis: recent advances and future challenges. Trends Biotechnol. 2013;31(7):415–25.CrossRefGoogle Scholar
  12. 12.
    Brady KA, Atwater SK, Lowell CA. Flow cytometric detection of CD10 (cALLA) on peripheral blood B lymphocytes of neonates. Br J Haematol. 1999;107(4):712–5.CrossRefGoogle Scholar
  13. 13.
    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.CrossRefGoogle Scholar
  14. 14.
    Chantepie SP, Cornet E, Salaün V, Reman O. Hematogones: an overview. Leuk Res. 2013;37(11):1404–11.CrossRefGoogle Scholar
  15. 15.
    McPherson R, Pincus M. Henry’s clinical diagnosis and management by laboratory methods E-book. Philadelphia: Elsevier Health Sciences; 2016.Google Scholar
  16. 16.
    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;74B(6):331–40.CrossRefGoogle Scholar
  17. 17.
    Coustan-Smith E, Song G, Clark C, Key L, Liu P, Mehrpooya M, et al. New markers for minimal residual disease detection in acute lymphoblastic leukemia. Blood. 2011;117(23):6267–76.CrossRefGoogle Scholar
  18. 18.
    Czader M. Hematological malignancies. Totowa: Humana Press; 2013.CrossRefGoogle Scholar
  19. 19.
    Shaver AC, Greig BW, Mosse CA, Seegmiller AC. B-ALL minimal residual disease flow cytometry: an application of a novel method for optimization of a single-tube model. Am J Clin Pathol. 2015;143(5):716–24.CrossRefGoogle Scholar
  20. 20.
    6 flow cytometry gating tips that most scientists forget|expert cytometry|flow cytometry training [internet]. Expert cytometry. 2014 [cited 2017 Dec 18].
  21. 21.
    Ghodke K, Bibi A, Rabade N, Patkar N, Subramanian PG, Kadam PA, et al. CD19 negative precursor B acute lymphoblastic leukemia (B-ALL)-immunophenotypic challenges in diagnosis and monitoring: a study of three cases: CD19 negative precursor B-ALL-immunophenotypic challenges in diagnosis and monitoring. Cytometry B Clin Cytom. 2017;92(4):315–8.CrossRefGoogle Scholar
  22. 22.
    Theunissen P, Mejstrikova E, Sedek L, van der Sluijs-Gelling AJ, Gaipa G, Bartels M, et al. Standardized flow cytometry for highly sensitive MRD measurements in B-cell acute lymphoblastic leukemia. Blood. 2017;129(3):347–57.CrossRefGoogle Scholar
  23. 23.
    Brüggemann 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(3):521–35.CrossRefGoogle Scholar
  24. 24.
    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(12):1834–40.CrossRefGoogle Scholar
  25. 25.
    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 Sep;106(3):634–43.CrossRefGoogle Scholar
  26. 26.
    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.CrossRefGoogle Scholar
  27. 27.
    Vora AJ, Goulden N, Mitchell CD, Hough R, Rowntree C, Richards SM. UKALL 2003, a randomised trial investigating treatment intensification for children and young adults with minimal residual disease defined high risk acute lymphoblastic leukaemia. Blood. 2012;120(21):136.Google Scholar
  28. 28.
    Rambaldi A, Borleri G, Dotti G, Bellavita P, Amaru R, Biondi A, et al. Innovative two-step negative selection of granulocyte colony-stimulating factor–mobilized circulating progenitor cells: adequacy for autologous and allogeneic transplantation. Blood. 1998;91(6):2189–96.PubMedGoogle Scholar
  29. 29.
    Patkar N, Alex A, Bargavi B, Ahmed R, Abraham A, George B, Vishwabandya A, Srivastava A, Mathews V. Standardization minimal residual disease by flow cytometry for precursor B lineage acute lymphoblastic leukemia in a developing country. Cytometry B Clin Cytom. 2012;82B:252–8.CrossRefGoogle Scholar

Copyright information

© Springer Nature Singapore Pte Ltd. 2019

Authors and Affiliations

  • Richa Chauhan
    • 1
  • Richa Juneja
    • 1
  • Rahul Sharma
    • 1
  • Renu Saxena
    • 1
  1. 1.Department of HematologyAll India Institute of Medical SciencesNew DelhiIndia

Personalised recommendations