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Flow Cytometric Minimal Residual Disease Analysis in Acute Leukemia: Current Status

  • Pulkit Rastogi
  • Man Updesh Singh SachdevaEmail author
Review Article
  • 18 Downloads

Abstract

Minimal residual disease (MRD) analysis for patients of acute leukemia has evolved as a significant prognostic factor. Based on the MRD results, the cases are risk-stratified after induction chemotherapy, and an alteration in further management is made to yield maximal therapeutic benefits. The two primary methodologies for MRD detection are multi-parameter flow cytometry (MFC) and polymerase chain reaction. MFC identifies the MRD based on characteristic ‘leukemia-associated immunophenotypes’ on the residual leukemia cells. MRD analysis by MFC is most frequently done at the post-induction stage of treatment and often can achieve a sensitivity of detecting one leukemic cell in 10,000 normal cells, or even higher at times. This review outlines the technical aspects and provides inputs on standard antibody panels used for MRD detection in B-, T-lineage acute lymphoblastic leukemias, and acute myeloid leukemia.

Keywords

Minimal residual disease (MRD) Multi-parameter flow cytometry (MFC) Immunophenotyping 

Notes

Compliance with Ethical Standards

Conflict of interest

The authors declare that they have no conflict of interest.

References

  1. 1.
    Arber DA, Orazi A, Hasserjian R et al (2016) The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood 127:2391–2405.  https://doi.org/10.1182/blood-2016-03-643544 CrossRefGoogle Scholar
  2. 2.
    Brown PA, Shah B, Fathi A et al (2017) NCCN guidelines insights: acute lymphoblastic leukemia, version 1.2017. J Natl Compr Cancer Netw 15:1091–1102.  https://doi.org/10.6004/jnccn.2017.0147 CrossRefGoogle Scholar
  3. 3.
    O’Donnell MR, Tallman MS, Abboud CN et al (2017) Acute myeloid leukemia, version 3.2017, NCCN clinical practice guidelines in oncology. J Natl Compr Cancer Netw 15:926–957.  https://doi.org/10.6004/jnccn.2017.0116 CrossRefGoogle Scholar
  4. 4.
    Borowitz MJ, Devidas M, Hunger SP et al (2008) 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 111:5477–5485.  https://doi.org/10.1182/blood-2008-01-132837 CrossRefGoogle Scholar
  5. 5.
    Cavé H, van der Werff ten Bosch J, Suciu S et al (1998) Clinical significance of minimal residual disease in childhood acute lymphoblastic leukemia. N Engl J Med 339:591–598.  https://doi.org/10.1056/NEJM199808273390904 CrossRefGoogle Scholar
  6. 6.
    Coustan-Smith E, Gajjar A, Hijiya N et al (2004) Clinical significance of minimal residual disease in childhood acute lymphoblastic leukemia after first relapse. Leukemia 18:499–504.  https://doi.org/10.1038/sj.leu.2403283 CrossRefGoogle Scholar
  7. 7.
    van Dongen JJM, van der Velden VHJ, Brüggemann M, Orfao A (2015) Minimal residual disease diagnostics in acute lymphoblastic leukemia: need for sensitive, fast, and standardized technologies. Blood 125:3996–4009.  https://doi.org/10.1182/blood-2015-03-580027 CrossRefGoogle Scholar
  8. 8.
    Neale G, Coustan-Smith E, Pan Q et al (1999) Tandem application of flow cytometry and polymerase chain reaction for comprehensive detection of minimal residual disease in childhood acute lymphoblastic leukemia. Leukemia 13:1221–1226CrossRefGoogle Scholar
  9. 9.
    Conter V, Bartram CR, Valsecchi MG et al (2010) 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 115:3206–3214.  https://doi.org/10.1182/blood-2009-10-248146 CrossRefGoogle Scholar
  10. 10.
    Stow P, Key L, Chen X et al (2010) Clinical significance of low levels of minimal residual disease at the end of remission induction therapy in childhood acute lymphoblastic leukemia. Blood 115:4657–4663.  https://doi.org/10.1182/blood-2009-11-253435 CrossRefGoogle Scholar
  11. 11.
    Eckert C, Biondi A, Seeger K et al (2001) Prognostic value of minimal residual disease in relapsed childhood acute lymphoblastic leukaemia. Lancet 358:1239–1241.  https://doi.org/10.1016/S0140-6736(01)06355-3 CrossRefGoogle Scholar
  12. 12.
    Knechtli CJC, Goulden NJ, Hancock JP et al (1998) Minimal residula disease status as a predictor of relapse after allogenic bone marrow transplantation for children with acute lymphoblastic leukaemia. Br J Haematol 102:860–871.  https://doi.org/10.1046/j.1365-2141.1998.00873.x CrossRefGoogle Scholar
  13. 13.
    Krejci O, van der Velden VHJ, Bader P et al (2003) 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 32:849–851.  https://doi.org/10.1038/sj.bmt.1704241 CrossRefGoogle Scholar
  14. 14.
    Bader P, Kreyenberg H, Henze GHR et al (2009) 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 27:377–384.  https://doi.org/10.1200/JCO.2008.17.6065 CrossRefGoogle Scholar
  15. 15.
    Bader P, Kreyenberg H, von Stackelberg A et al (2015) 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 33:1275–1284.  https://doi.org/10.1200/JCO.2014.58.4631 CrossRefGoogle Scholar
  16. 16.
    Grupp SA, Kalos M, Barrett D et al (2013) Chimeric antigen receptor-modified T cells for acute lymphoid leukemia. N Engl J Med 368:1509–1518.  https://doi.org/10.1056/NEJMoa1215134 CrossRefGoogle Scholar
  17. 17.
    Topp MS, Gökbuget N, Stein AS et al (2015) 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 16:57–66.  https://doi.org/10.1016/S1470-2045(14)71170-2 CrossRefGoogle Scholar
  18. 18.
    Topp MS, Kufer P, Gökbuget N et al (2011) 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 29:2493–2498.  https://doi.org/10.1200/JCO.2010.32.7270 CrossRefGoogle Scholar
  19. 19.
    Appelbaum FR, Rosenblum D, Arceci RJ et al (2007) End points to establish the efficacy of new agents in the treatment of acute leukemia. Blood 109:1810–1816.  https://doi.org/10.1182/blood-2006-08-041152 CrossRefGoogle Scholar
  20. 20.
    van Dongen JJ, Seriu T, Panzer-Grümayer ER et al (1998) Prognostic value of minimal residual disease in acute lymphoblastic leukaemia in childhood. Lancet 352:1731–1738.  https://doi.org/10.1016/S0140-6736(98)04058-6 CrossRefGoogle Scholar
  21. 21.
    Bruggemann M, Raff T, Flohr T et al (2005) Clinical significance of minimal residual disease quantification in adult patients with standard-risk acute lymphoblastic leukemia. Blood 107:1116–1123.  https://doi.org/10.1182/blood-2005-07-2708 CrossRefGoogle Scholar
  22. 22.
    Percival M-E, Lai C, Estey E, Hourigan CS (2017) Bone marrow evaluation for diagnosis and monitoring of acute myeloid leukemia. Blood Rev 31:185–192.  https://doi.org/10.1016/j.blre.2017.01.003 CrossRefGoogle Scholar
  23. 23.
    Al-Mawali A, Gillis D, Lewis I (2009) The role of multiparameter flow cytometry for detection of minimal residual disease in acute myeloid leukemia. Am J Clin Pathol 131:16–26.  https://doi.org/10.1309/AJCP5TSD3DZXFLCX CrossRefGoogle Scholar
  24. 24.
    Campana D, Coustan-Smith E (1999) Detection of minimal residual disease in acute leukemia by flow cytometry. Cytometry 38:139–152CrossRefGoogle Scholar
  25. 25.
    Campana D (2003) Flow-cytometry—based studies of minimal residual disease in children with acute lymphoblastic leukemia, pp 21–36.  https://doi.org/10.1007/978-1-59259-318-7_2
  26. 26.
    Behm FG, Raimondi SC, Schell MJ et al (1992) Lack of CD45 Antigen on blast cells in childhood acute lymphoblastic leukemia is associated with chromosomal hyperdiploidy and other favorable prognostic features. Blood 79:1011–1016Google Scholar
  27. 27.
    DiGiuseppe JA, Fuller SG, Borowitz MJ (2009) Overexpression of CD49f in precursor B-cell acute lymphoblastic leukemia: potential usefulness in minimal residual disease detection. Cytom Part B Clin Cytom 76B:150–155.  https://doi.org/10.1002/cyto.b.20440 CrossRefGoogle Scholar
  28. 28.
    Kamazani FM, Bahoush GR, Aghaeipour M et al (2013) CD44 and CD27 expression pattern in B cell precursor acute lymphoblastic leukemia and its clinical significance. Med Oncol 30:359.  https://doi.org/10.1007/s12032-012-0359-9 CrossRefGoogle Scholar
  29. 29.
    Cox CV, Diamanti P, Blair A (2011) Investigating the expression of the MRD Marker CD58 on leukaemia initiating cells in childhood acute lymphoblastic leukaemia. Blood 118:1887Google Scholar
  30. 30.
    Zeidan MA, Kamal HM, Shabrawy EL, Shabrawy DA et al (2016) Significance of CD34/CD123 expression in detection of minimal residual disease in B-ACUTE lymphoblastic leukemia in children. Blood Cells Mol Dis 59:113–118.  https://doi.org/10.1016/j.bcmd.2016.05.005 CrossRefGoogle Scholar
  31. 31.
    Tembhare PR, Ghogale S, Ghatwai N et al (2018) Evaluation of new markers for minimal residual disease monitoring in B-cell precursor acute lymphoblastic leukemia: CD73 and CD86 are the most relevant new markers to increase the efficacy of MRD 2016; 00B: 000-000. Cytom Part B Clin Cytom 94:100–111.  https://doi.org/10.1002/cyto.b.21486 CrossRefGoogle Scholar
  32. 32.
    Sędek Ł, Theunissen P, Sobral da Costa E et al (2018) Differential expression of CD73, CD86 and CD304 in normal vs. leukemic B-cell precursors and their utility as stable minimal residual disease markers in childhood B-cell precursor acute lymphoblastic leukemia. J Immunol Methods 5:4.  https://doi.org/10.1016/j.jim.2018.03.005 Google Scholar
  33. 33.
    Tsitsikov E, Harris MH, Silverman LB et al (2018) Role of CD81 and CD58 in minimal residual disease detection in pediatric B lymphoblastic leukemia. Int J Lab Hematol 40:343–351.  https://doi.org/10.1111/ijlh.12795 CrossRefGoogle Scholar
  34. 34.
    Cherian S, Miller V, McCullouch V et al (2018) A novel flow cytometric assay for detection of residual disease in patients with B-lymphoblastic leukemia/lymphoma post anti-CD19 therapy. Cytom Part B Clin Cytom 94:112–120.  https://doi.org/10.1002/cyto.b.21482 CrossRefGoogle Scholar
  35. 35.
    Rhein P, Mitlohner R, Basso G et al (2010) CD11b is a therapy resistance- and minimal residual disease-specific marker in precursor B-cell acute lymphoblastic leukemia. Blood 115:3763–3771.  https://doi.org/10.1182/blood-2009-10-247585 CrossRefGoogle Scholar
  36. 36.
    Porwit-MacDonald A, Björklund E, Lucio P et al (2000) 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 14:816–825CrossRefGoogle Scholar
  37. 37.
    Roshal M, Fromm JR, Winter S et al (2010) Immaturity associated antigens are lost during induction for T cell lymphoblastic leukemia: implications for minimal residual disease detection. Cytom Part B Clin Cytom 78B:139–146.  https://doi.org/10.1002/cyto.b.20511 CrossRefGoogle Scholar
  38. 38.
    Macedo A, Orfão A, Vidriales MB et al (1995) Characterization of aberrant phenotypes in acute myeloblastic leukemia. Ann Hematol 70:189–194CrossRefGoogle Scholar
  39. 39.
    Al-Mawali A, Gillis D, Hissaria P, Lewis I (2008) Incidence, sensitivity, and specificity of leukemia-associated phenotypes in acute myeloid leukemia using specific five-color multiparameter flow cytometry. Am J Clin Pathol 129:934–945.  https://doi.org/10.1309/FY0UMAMM91VPMR2W CrossRefGoogle Scholar
  40. 40.
    Xu J, Jorgensen JL, Wang SA (2017) How do we use multicolor flow cytometry to detect minimal residual disease in acute myeloid leukemia? Clin Lab Med 37:787–802.  https://doi.org/10.1016/J.CLL.2017.07.004 CrossRefGoogle Scholar
  41. 41.
    Cruz NM, Mencia-Trinchant N, Hassane DC, Guzman ML (2017) Minimal residual disease in acute myelogenous leukemia. Int J Lab Hematol 39:53–60.  https://doi.org/10.1111/ijlh.12670 CrossRefGoogle Scholar
  42. 42.
    Zeijlemaker W, Kelder A, Oussoren-Brockhoff YJM et al (2016) A simple one-tube assay for immunophenotypical quantification of leukemic stem cells in acute myeloid leukemia. Leukemia 30:439–446.  https://doi.org/10.1038/leu.2015.252 CrossRefGoogle Scholar
  43. 43.
    Coustan-Smith E, Sancho J, Hancock ML et al (2002) Use of peripheral blood instead of bone marrow to monitor residual disease in children with acute lymphoblastic leukemia. Blood 100:2399–2402.  https://doi.org/10.1182/blood-2002-04-1130 CrossRefGoogle Scholar
  44. 44.
    Brisco MJ, Sykes PJ, Hughes E et al (1997) Monitoring minimal residual disease in peripheral blood in B-lineage acute lymphoblastic leukaemia. Br J Haematol 99:314–319.  https://doi.org/10.1046/j.1365-2141.1997.3723186.x CrossRefGoogle Scholar
  45. 45.
    van der Velden VHJ, Jacobs DCH, Wijkhuijs AJM et al (2002) 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 16:1432–1436.  https://doi.org/10.1038/sj.leu.2402636 CrossRefGoogle Scholar
  46. 46.
    Velden VHJ, Hoogeveen PG, Pieters R, Dongen JJM (2006) Impact of two independent bone marrow samples on minimal residual disease monitoring in childhood acute lymphoblastic leukaemia. Br J Haematol 133:382–388.  https://doi.org/10.1111/j.1365-2141.2006.06056.x CrossRefGoogle Scholar
  47. 47.
    Gaipa G, Basso G, Biondi A, Campana D (2013) Detection of minimal residual disease in pediatric acute lymphoblastic leukemia. Cytom Part B Clin Cytom 84:359–369.  https://doi.org/10.1002/cyto.b.21101 CrossRefGoogle Scholar
  48. 48.
    Preffer F, Dombkowski D (2009) Advances in complex multiparameter flow cytometry technology: applications in stem cell research. Cytom Part B Clin Cytom 76B:295–314.  https://doi.org/10.1002/cyto.b.20480 CrossRefGoogle Scholar
  49. 49.
    Wood BL (2013) Flow cytometric monitoring of residual disease in acute leukemia. Humana Press, Totowa, pp 123–136Google Scholar
  50. 50.
    Theunissen P, Mejstrikova E, Sedek L et al (2017) Standardized flow cytometry for highly sensitive MRD measurements in B-cell acute lymphoblastic leukemia. Blood 129:347–357.  https://doi.org/10.1182/blood-2016-07-726307 CrossRefGoogle Scholar
  51. 51.
    Patkar N, Alex AA, Bargavi B et al (2012) Standardizing minimal residual disease by flow cytometry for precursor B lineage acute lymphoblastic leukemia in a developing country. Cytom Part B Clin Cytom 82B:252–258.  https://doi.org/10.1002/cyto.b.21017 CrossRefGoogle Scholar
  52. 52.
    Malec M, van der Velden VHJ, Björklund E et al (2004) 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 18:1630–1636.  https://doi.org/10.1038/sj.leu.2403444 CrossRefGoogle Scholar
  53. 53.
    Neale GAM, Coustan-Smith E, Stow P et al (2004) Comparative analysis of flow cytometry and polymerase chain reaction for the detection of minimal residual disease in childhood acute lymphoblastic leukemia. Leukemia 18:934–938.  https://doi.org/10.1038/sj.leu.2403348 CrossRefGoogle Scholar
  54. 54.
    Costa ES, Pedreira CE, Barrena S et al (2010) 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 24:1927–1933.  https://doi.org/10.1038/leu.2010.160 CrossRefGoogle Scholar
  55. 55.
    Pedreira CE, Costa ES, Lecrevisse Q et al (2013) Overview of clinical flow cytometry data analysis: recent advances and future challenges. Trends Biotechnol 31:415–425.  https://doi.org/10.1016/j.tibtech.2013.04.008 CrossRefGoogle Scholar
  56. 56.
    Gaipa G, Basso G, Maglia O et al (2005) Drug-induced immunophenotypic modulation in childhood ALL: implications for minimal residual disease detection. Leukemia 19:49–56.  https://doi.org/10.1038/sj.leu.2403559 CrossRefGoogle Scholar
  57. 57.
    van Dongen JJM, Lhermitte L, Böttcher S et al (2012) EuroFlow antibody panels for standardized n-dimensional flow cytometric immunophenotyping of normal, reactive and malignant leukocytes. Leukemia 26:1908–1975.  https://doi.org/10.1038/leu.2012.120 CrossRefGoogle Scholar
  58. 58.
    Kalina T, Flores-Montero J, van der Velden VHJ et al (2012) EuroFlow standardization of flow cytometer instrument settings and immunophenotyping protocols. Leukemia 26:1986–2010.  https://doi.org/10.1038/leu.2012.122 CrossRefGoogle Scholar
  59. 59.
    Reyes-Barron C, Burack WR, Rothberg PG, Ding Y (2017) Next-generation sequencing for minimal residual disease surveillance in acute lymphoblastic leukemia: an update. Crit Rev Oncog 22:559–567.  https://doi.org/10.1615/CritRevOncog.2017020588 CrossRefGoogle Scholar

Copyright information

© Indian Society of Hematology and Blood Transfusion 2019

Authors and Affiliations

  1. 1.Department of Histopathology, Level 5, Research Block APostgraduate Institute of Medical Education and ResearchChandigarhIndia
  2. 2.Department of Hematology, Level 5, Research Block APostgraduate Institute of Medical Education and ResearchChandigarhIndia

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