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Minimal residual disease

Leukemia Supplements volume 1, pages S3–S4 (2012)Cite this article

Abstract

The aim of minimal residual disease (MRD) studies in patients with acute leukemia is to measure initial treatment response accurately, provide an assessment of the residual leukemic burden throughout therapy and detect relapse early. Therefore, information resulting from MRD monitoring can substantially improve many facets of clinical management. Methods for MRD detection, namely flow cytometry and PCR, have been applied to study the remission status of thousands of patients with acute lymphoblastic leukemia and acute myeloid leukemia. Collectively, the data indicate that MRD is a powerful prognostic indicator and an indispensable parameter for risk-adapted therapy. The current status of MRD in acute leukemia is briefly reviewed in this paper.

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References

  1. 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: 521–535.

    Article  CAS  Google Scholar 

  2. Shook D, Coustan-Smith E, Ribeiro RC, Rubnitz JE, Campana D . Minimal residual disease quantitation in acute myeloid leukemia. Clin Lymphoma Myeloma 2009; 9 (Suppl 3): S281–S285.

    Article  Google Scholar 

  3. Pui CH, Campana D, Pei D, Bowman WP, Sandlund JT, Kaste SC et al. Treating childhood acute lymphoblastic leukemia without cranial irradiation. N Engl J Med 2009; 360: 2730–2741.

    Article  CAS  Google Scholar 

  4. Rubnitz JE, Inaba H, Dahl GV, Ribeiro RC, Bowman WP, Taub JW et al. Minimal residual disease-directed therapy for childhood acute myeloid leukemia: results of the AML02 multicenter trial. Lancet Oncol 2010; 11: 543–552.

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  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: 5477–5485.

    Article  CAS  Google Scholar 

  7. 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: 3206–3214.

    Article  CAS  Google Scholar 

  8. Pui CH, Pei D, Campana D, Bowman WP, Sandlund JT, Kaste SC et al. Improved prognosis for older adolescents with acute lymphoblastic leukemia. J Clin Oncol 2011; 29: 386–391.

    Article  Google Scholar 

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

    Article  CAS  Google Scholar 

  10. 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: 2077–2084.

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  12. 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: 5168–5174.

    Article  Google Scholar 

  13. Stow P, Key L, Chen X, Pan Q, Neale GA, Coustan-Smith E et al. Clinical significance of low levels of minimal residual disease at the end of remission induction therapy in childhood acute lymphoblastic leukemia. Blood 2010; 115: 4657–4663.

    Article  CAS  Google Scholar 

  14. Raetz EA, Borowitz MJ, Devidas M, Linda SB, Hunger SP, Winick NJ et al. Reinduction platform for children with first marrow relapse of acute lymphoblastic Leukemia: A Children's Oncology Group Study. J Clin Oncol 2008; 26: 3971–3978.

    Article  CAS  Google Scholar 

  15. 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: 377–384.

    Article  Google Scholar 

  16. Leung W, Campana D, Yang J, Pei D, Coustan-Smith E, Gan K et al. High success rate of hematopoietic cell transplantation regardless of donor source in children with very high-risk leukemia. Blood 2011; 118: 223–230.

    Article  CAS  Google Scholar 

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

    Article  Google Scholar 

  18. 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: 910–915.

    Article  CAS  Google Scholar 

  19. 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 MRD in adult ALL. Blood 2009; 113: 4153–4162.

    Article  CAS  Google Scholar 

  20. Patel B, Rai L, Buck G, Richards SM, Mortuza Y, Mitchell W et al. Minimal residual disease is a significant predictor of treatment failure in non T-lineage adult acute lymphoblastic leukaemia: final results of the international trial UKALL XII/ECOG2993. Br J Haematol 2010; 148: 80–89.

    Article  CAS  Google Scholar 

  21. Giebel S, Stella-Holowiecka B, Krawczyk-Kulis M, Gokbuget N, Hoelzer D, Doubek M et al. Status of minimal residual disease determines outcome of autologous hematopoietic SCT in adult ALL. Bone Marrow Transplant 2009; 45: 1095–1101.

    Article  Google Scholar 

  22. Sievers EL, Lange BJ, Alonzo TA, Gerbing RB, Bernstein ID, Smith FO et al. Immunophenotypic evidence of leukemia after induction therapy predicts relapse: results from a prospective Children's Cancer Group study of 252 acute myeloid leukemia patients. Blood 2003; 101: 3398–3406.

    Article  CAS  Google Scholar 

  23. Coustan-Smith E, Ribeiro RC, Rubnitz JE, Razzouk BI, Pui CH, Pounds S et al. Clinical significance of residual disease during treatment in childhood acute myeloid leukemia. Br J Haematol 2003; 123: 243–252.

    Article  Google Scholar 

  24. Langebrake C, Creutzig U, Dworzak M, Hrusak O, Mejstrikova E, Griesinger F et al. Residual disease monitoring in childhood acute myeloid leukemia by multiparameter flow cytometry: the MRD-AML-BFM Study Group. J Clin Oncol 2006; 24: 3686–3692.

    Article  Google Scholar 

  25. van der Velden VH, Sluijs-Geling A, Gibson BE, te Marvelde JG, Hoogeveen PG, Hop WC et al. Clinical significance of flowcytometric minimal residual disease detection in pediatric acute myeloid leukemia patients treated according to the DCOG ANLL97/MRC AML12 protocol. Leukemia 2010; 24: 1599–1606.

    Article  CAS  Google Scholar 

  26. San Miguel JF, Vidriales MB, Lopez-Berges C, Diaz-Mediavilla J, Gutierrez N, Canizo C et al. Early immunophenotypical evaluation of minimal residual disease in acute myeloid leukemia identifies different patient risk groups and may contribute to postinduction treatment stratification. Blood 2001; 98: 1746–1751.

    Article  CAS  Google Scholar 

  27. Kern W, Voskova D, Schoch C, Hiddemann W, Schnittger S, Haferlach T . Determination of relapse risk based on assessment of minimal residual disease during complete remission by multiparameter flow cytometry in unselected patients with acute myeloid leukemia. Blood 2004; 104: 3078–3085.

    Article  CAS  Google Scholar 

  28. Maurillo L, Buccisano F, Del Principe MI, Del PG, Spagnoli A, Panetta P et al. Toward optimization of postremission therapy for residual disease-positive patients with acute myeloid leukemia. J Clin Oncol 2008; 26: 4944–4951.

    Article  Google Scholar 

  29. Campana D . Minimal residual disease in acute lymphoblastic leukemia. Hematology Am Soc Hematol Educ Program 2010; 2010: 7–12.

    Article  Google Scholar 

  30. Coustan-Smith E, Mullighan CG, Onciu M, Behm FG, Raimondi SC, Pei D et al. Early T-cell precursor leukaemia: a subtype of very high-risk acute lymphoblastic leukaemia. Lancet Oncol 2009; 10: 147–156.

    Article  CAS  Google Scholar 

  31. Mullighan CG, Su X, Zhang J, Radtke I, Phillips LA, Miller CB et al. Deletion of IKZF1 and prognosis in acute lymphoblastic leukemia. N Engl J Med 2009; 360: 470–480.

    Article  CAS  Google Scholar 

  32. Cario G, Stanulla M, Fine BM, Teuffel O, Neuhoff NV, Schrauder A et al. Distinct gene expression profiles determine molecular treatment response in childhood acute lymphoblastic leukemia. Blood 2005; 105: 821–826.

    Article  CAS  Google Scholar 

  33. Flotho C, Coustan-Smith E, Pei D, Cheng C, Song G, Pui CH et al. A set of genes that regulate cell proliferation predicts treatment outcome in childhood acute lymphoblastic leukemia. Blood 2007; 110: 1271–1277.

    Article  CAS  Google Scholar 

  34. Yang JJ, Cheng C, Yang W, Pei D, Cao X, Fan Y et al. Genome-wide interrogation of germline genetic variation associated with treatment response in childhood acute lymphoblastic leukemia. JAMA 2009; 301: 393–403.

    Article  CAS  Google Scholar 

  35. 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: 6267–6276.

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  37. Faham M, Willis T, Moorhead M, Carlton V, Zheng J, Campana D . Highly sensitive detection of minimal residual disease in acute lymphoblastic leukemia using next-generation sequencing of immunoglobulin heavy chain variable region. Blood (ASH Annual Meeting Abstracts) 2011; 118: 2540.

    Google Scholar 

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Acknowledgements

This work was supported by grants from the National Medical Research Council of Singapore, the National Cancer Institute and by the American Lebanese Syrian Associated Charities (ALSAC).

This article was published as part of a supplement that was supported by Novartis, MSD Italia, Roche, Celgene, GlaxoSmithKline, Sanofi, Gilead, Adienne, Italfarmaco, Pierre Fabre Pharmaceuticals with an unrestricted educational contribution to AREO—Associazione Ricerche Emato-Oncologiche (Genoa) and AMS—Associazione Malattie del Sangue (Milan) for the purpose of advancing research in acute and chronic leukemia.

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  1. Department of Paediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Centre for Translational Medicine, Singapore, Singapore

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Correspondence to D Campana.

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Campana, D. Minimal residual disease. Leukemia Suppl 1 (Suppl 2), S3–S4 (2012). https://doi.org/10.1038/leusup.2012.5

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