Clinical Use of Measurable Residual Disease in Acute Myeloid Leukemia
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Treatment of acute myeloid leukemia (AML) remains a high-risk venture for the patient suffering from the disease. There is a real risk of succumbing to the treatment rather than the disease, and even so, cure is much less than certain. Since the establishment of complete remission as a prerequisite for cure in the 1960s, a number of years passed before advanced techniques for detecting minute amounts of disease matured sufficiently for clinical implementation. The two main techniques for detection of measurable residual disease (MRD) remain qPCR and multicolor flow cytometry. When performed in expert laboratories, both these modalities offer treating physicians excellent opportunity to follow the amount of residual disease upon treatment and offer unparalleled prognostication. In some AML and age group subsets, evidence now exist to support the choice of both proceeding to allogeneic transplant and not doing so. In other AML subgroups, MRD has sufficient discriminative power to identify patients likely to benefit from allogeneic transplant and patients likely not to. After treatment or transplantation, follow-up by molecular techniques can, with high certainty, predict relapse months before bone marrow function deterioration. On the other hand, options upon so-called molecular relapse are less well tested but recent evidence supports the use of azacitidine both in transplanted patients and patients consolidated with chemotherapy. In conclusion, MRD testing during treatment is a superb prognosticator and a major tool when choosing whether a patient should be transplanted or not. The exact use of MRD testing after treatment is less well defined but evidence is mounting for the instigation of treatment upon rising MRD levels (pre-emptive treatment) before morphologically detectable relapse.
KeywordsAcute myeloid leukemia, AML Measurable residual disease, MRD Pre-emptive treatment Allogeneic stem cell transplantation qPCR Multicolor flow cytometry Surveillance Complete remission
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Conflict of Interest
The authors declare that they have no conflict of interest.
Human and Animal Rights and Informed Consent
This article does not contain any studies with human or animal subjects performed by any of the authors.
References and Recommended Reading
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- 1.Döhner H, Weisdorf DJ, Bloomfield CD. Acute myeloid leukemia. Longo DL, editor. N Engl J Med [Internet]. Massachusetts Medical Society; 2015 [cited 2019 Jan 14];373:1136–52. https://doi.org/10.1056/NEJMra1406184.
- 2.••Döhner H, Estey E, Grimwade D, Amadori S, Appelbaum FR, Büchner T, et al. Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel. Blood. 2017;129:424–47. The most recently updated ELN recommendations in clinical management of AML patients including updated response criteria including MRD quantification.CrossRefGoogle Scholar
- 3.•O’Donnell MR, Tallman MS, Abboud CN, Altman JK, Appelbaum FR, Arber DA, et al. Acute myeloid leukemia, version 3.2017, NCCN clinical practice guidelines in oncology. J Natl Compr Canc Netw [internet]. Harborside Press, LLC; 2017 [cited 2019 Jan 14];15:926–57. Available from: http://www.ncbi.nlm.nih.gov/pubmed/28687581 . Updated NCCN guidelines in clinical management of AML patients.
- 4.Chen X, Xie H, Wood BL, Walter RB, Pagel JM, Becker PS, et al. Relation of clinical response and minimal residual disease and their prognostic impact on outcome in acute myeloid leukemia. J Clin Oncol [Internet]. American Society of Clinical Oncology; 2015 [cited 2019 Jan 14];33:1258–64. https://doi.org/10.1200/JCO.2014.58.3518.
- 5.Ossenkoppele G, Schuurhuis GJ. MRD in AML: time for redefinition of CR? Blood [Internet]. American Society of Hematology; 2013 [cited 2019 Jan 14];121:2166–8. Available from: http://www.ncbi.nlm.nih.gov/pubmed/23520326.
- 6.Tomlinson B, Lazarus HM. Enhancing acute myeloid leukemia therapy - monitoring response using residual disease testing as a guide to therapeutic decision-making. Expert Rev Hematol [Internet]. Taylor & Francis; 2017 [cited 2019 Jan 14];10:563–74. https://doi.org/10.1080/17474086.2017.1326811.
- 7.Percival M-E, Lai C, Estey E, Hourigan CS. Bone marrow evaluation for diagnosis and monitoring of acute myeloid leukemia. Blood Rev [Internet]. Churchill Livingstone; 2017 [cited 2019 Jan 14];31:185–92. Available from: https://www.sciencedirect.com/science/article/pii/S0268960X16300509?via%3Dihub.
- 8.Craddock C, Raghavan M. Which patients with acute myeloid leukemia in CR1 can be spared an allogeneic transplant? Curr Opin Hematol [Internet]. 2018 [cited 2019 Jan 14];1. Available from: http://insights.ovid.com/crossref?an=00062752-900000000-99282.
- 9.••Schuurhuis GJ, Heuser M, Freeman S, Béné M-C, Buccisano F, Cloos J, et al. Minimal/measurable residual disease in AML: a consensus document from the European LeukemiaNet MRD Working Party. Blood [internet]. American Society of Hematology; 2018 [cited 2019 Jan 14];131:1275–91. Available from: http://www.ncbi.nlm.nih.gov/pubmed/29330221. The ELN consensus MRD paper.
- 10.•Ravandi F, Walter RB, Freeman SD. Evaluating measurable residual disease in acute myeloid leukemia. Blood Adv [internet]. American Society of Hematology; 2018 [cited 2019 Jan 14];2:1356–66. Available from: http://www.ncbi.nlm.nih.gov/pubmed/29895626. An updated review on different MRD quantification techniques with emphasis on future challenges.
- 11.Goldman JM, Gale RP. What does MRD in leukemia really mean? Leukemia [Internet]. Nature Publishing Group; 2014 [cited 2019 Jan 14];28:1131–1131. Available from: http://www.nature.com/articles/leu2013318.
- 12.Grimwade D, Freeman SD. Defining minimal residual disease in acute myeloid leukemia: which platforms are ready for “prime time”? Blood [Internet]. American Society of Hematology; 2014 [cited 2019 Jan 14];124:3345–55. Available from: http://www.ncbi.nlm.nih.gov/pubmed/25049280.
- 13.Buccisano F, Maurillo L, Gattei V, Del Poeta G, Del Principe MI, Cox MC, et al. The kinetics of reduction of minimal residual disease impacts on duration of response and survival of patients with acute myeloid leukemia. Leukemia [Internet]. Nature Publishing Group2006 [cited 2019 Jan 14];20:1783–9. Available from: http://www.nature.com/articles/2404313.
- 14.Zeijlemaker W, Grob T, Meijer R, Hanekamp D, Kelder A, Carbaat-Ham JC, et al. CD34+CD38− leukemic stem cell frequency to predict outcome in acute myeloid leukemia. Leukemia [Internet]. Nature Publishing Group; 2018 [cited 2019 Jan 14];1. Available from: http://www.nature.com/articles/s41375-018-0326-3.
- 15.••Balsat M, Renneville A, Thomas X, de Botton S, Caillot D, Marceau A, et al. Postinduction minimal residual disease predicts outcome and benefit from allogeneic stem cell transplantation in acute myeloid leukemia with NPM1 mutation: a study by the Acute Leukemia French Association Group. J Clin Oncol [Internet]. American Society of Clinical Oncology; 2017 [cited 2019 Jan 14];35:185–93. https://doi.org/10.1200/JCO.2016.67.1875. A pivotal paper documenting that, in NPM1+FLT3-ITD+ patients with a very good MRD response, allogeneic transplantation is unnecessary.
- 16.Zhu H-H, Zhang X-H, Qin Y-Z, Liu D-H, Jiang H, Chen H, et al. MRD-directed risk stratification treatment may improve outcomes of t(8;21) AML in the first complete remission: results from the AML05 multicenter trial. Blood [Internet]. American Society of Hematology; 2013 [cited 2019 Jan 14];121:4056–62. Available from: http://www.ncbi.nlm.nih.gov/pubmed/23535063.
- 17.Becker H, Marcucci G, Maharry K, Radmacher MD, Mrózek K, Margeson D, et al. Favorable prognostic impact of NPM1 mutations in older patients with cytogenetically normal de novo acute myeloid leukemia and associated gene- and microRNA-expression signatures: a Cancer and Leukemia Group B study. J Clin Oncol [Internet]. American Society of Clinical Oncology ; 2010 [cited 2019 Jan 14];28:596–604. https://doi.org/10.1200/JCO.2009.25.1496.
- 18.Lazenby M, Gilkes AF, Marrin C, Evans A, Hills RK, Burnett AK. The prognostic relevance of flt3 and npm1 mutations on older patients treated intensively or non-intensively: a study of 1312 patients in the UK NCRI AML16 trial. Leukemia [Internet]. Nature Publishing Group; 2014 [cited 2019 Jan 14];28:1953–9. Available from: http://www.nature.com/articles/leu201490.
- 19.Ostronoff F, Othus M, Lazenby M, Estey E, Appelbaum FR, Evans A, et al. Prognostic significance of NPM1 mutations in the absence of FLT3-internal tandem duplication in older patients with acute myeloid leukemia: a SWOG and UK National Cancer Research Institute/Medical Research Council report. J Clin Oncol [Internet]. American Society of Clinical Oncology; 2015 [cited 2019 Jan 14];33:1157–64. https://doi.org/10.1200/JCO.2014.58.0571.
- 20.••Freeman SD, Hills RK, Virgo P, Khan N, Couzens S, Dillon R, et al. Measurable residual disease at induction redefines partial response in acute myeloid leukemia and stratifies outcomes in patients at standard risk without NPM1 mutations. J Clin Oncol [internet]. American Society of Clinical Oncology; 2018 [cited 2019 Jan 14];36:1486–97. https://doi.org/10.1200/JCO.2017.76.3425. The UK experience of using MRD in prognosticating younger adults.
- 21.Krönke J, Schlenk RF, Jensen K-O, Tschürtz F, Corbacioglu A, Gaidzik VI, et al. Monitoring of minimal residual disease in NPM1-mutated acute myeloid leukemia: a study from the German-Austrian acute myeloid leukemia study group. J Clin Oncol [Internet]. American Society of Clinical Oncology; 2011 [cited 2019 Jan 14];29:2709–16. https://doi.org/10.1200/JCO.2011.35.0371.
- 22.••Ivey A, Hills RK, Simpson MA, Jovanovic J V., Gilkes A, Grech A, et al. Assessment of minimal residual disease in standard-risk AML. N Engl J Med [Internet]. Massachusetts Medical Society; 2016 [cited 2019 Jan 14];374:422–33. https://doi.org/10.1056/NEJMoa1507471. The UK NPM1 qPCR experience. In the paper, MRD is shown to be a superior prognostic marker compared to several pre-treatment molecular aberrations. NPM1 positivity in PB after second course of chemotherapy is shown to have unparalleled discriminative power regarding patients likely to relapse or not.
- 23.Yin JAL, O’Brien MA, Hills RK, Daly SB, Wheatley K, Burnett AK, et al. Minimal residual disease monitoring by quantitative RT-PCR in core binding factor AML allows risk stratification and predicts relapse: results of the United Kingdom MRC AML-15 trial. Blood [Internet]. American Society of Hematology; 2012 [cited 2019 Jan 14];120:2826–35. Available from: http://www.ncbi.nlm.nih.gov/pubmed/10648391.
- 24.Terwijn M, van Putten WLJ, Kelder A, van der Velden VHJ, Brooimans RA, Pabst T, et al. High prognostic impact of flow cytometric minimal residual disease detection in acute myeloid leukemia: data from the HOVON/SAKK AML 42A study. J Clin Oncol [Internet]. American Society of Clinical Oncology; 2013 [cited 2019 Jan 14];31:3889–97. https://doi.org/10.1200/JCO.2012.45.9628.
- 25.••Buccisano F, Dillon R, Freeman S, Venditti A, Buccisano F, Dillon R, et al. Role of minimal (measurable) residual disease assessment in older patients with acute myeloid leukemia. Cancers (Basel) [internet]. Multidisciplinary digital publishing institute; 2018 [cited 2019 Jan 14];10:215. Available from: http://www.mdpi.com/2072-6694/10/7/215. A very recent review regarding the use of MRD in the elderly with several insightful considerations.
- 26.Freeman SD, Virgo P, Couzens S, Grimwade D, Russell N, Hills RK, et al. Prognostic relevance of treatment response measured by flow cytometric residual disease detection in older patients with acute myeloid leukemia. J Clin Oncol [Internet]. American Society of Clinical Oncology; 2013 [cited 2019 Jan 14];31:4123–31. https://doi.org/10.1200/JCO.2013.49.1753.
- 27.Buccisano F, Maurillo L, Piciocchi A, Del Principe MI, Sarlo C, Cefalo M, et al. Minimal residual disease negativity in elderly patients with acute myeloid leukemia may indicate different postremission strategies than in younger patients. Ann Hematol [Internet]. Springer Berlin Heidelberg; 2015 [cited 2019 Jan 14];94:1319–26. Available from: http://link.springer.com/10.1007/s00277-015-2364-5.
- 28.••Liu J, Zhao X-S, Liu Y-R, Xu L-P, Zhang X-H, Chen H, et al. Association of persistent minimal residual disease with poor outcomes of patients with acute myeloid leukemia undergoing allogeneic hematopoietic stem cell transplantation. Chin Med J (Engl) [Internet]. Wolters Kluwer -- Medknow Publications; 2018 [cited 2019 Jan 14];131:2808–16. Available from: http://www.ncbi.nlm.nih.gov/pubmed/30511683. A noteworthy paper demonstrating the clinical experience from the last 15 years: patients who are MRD positive before transplant relapses!
- 29.Jacobsohn DA, Tse WT, Chaleff S, Rademaker A, Duerst R, Olszewski M, et al. High WT1 gene expression before haematopoietic stem cell transplant in children with acute myeloid leukemia predicts poor event-free survival. Br J Haematol [Internet]. John Wiley & Sons, Ltd (10.1111); 2009 [cited 2019 Jan 14];146:669–74. https://doi.org/10.1111/j.1365-2141.2009.07770.x.
- 30.Ommen HB, Hokland P, Haferlach T, Abildgaard L, Alpermann T, Haferlach C, et al. Relapse kinetics in acute myeloid leukaemias with MLL translocations or partial tandem duplications within the MLL gene. Br J Haematol [Internet]. John Wiley & Sons, Ltd (10.1111); 2014 [cited 2019 Jan 14];165:618–28. https://doi.org/10.1111/bjh.12792.
- 31.••Platzbecker U, Middeke JM, Sockel K, Herbst R, Wolf D, Baldus CD, et al. Measurable residual disease-guided treatment with azacitidine to prevent haematological relapse in patients with myelodysplastic syndrome and acute myeloid leukemia (RELAZA2): an open-label, multicentre, phase 2 trial. Lancet Oncol [Internet]. Elsevier; 2018 [cited 2019 Jan 14];19:1668–79. Available from: https://www.sciencedirect.com/science/article/pii/S1470204518305801?via%3Dihub. The first trial to show in a bigger cohort the benefit of +pre-emptive treatment.
- 32.Campana D, Pui C. Detection of minimal residual disease in acute leukemia: methodologic advances and clinical significance [see comments]. Blood [Internet]. 1995 [cited 2019 Jan 14];85. Available from: http://www.bloodjournal.org/content/85/6/1416.long?sso-checked=true.
- 33.Ommen HB, Nyvold CG, Brændstrup K, Andersen BL, Ommen IB, Hasle H, et al. Relapse prediction in acute myeloid leukemia patients in complete remission using WT1 as a molecular marker: development of a mathematical model to predict time from molecular to clinical relapse and define optimal sampling intervals. Br J Haematol [Internet]. John Wiley & Sons, Ltd (10.1111); 2008 [cited 2019 Jan 14];141:782–91. https://doi.org/10.1111/j.1365-2141.2008.07132.x.
- 34.Ommen HB, Schnittger S, Jovanovic J V, Ommen IB, Hasle H, Østergaard M, et al. Strikingly different molecular relapse kinetics in NPM1c, PML-RARA, RUNX1-RUNX1T1, and CBFB-MYH11 acute myeloid leukemias. Blood [Internet]. American Society of Hematology; 2010 [cited 2019 Jan 14];115:198–205. Available from: http://www.ncbi.nlm.nih.gov/pubmed/19901261.
- 35.Schnittger S, Kern W, Tschulik C, Weiss T, Dicker F, Falini B, et al. Minimal residual disease levels assessed by NPM1 mutation-specific RQ-PCR provide important prognostic information in AML. Blood [Internet]. American Society of Hematology; 2009 [cited 2019 Jan 14];114:2220–31. Available from: http://www.ncbi.nlm.nih.gov/pubmed/19587375.
- 36.Schnittger S, Kern W, Schoch C, Haferlach T. RT-PCR-based MRD detection in NPM1 mutated AML: a prospective follow-up study in 130 patients. Blood. 2007;110.Google Scholar
- 37.Bornhäuser M, Oelschlaegel U, Platzbecker U, Bug G, Lutterbeck K, Kiehl MG, et al. Monitoring of donor chimerism in sorted CD34+ peripheral blood cells allows the sensitive detection of imminent relapse after allogeneic stem cell transplantation. Haematologica [Internet]. Haematologica; 2009 [cited 2019 Jan 14];94:1613–7. Available from: http://www.ncbi.nlm.nih.gov/pubmed/19880783.