Main Article Content

Maria Ilaria Del Principe


acute myeloid leukemia, minimal residual disease, flow cytometry, PCR, prognosis


Pretreatment assessment of cytogenetic/genetic signature of acute myeloid leukemia (AML) has been consistently shown to play a major prognostic role but also to fail at predicting outcome on individual basis, even in low-risk AML. Therefore, we are in need of further accurate methods to refine the patients’ risk allocation process, distinguishing more adequately those who are likely to recur from those who are not. In this view, there is now evidence that the submicroscopic amounts of leukemic cells (called minimal residual disease, MRD), measured during the course of treatment, indicate the quality of response to therapy. Therefore, MRD might serve as an independent, additional biomarker to help identifying patients at higher risk of relapse. Detection of MRD requires the use of highly sensitive ancillary techniques, such as polymerase chain reaction (PCR) and multiparametric flow cytometry (MPFC). In the present manuscript, we will review the current approaches to investigate MRD and its clinical applications in AML management.


Download data is not yet available.

Abstract 4059
PDF Downloads 1039
HTML Downloads 1635
Untitled Downloads 0
Untitled Downloads 0


1) Estey EH. Acute myeloid leukemia: 2013 update on risk stratification and management. Am J Hematolol. 2013; 88(4): 318-327

2) Ferrara F, Schiffer CA: Acute myeloid leukemia in adults. Lancet 2013; 381: 484-495

3) Lowenberg B. Strategies in the treatment of acute myeloid leukemia. Haematologica 2004; 89: 1029-1032

4) Chen X, Xie H, Wood BL, Walter RB, Pagel JM, Becker PS, Sandhu VK, Abkowitz JL, Appelbaum FR, Estey EH. Relation of clinical response and minimal residual disease and their prognostic impact on outcome in acute myeloid leukemia. J ClinOncol. 2015; 33(11):1258-1264

5) Döhner H, Estey EH, Amadori S, Appelbaum FR, Büchner T, Burnett AK, Dombret H, Fenaux P, Grimwade D, Larson RA, Lo-Coco F, Naoe T, Niederwieser D, Ossenkoppele GJ, Sanz MA, Sierra J, Tallman MS, Löwenberg B, Bloomfield CD; European Leukemia Net. Diagnosis and management of acute myeloid leukemia in adults: recommendations from an international expert panel, on behalf of the European Leukemia Net.Blood. 2010;115(3):453-474

6) Kayser S, Walter RB, Stock W, Schlenk RF. Minimal residual disease in acute myeloid leukemia-current status and future perspectives. Curr Hematol Malig Rep. 2015;10(2):132-144

7) Grimwade D, Freeman SD. Defining minimal residual disease in acute myeloid leukemia: which platforms are ready for "prime time"? Blood. 2014;124(23):3345-3355

8) Chou WC, Tang JL, Wu SJ, Tsay W, Yao M, Huang SY, Huang KC, Chen CY, Huang CF, Tien HF. Clinical implications of minimal residual disease monitoring by quantitative polymerase chain reaction in acute myeloid leukemia patients bearing nucleophosmin (NPM1) mutations. Leukemia 2007; 21(5): 998-1004

9) Yin JA, O’Brien MA, Hills RK, Daly SB, Wheatley K, Burnett AK. 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. 2012;120(14): 2826-2835

10) Cilloni D, Renneville A, Hermitte F, Robert K. Hills RK, Daly S, JovanovicJV,Gottardi E, Fava M, Schnittger S, Weiss T, Izzo B, Nomdedeu J, van der Heijden A, van der Reijden BA, Jansen JH,. van der Velden VHJ, Ommen H, Preudhomme C, Saglio G, Grimwade D. Real-Time Quantitative Polymerase Chain Reaction detection of minimal residual disease by standardized WT1 assay to enhance risk stratification in acute myeloid leukemia: A European Leukemia Net Study. J Clin Oncol. 2009; 27(31): 5195-5201

11) Scholl C, Breitinger H, Schlenk RF, Döhner H, Fröhling S, Döhner K;.Development of a real-time RT-PCR assay for the quantification of the most frequent MLL/AF9 fusion types resulting from translocation t(9;11)(p22;q23) in acute myeloid leukemia. Genes, Chromosomes Cancer. 2003; 38(3): 274-280

12) Scholl C, Schlenk RF, Eiwen K, Döhner H, Fröhling S, Döhner K; AML Study GroupThe prognostic value of MLL-AF9 detection in patients with t(9;11)(p22;q23)-positive acute myeloid leukemia. Haematologica.2005; 90(12): 1626-1634

13) Perea G, Lasa A, Aventín A, Domingo A, Villamor N, Queipo de Llano MP, Llorente A, Juncà J, Palacios C, Fernández C, Gallart M, Font L, Tormo M, Florensa L, Bargay J, Martí JM, Vivancos P, Torres P, Berlanga JJ, Badell I, Brunet S, Sierra J, Nomdedéu JF; GrupoCooperativo para el Estudio y Tratamiento de las LeucemiasAgudas y Miel. Prognostic value of minimal residual disease (MRD) in acute myeloid leukemia with favorable cytogenetics [t(8;21) and inv(16)]. Leukemia 2006; 20(1): 87-94

14) Martinelli G, Rondoni M, Buonamici S, Ottaviani E, Piccaluga PP, Malagola M, Baccarani M. Molecular monitoring to identify a threshold of CBFbeta/MYH11 transcript below which continuous complete remission of acute myeloid leukemia inv16 is likely. Haematologica. 2004;89:495-497

15) Corbacioglu A, Scholl C, Schlenk RF, Eiwen K, Du J, Bullinger L, Fröhling S, Reimer P, Rummel M, Derigs HG, Nachbaur D, Krauter J, Ganser A, Döhner H, Döhner KPrognosticimpact of minimal residual disease in CBFB-MYH11-positive acute myeloid leukemia. J Clin Oncol. 2010;28:3724-3729

16) Jourdan E, Boissel N, Chevret S, Delabesse E, Renneville A, Cornillet P, Blanchet O, Cayuela JM, Recher C, Raffoux E, Delaunay J, Pigneux A, Bulabois CE, Berthon C, Pautas C, Vey N, Lioure B, Thomas X, Luquet I, Terré C, Guardiola P, Béné MC, Preudhomme C, Ifrah N, Dombret H; French AML Intergroup. Prospective evaluation of gene mutations and minimal residual disease in patients with core binding factor acute myeloid leukemia. Blood. 2013;121(12):2213-2223

17) Schnittger S, Weisser M, Schoch C, HiddemannW, Haferlach T, Kern W. New score predicting for prognosis in PML-RARA1, AML1-ETO1, or CBFBMYH111 acute myeloid leukemia based on quantification of fusion transcripts. Blood. 2003;102(8):2746-2755

18) Leroy H, de Botton S, Grardel-Duflos N, Darre S, Leleu X, Roumier C, Morschhauser F, Lai JL, Bauters F, Fenaux P, Preudhomme C. Prognostic value of real-time quantitative PCR(RQ-PCR) in AML with t(8;21). Leukemia. 2005;19(3):367-372

19) Zhu HH, Zhang XH, Qin YZ, Liu DH, Jiang H, Chen H, Jiang Q, Xu LP, Lu J, Han W, Bao L, Wang Y, Chen YH, Wang JZ, Wang FR, Lai YY, Chai JY, Wang LR, Liu YR, Liu KY, Jiang B, Huang XJ. 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 2013; 121(20): 4056-4062

20) Schlenk RF, Döhner K, Krauter J, Fröhling S, Corbacioglu A, Bullinger L, Habdank M, Späth D, Morgan M, Benner A, Schlegelberger B, Heil G, Ganser A, Döhner H; German-Austrian Acute Myeloid Leukemia Study Group. Mutations and treatment outcome in cytogenetically normal acute myeloid leukemia. N Engl J Med. 2008;358(18):1909-1918

21) Grunwald MR, Levis MJ. FLT3 inhibitors for acute myeloid leukemia: a review of their efficacy and mechanisms of resistance. Int J Hematol 2013; 97: 683-694

22) Cloos J, Goemans BF, Hess CJ, et al. Stability and prognostic influence of FLT3 mutations in paired initial and relapsed AML samples. Leukemia. 2006 ;20(7):1217-1220

23) Paietta E. Minimal residual disease in acute myeloid leukemia: coming of age. Hematol Educ Program. 2012; 2012: 35-42

24) Thol F, Kölking B, Damm F, Reinhardt K, Klusmann JH, Reinhardt D, von Neuhoff N, Brugman MH, Schlegelberger B, Suerbaum S, Krauter J, Ganser A, Heuser MNext-generation sequencing for minimal residual disease monitoring in acute myeloid leukemia patients with FLT3-ITD or NPM1 mutations. Genes Chromosome Cancer. 2012; 51 (7): 689-695

25) Spencer DH, Abel HJ, Lockwood CM, Payton JE, Szankasi P, Kelley TW, Kulkarni S, Pfeifer JD, Duncavage EJ. Detection of FLT3 internal tandem duplication in targeted, short-read-length, next-generation sequencing data. J Mo lDiagn. 2013;15(1):81-93

26) Bibault JE, Figeac M, Hélevaut N, Rodriguez C, Quief S, Sebda S, Renneville A, Nibourel O, Rousselot P, Gruson B, Dombret H, Castaigne S, Preudhomme C. Next-generation sequencing of FLT3 internal tandem duplications for minimal residual disease monitoring in acute myeloid leukemia. Oncotarget. 2015 6(26):22812-22821

27) Zuffa E, Franchini E, Papayannidis C, Baldazzi C, Simonetti G, Testoni N, Abbenante MC, Paolini S, Sartor C, Parisi S, Marconi G, Cattina F, Bochicchio MT, Venturi C, Ottaviani E, Cavo M, Martinelli G1Revealing very small FLT3 ITD mutated clones by ultra-deep sequencing analysis has important clinical implications in AML patients. Oncotarget. 2015;;6(31):31284-94

28) Gorello P, Cazzaniga G, Alberti F, Dell'Oro MG, Gottardi E, Specchia G, Roti G, Rosati R, Martelli MF, Diverio D, Lo Coco F, Biondi A, Saglio G, Mecucci C, Falini B: Quantitative assessment of minimal residual disease in acute myeloid leukemia carrying nucleophosmin (NPM1) gene mutations. Leukemia 2006; 20:1103-1108

29) Falini B, Mecucci C, Tiacci E, Alcalay M, Rosati R, Pasqualucci L, La Starza R, Diverio D, Colombo E, Santucci A, Bigerna B, Pacini R, Pucciarini A, Liso A, Vignetti M, Fazi P, Meani N, Pettirossi V, Saglio G, Mandelli F, Lo-Coco F, Pelicci PG, Martelli MF; GIMEMA Acute Leukemia Working Party.Cytoplasmic nucleophosmin in acute myelogenous leukemia with a normal karyotype.NEngl J Med. 2005;352(3):254-266

30) Kramer M, Bornhäuser M, Schaich M, Schetelig J, Platzbecker U, Röllig C, Heiderich C, Landt O, Ehninger G, Thiede C; Study Alliance Leukemia (SAL). The level of residual disease based on mutant NPM1 is an independent prognostic factor for relapse and survival in AML.Blood. 2013; 122(1):83-92

31) Schnittger S, Kern W, Tschulik C, Weiss T, Dicker F, Falini B, Haferlach C, Haferlach T. Minimal residual disease levels assessed by NPM1 mutation-specific RQ-PCR provide important prognostic information in AML.Blood. 2009;114(11):2220-2231

32) Krönke J, Schlenk RF, Jensen KO, Tschürtz F, Corbacioglu A, Gaidzik VI, Paschka P, Onken S, Eiwen K, Habdank M, Späth D, Lübbert M, Wattad M, Kindler T, Salih HR, Held G, Nachbaur D, von Lilienfeld-Toal M, Germing U, Haase D, Mergenthaler HG, Krauter J, Ganser A, Göhring G, Schlegelberger B, Döhner H, Döhner K. 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. 2011;29(19): 2709-2716

33) Ivey A, Hills RK, Simpson MA, Jovanovic JV, Gilkes A, Grech A, Patel Y, Bhudia N, Farah H, Mason J, Wall K, Akiki S, Griffiths M, Solomon E, McCaughan F, Linch DC, Gale RE, Vyas P, Freeman SD, Russell N, Burnett AK, Grimwade D; UK National Cancer Research Institute AML Working Group. Assessment of Minimal Residual Disease in Standard-Risk AML.N Engl J Med.2016;374(5):422-433

34) Ley T , Ding L, Walter M, McLellan MD, Lamprecht T, Larson DE, Kandoth C, Payton JE, Baty J, Welch J, Harris CC, Lichti CF, Townsend RR, Fulton RS, Dooling DJ, Koboldt DC, Schmidt H, Zhang Q, Osborne JR, Lin L, O'Laughlin M, McMichael JF, Delehaunty KD, McGrath SD, Fulton LA, Magrini VJ, Vickery TL, Hundal J, Cook LL, Conyers JJ, Swift GW, Reed JP, Alldredge PA, Wylie T, Walker J, Kalicki J, Watson MA, Heath S, Shannon WD, Varghese N, Nagarajan R, Westervelt P, Tomasson MH, Link DC, Graubert TA, DiPersio JF, Mardis ER, Wilson RK. DNMT3A mutations in acute myeloid leukemia. N Engl J Med. 2010; 363 (25): 2424-2433

35) Yan XJ, Xu J, Gu ZH,Pan CM, Lu G, Shen Y, Shi JY, Zhu YM, Tang L, Zhang XW, Liang WX, Mi JQ, Song HD, Li KQ, Chen Z, Chen SJ.. Exome sequencing identifies somatic mutations of DNA methyltransferase gene DNMT3A in acute monocytic leukemia. Nat Genet. 2011; 43(4): 309-315
36) Pløen GG, Nederby L, Guldberg P, Hansen M, Ebbesen LH, Jensen UB, Hokland P, Aggerholm A. Persistence of DNMT3A mutations at long-term remission in adult patients with AML. Br J Haematol. 2014; 167 (4): 478-486

37) Nomdedéu JF, Hoyos M, Carricondo M, Bussaglia E, Estivill C, Esteve J, Tormo M, Duarte R, Salamero O, de Llano MP, García A, Bargay J, Heras I, Martí-Tutusaus JM, Llorente A, Ribera JM, Gallardo D, Aventin A, Brunet S, Sierra J; CETLAM Group. Bone marrow WT1 levels at diagnosis, post-induction and post-intensification in adult de novo AML. Leukemia.2013;27(11):2157-2164

38) Lambert J, Lambert J, Nibourel O, Pautas C, Hayette S, Cayuela JM, Terré C, Rousselot P, Dombret H, Chevret S, Preudhomme C, Castaigne S, Renneville A. MRD assessed by WT1 and NPM1 transcript levels identifies distinct outcomes in AML patients and is influenced by gemtuzumabozogamicin. Oncotarget. 2014;5(15):6280-6288

39) Rossi G1, Minervini MM, Melillo L, di Nardo F, de Waure C, Scalzulli PR, Perla G, Valente D, Sinisi N, Cascavilla N. Predictive role of minimal residual disease and log clearance in acute myeloid leukemia: a comparison between multiparameter flow cytometry and Wilm's tumor 1 levels. Ann Hematol. 2014;93(7):1149-1157

40) Zhong L, Wei L, Chen J, Huang X, Gong Y, Lu Y. WT1 expression in circulating RNA as a minimal residual disease marker for AML patients after stem cell transplantation. MolDiagnTher 2015 ;19(4):205-212

41) Zhang R, Yang JY, Sun HQ, Jia H, Liao J, Shi YJ, Li G. Comparison of minimal residual disease (MRD) monitoring by WT1 quantification between childhood acute myeloid leukemia and acute lymphoblastic leukemia. Eur Rev Med Pharmacol Sci. 2015;19(14):2679-2688

42) Hasle H, Kjeldsen E, Hokland P.WT1 gene expression: an excellent tool for monitoring minimal residual disease in 70% of acute myeloid leukemia patients: results from a single centre study. Br J Haematol. 2004;125(5):590-600

43) Ommen HB, Nyvold CG, Braendstrup K, Andersen BL, Ommen IB, Hasle H, Hokland P, Ostergaard M. Relapse prediction in acute myeloid leukaemia 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. 2008;141(6):782-791

44) Goswami M, McGowan KS, Lu K, Jain N, Candia J, Hensel NF, Tang J, Calvo KR, Battiwalla M, Barrett AJ, Hourigan CS. A multigene array for measurable residual disease detection in AML patients undergoing SCT. Bone Marrow Transplant. 2015;50(5):642-651

45) Ossenkoppele GJ, van de Loosdrecht AA, Schuurhuis GJ Review of the relevance of aberrant antigen expression by flow cytometry in myeloid neoplasms.Br J Haematol. 2011 May;153(4):421-436

46) San Miguel JF, Vidriales MB, Lopez-Berges C López-Berges C, Díaz-Mediavilla J, Gutiérrez N, Cañizo C, Ramos F, Calmuntia MJ, Pérez JJ, González M, Orfao A. 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(6): 1746-1751

47) Olaru D, Campos L, Flandrin P, Nadal N, Duval A, Chautard S, Guyotat D. Multiparametric analysis of normal and postchemotherapy bone marrow: Implication for the detection of leukemia-associated immunophenotypes. Cytometry B ClinCytom. 2008;74(1):17-24

48) Macedo A, Orfao A, Ciudad J, Gonzalez M, Vidriales B, Lopez-BergesMC, Martinez A, Landolfi C, Canizo C, San Miguel JF. Phenotypicanalysis of CD34 subpopulations in normal human bone marrowand its application for the detection of minimal residual disease.Leukemia 1995;9:1896–1901

49) Béné MC, Nebe T, Bettelheim P, Buldini B, Bumbea H, Kern W, Lacombe F, Lemez P, Marinov I, Matutes E, Maynadié M, Oelschlagel U, Orfao A, Schabath R, Solenthaler M, Tschurtschenthaler G, Vladareanu AM, Zini G, Faure GC, Porwit A. Immunophenotyping of acute leukemia and lymphoproliferative disorders: a consensus proposal of the European LeukemiaNet Work Package 10.Leukemia. 2011;25(4):567-574

50) Johansson U, Bloxham D, Couzens S, Jesson J, Morilla R, Erber W, Macey M; British Committee for Standards in Haematology. Guidelines on the use of multicolour flow cytometry in the diagnosis of haematological neoplasms. British Committee for Standards in Haematology.Br J Haematol. 2014 ;165(4):455-488

51) San Miguel JF, Martinez a, MacedoA, Vidriales MB, Lopez-Berges C,Gonzalez M, Caballero D, Garc?a-Marcos M a, Ramos F, Fernandez-Calvo J, Calmuntia MJ, Diaz-Mediavilla J, Orfao A. Immunophenotyping investigation of minimal residual disease is a useful approach forpredicting relapse in acute myeloid leukemia patients. Blood 1997;90:2465–2470

52) Kern W, Schnittger S. Monitoring of acute myeloid leukemia by flow cytometry. CurrOncol Rep. 2003;5:405–412

53) Venditti A, Buccisano F, Del Poeta G, Maurillo L, Tamburini A, Cox C, Battaglia A, Catalano G, Del Moro B, Cudillo L, Postorino M, Masi M, Amadori S. Level of minimal residual disease after consolidation therapy predicts outcome in acute myeloid leukemia: Presented inpart at the 41st Annual Meeting of the American Society of Hematology, December 3–7, 1999, New Orleans, LA. Blood 2000;96:3948–3952

54) 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

55) Kern W, Haferlach T, Schoch C, Loffler H, Gassmann W, Heinecke A, Sauerland MC, Berdel W, Buchner T, Hiddemann W.Early blast clearance by remission induction therapy is a major independent prognostic factor for both achievement of complete remission and long-term outcome in acute myeloid leukemia: data from the German AML Cooperative Group (AMLCG) 1992 Trial. Blood 2003; 101, 64-70

56) Gianfaldoni G, Mannelli F, Bencini S, Leoni F, Baldini S, Bosi A. Peripheral blood blast clearance during induction therapy in acute myeloid leukemia. Blood. 2008;111:1746-1747

57) Elliott MA, Litzow MR, Letendre LL, Wolf RC, Hanson CA, Tefferi A, Tallman MS.Early peripheral blood blast clearance during induction chemotherapy for acute myeloid leukemia predicts superior relapse-free survival. Blood. 2007;110:4172-4174

58) Maurillo L, Buccisano F, Piciocchi A, Del Principe MI, Sarlo C, Di Veroli A, Panetta P, Irno-Consalvo M, Nasso D, Ditto C, Refrigeri M, De Angelis G, Cerretti R, Arcese W, Sconocchia G, Lo-Coco F, Amadori S, Venditti A. Minimal residual disease as biomarker for optimal biologic dosing of ARA-C in patients with acute myeloid leukemia.Am J Hematol. 2015 Feb;90(2):125-131

59) Köhnke T, Sauter D, Ringel K, Hoster E, Laubender RP, Hubmann M, Bohlander SK, Kakadia PM,Schneider S, Dufour A, Sauerland M-C, Berdel WE, Büchner T, Wörmann B, Braess J, Hiddemann W, Spiekermann K, Subklewe M. Early assessment of minimal residua ldisease in AML by flowcytometry during aplasia identifies patients at increased riskof relapse. Leukemia 2014; 1-10

60) Al-Mawali A, Gillis D, Lewis I. The use of receiver operating characteristic analysis for detection of minimal residual disease using five-color multiparameter flow cytometry in acute myeloid leukemia identifies patients with high risk of relapse. Cytometry B Clin Cytom 2009; 76, 91-101

61) Terwijn M, van Putten WL, Kelder A, van der Velden VH, Brooimans RA, Pabst T, Maertens J, Boeckx N, de Greef GE, Valk PJ, Preijers FW, Huijgens PC, Dräger AM, Schanz U, Jongen-Lavrecic M, Biemond BJ, Passweg JR, van Gelder M, Wijermans P, Graux C, Bargetzi M, Legdeur MC, Kuball J, de Weerdt O, Chalandon Y, Hess U, Verdonck LF, Gratama JW, Oussoren YJ, Scholten WJ, Slomp J, Snel AN, Vekemans MC, Löwenberg B, Ossenkoppele GJ, Schuurhuis GJ. J Clin Oncol. 2013;31(31):3889-3897

62) Freeman SD, Virgo P, Couzens S, Grimwade D, Russell N, Hills RK, Burnett AK Prognostic relevance of treatment response measured by flow cytometric residual disease detection in older patients with acute myeloid leukemia. J Clin Oncol. 2013;31(32):4123-4131

63) Venditti A, Buccisano F, Del Poeta G, Maurillo L, Tamburini A, Cox C, Battaglia A, Catalano G, Del Moro B, Cudillo L, Postorino M, Masi M, Amadori S.Level of minimal residual disease after consolidation therapy predicts outcome in acute myeloid leukemia. Blood 2000; 96, 3948-3952
64) Buccisano F, Maurillo L, Gattei V, Del Poeta G, Del Principe MI, Cox MC, Panetta P, Consalvo MI, Mazzone C, Neri B, Ottaviani L, Fraboni D, Tamburini A, Lo-Coco F, Amadori S, Venditti A The kinetics of reduction of minimal residual disease impacts on duration of response and survival of patients with acute myeloid leukemia. Leukemia 2006; 20, 1783-1789

65) Maurillo L, Buccisano F, Del Principe MI, Sarlo C, Di Caprio L, Ditto C, Giannotti F, Nasso D, Ceresoli E, Postorino M, Refrigeri M, Amadori S, Venditti A.. Toward Optimization of Postremission Therapy for Residual Disease-Positive Patients With Acute Myeloid Leukemia. J Clin Oncol 2008; 26:4944-4951

66) Walter RB, Buckley SA, Pagel JM, Wood BL, Storer BE, Sandmaier BM,Fang M, Gyurkocza B, Delaney C, Radich JP, Estey EH, Appelbaum FR. Significance of minimal residual disease before myeloablative allogeneic hematopoietic cell transplantation for AML in first and second complete remission. Blood. 2013; 122(10):1813–1821

67) Walter RB, Gyurkocza B, Storer BE, Godwin CD, Pagel JM, Buckley SA, Sorror ML, Wood BL, Storb R, Appelbaum FR, Sandmaier BM. Comparison of minimal residual disease as outcome predictor for AML patients in first complete remission undergoing myeloablative or nonmyeloablative allogeneic hematopoietic cell transplantation. Leukemia 2015; 29(1): 137-144

68) Zhou Y, Othus M, Araki D, Wood BL, Radich JP, Halpern AB, Mielcarek M, Estey EH, Appelbaum FR, Walter RB. Pre- and post-transplant quantification of measurable ('minimal') residual disease via multiparameter flow cytometry in adult acute myeloid leukemia. Leukemia. 2016 doi: 10.1038/leu.2016.46. [Epub ahead of print]

69) Braess J, Spiekermann K, Staib P, Grüneisen A, Wörmann B, Ludwig WD, Serve H, Reichle A, Peceny R, Oruzio D, Schmid C, Schiel X, Hentrich M, Sauerland C, Unterhalt M, Fiegl M, Kern W, Buske C, Bohlander S, Heinecke A, Baurmann H, Beelen DW, Berdel WE, Büchner T, Hiddemann W. Dose-dense induction with sequential high-dose cytarabine and mitoxantone (S-HAM) and pegfilgrastim results in a high efficacy and a short duration of critical neutropenia in de novo acute myeloid leukemia: a pilot study of the AMLCG. Blood 2009; 113, 3903-3910

70) Schaich M, Illmer T, Aulitzky WE, BornhaeuserM, GriesshammerM, s Haenel M, Ho AD, Link H, Neubauer A, Schmitz N, Serve H, Thiede C, Thiel E, WagnerT, WandtH, BerdelW, GEhninger G on behalf of the Study Alliance Leukemia (SAL)Upfront Allogeneic Stem Cell Transplantation for Remission Induction in High-Risk Acute Myeloid Leukemia Patients within the Randomized Multi- Center Trial AML2003. Blood 2008; 112, 978a.

71) Buccisano F, Maurillo L, Piciocchi A, Del Principe MI, Sarlo C, Cefalo M, Ditto C, Di Veroli A, De Santis G, Irno Consalvo M, Fraboni D, Panetta P, Palomba P, Attrotto C, Del Poeta G, Sconocchia G, Lo-Coco F, Amadori S, Venditti A. Minimal residual disease negativity in elderly patients with acute myeloid leukemia may indicate different postremission strategies than in younger patients. Ann Hematol. 2015; 94(8):1319-1326

72) Buccisano F, Maurillo L, Del Principe MI, Del Poeta G, Sconocchia G, Lo-Coco F, Arcese W, Amadori S, Venditti A. Prognostic and therapeutic implications of minimal residual disease detection in acute myeloid leukemia.Blood. 2012, 119, 332-341

73) Buccisano F, Maurillo L, Spagnoli A, Del Principe MI, Fraboni D, Panetta P, Ottone T, Consalvo MI, Lavorgna S, Bulian P, Ammatuna E, Angelini DF, Diamantini A, Campagna S, Ottaviani L, Sarlo C, Gattei V, Del Poeta G, Arcese W, Amadori S, Lo Coco F, Venditti ACytogenetic and molecular diagnostic characterization combined to post-consolidation minimal residual disease assessment by flow-cytometry improves risk stratification in adult acute myeloid leukemia. Blood. 2010;116:2295-2303
74) Langebrake C, Brinkmann I, Teigler-Schlegel A, CreutzigU, Griesinger F, Puhlmann U, Reinhardt D. Immunophenotypic differences between diagnosis and relapse in childhood AML: Implications for MRD monitoring. Cytometry B Clin Cytom 2005;63B:1–9

75) Baer MR, Stewart CC, Dodge RK, Leget G, Sule N, MrozekK,Schiffer CA, Powell BL, Kolitz JE, Moore JO, Stone RM, Davey FR, Carroll AJ, Larson RA, Bloomfield CD. High frequency of immunophenotype changes in acute myeloid leukemia at relapse: Implications for residual disease detection (Cancer and Leukemia Group B Study 8361). Blood 2001;97:3574–3580

76) Voskova D, Schoch C, Schnittger S, Hiddemann W, HaferlachT,Kern W. Stability of leukemia-associated aberrant immunophenotypes in patients with acute myeloid leukemia between diagnosis and relapse: comparison with cytomorphologic, cytogenetic, and molecular genetic findings. Cytometry B ClinCytom 2004;62B:25–38

77) Van der Velden VHJ, van der Sluijs-Geling A, Gibson BES, teMarvelde JG, Hoogeveen PG, Hop WCJ, Wheatley K, Bierings MB, Schuurhuis GJ, de Graaf SSN, van Wering ER, van Dongen JJM. Clinical significance of flow cytometric minimal residual disease detection in pediatric acute myeloid leukemia patients treated according to the DCOG ANLL97/MRC AML12 protocol. Leukemia 2010;24:1599–1606

78) Bachas C, Schuurhuis GJ, Assaraf YG, Kwidama ZJ, Kelder A, Wouters F, Snel a N, Kaspers GJL, Cloos J. The role of minor subpopulations within the leukemic blast compartment of AML patients at initial diagnosis in the development of relapse. Leukemia 2012;26:1313–1320

79) Angelini DF, Ottone T, Guerrera G, Lavorgna S, Cittadini M, Buccisano F, De Bardi M, Gargano F, Maurillo L, Divona M, Noguera NI, Consalvo MI, Borsellino G, Bernardi G, Amadori S, Venditti A, Battistini L, Lo-Coco F. A Leukemia-Associated CD34/CD123/CD25/CD99+ Immunophenotype Identifies FLT3-Mutated Clones in Acute Myeloid Leukemia.Clin Cancer Res. 2015 1;21(17):3977-3985

80) Maurillo L, Buccisano F, Spagnoli A, Del Poeta G, Panetta P, Neri B, Del Principe MI, Mazzone C, Consalvo MI, Tamburini A, Ottaviani L, Fraboni D, Sarlo C, De Fabritiis P, Amadori S, Venditti A.Monitoring of minimal residual disease in adult acute myeloid leukemia using peripheral blood as an alternative source to bone marrow. Haematologica. 2007 ;92(5):605-611

81) Zeijlemaker W, Kelder A, Oussoren-Brockhoff YJ, Scholten WJ, Snel AN, Veldhuizen D, Cloos J, Ossenkoppele GJ, Schuurhuis GJ. Peripheral blood minimal residual disease may replace bone marrow minimal residual disease as an immunophenotypic biomarker for impending relapse in acute myeloid leukemia. Leukemia. 2016;30(3):708-715

82) Anguille S, Van Tendeloo VF, Berneman ZN. Leukemia-associated antigens and their relevance to the immunotherapy of acute myeloid leukemia. Leukemia. 2012;26(10):2186-2196

83) Terwijn M, Zeijlemaker W, Kelder A, Rutten AP, Snel AN, Scholten WJ, Pabst T, Verhoef G, Löwenberg B, Zweegman S, Ossenkoppele GJ, Schuurhuis GJ. Leukemic Stem Cell Frequency: A Strong Biomarker for Clinical Outcome in Acute Myeloid Leukemia. Plos One 2014; :e107587

84) Majeti R, Chao MP, Alizadeh AA, Pang WW, Jaiswal S, Gibbs KD Jr, van Rooijen N, Weissman IL. CD47 is an adverse prognostic factor and therapeutic antibody target on human acute myeloid leukemia stem cells. Cell. 2009;138(2): 286-299

85) van Rhenen A, van Dongen GA, Kelder A, Rombouts EJ, Feller N, Moshaver B, Stigter-van Walsum M, Zweegman S, Ossenkoppele GJ, Jan Schuurhuis G The novel AML stem cell associated antigen CLL-1 aids in discrimination between normal and leukemic stem cells. Blood. 2007 ;110(7):2659-2666

86) Will B, Steidl U. Multiparameter fluorescence-activated cell sorting and analysis of stem and progenitor cells in myeloid malignancies. Best Pract Res ClinHaematol. 2010; 23(3): 391-401

87) van Rhenen A, Moshaver B, Kelder A, Feller N, Nieuwint AW, Zweegman S, Ossenkoppele GJ, Schuurhuis GJ.Aberrant marker expression patterns on the CD34+CD38- stem cell compartment in acute myeloid leukemia allows to distinguish the malignant from the normal stem cell compartment both at diagnosis and in remission. Leukemia. 2007 ;21(8):1700-1707

88) van Rhenen A, Feller N, Kelder A, Westra AH, Rombouts E, Zweegman S, van der Pol MA, Waisfisz Q, Ossenkoppele GJ, Schuurhuis GJ.High stem cell frequency in acute myeloid leukemia at diagnosis predicts high minimal residual disease and poor survival.Clin Cancer Res. 2005;11(18):6520-6527

89) Zeijlemaker W, Kelder A, Oussoren-Brockhoff YJ, Scholten WJ, Snel AN, Veldhuizen D, Cloos J, Ossenkoppele GJ, Schuurhuis GJ. A simple one-tube assay for immunophenotypical quantification of leukemic stem cells in acute myeloid leukemia. Leukemia. 2016;30(2):439-446

Similar Articles

You may also start an advanced similarity search for this article.