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Association of Measurable Residual Disease With Survival Outcomes in Patients With Acute Myeloid LeukemiaA Systematic Review and Meta-analysis

Educational Objective
To learn the association of measurable residual disease (MRD) with survival outcomes in patients with acute myeloid leukemia (AML).
1 Credit CME
Key Points

Question  What is the association between measurable residual disease (MRD) and survival outcomes in patients with acute myeloid leukemia?

Findings  In a systematic review and meta-analysis of 81 publications reporting on 11 151 patients with acute myeloid leukemia, the estimated 5-year disease-free survival was 64% for patients without MRD and 25% for those with MRD. The estimated overall survival was 68% for patients without MRD and 34% for those with MRD.

Meaning  The findings of this study suggest that, in patients with acute myeloid leukemia, achievement of MRD negativity is associated with superior long-term survival and warrants consideration as a clinical trial end point that may allow for more rapid evaluation of the efficacy of novel therapies.

Abstract

Importance  Measurable residual disease (MRD) refers to neoplastic cells that cannot be detected by standard cytomorphologic analysis. In patients with acute myeloid leukemia (AML), determining the association of MRD with survival may improve prognostication and inform selection of efficient clinical trial end points.

Objective  To examine the association between MRD status and disease-free survival (DFS) and overall survival (OS) in patients with AML using scientific literature.

Data Sources  Clinical studies on AML published between January 1, 2000, and October 1, 2018, were identified via searches of PubMed, Embase, and MEDLINE.

Study Selection  Literature search and study screening were performed according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines. Studies that assessed DFS or OS by MRD status in patients with AML were included. Reviews, non–English-language articles, and studies reporting only outcomes after hematopoietic cell transplantation or those with insufficient description of MRD information were excluded.

Data Extraction and Synthesis  Study sample size, median patient age, median follow-up time, MRD detection method, MRD assessment time points, AML subtype, specimen source, and survival outcomes were extracted. Meta-analyses were performed separately for DFS and OS using bayesian hierarchical modeling.

Main Outcomes and Measures  Meta-analyses of survival probabilities and hazard ratios (HRs) were conducted for OS and DFS according to MRD status.

Results  Eighty-one publications reporting on 11 151 patients were included. The average HR for achieving MRD negativity was 0.36 (95% bayesian credible interval [CrI], 0.33-0.39) for OS and 0.37 (95% CrI, 0.34-0.40) for DFS. The estimated 5-year DFS was 64% for patients without MRD and 25% for those with MRD, and the estimated OS was 68% for patients without MRD and 34% for those with MRD. The association of MRD negativity with DFS and OS was significant for all subgroups, with the exception of MRD assessed by cytogenetics or fluorescent in situ hybridization.

Conclusions and Relevance  The findings of this meta-analysis suggest that achievement of MRD negativity is associated with superior DFS and OS in patients with AML. The value of MRD negativity appears to be consistent across age groups, AML subtypes, time of MRD assessment, specimen source, and MRD detection methods. These results support MRD status as an end point that may allow for accelerated evaluation of novel therapies in AML.

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Article Information

Accepted for Publication: July 20, 2020.

Corresponding Author: Farhad Ravandi, MD, Department of Leukemia, Unit 428, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030 (fravandi@mdanderson.org).

Published Online: October 8, 2020. doi:10.1001/jamaoncol.2020.4600

Author Contributions: Dr Ravandi had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Drs Short and Zhou contributed equally to this work.

Concept and design: Short, Zhou, Berry, Freeman, Hourigan, Kantarjian, Ravandi.

Acquisition, analysis, or interpretation of data: Short, Zhou, Fu, Berry, Walter, Freeman, Huang, Nogueras Gonzalez, Hwang, Qi, Ravandi.

Drafting of the manuscript: Short, Zhou, Fu, Huang, Hwang, Qi, Ravandi.

Critical revision of the manuscript for important intellectual content: Short, Berry, Walter, Freeman, Hourigan, Nogueras Gonzalez, Kantarjian, Ravandi.

Statistical analysis: Short, Zhou, Fu, Berry, Huang, Nogueras Gonzalez, Hwang, Qi, Kantarjian.

Obtained funding: Ravandi.

Administrative, technical, or material support: Ravandi.

Supervision: Kantarjian, Ravandi.

Conflict of Interest Disclosures: Dr Berry is co-owner of Berry Consultants LLC, a company that designs bayesian and adaptive clinical trials. Dr Freeman reported receiving personal fees from JAZZ outside the submitted work. Dr Hourigan reported receiving research funding from Sellas and Merck during the conduct of the study. No other disclosures were reported.

Funding/Support: The study was supported by MD Anderson Cancer Center support grant CA016672 and Specialized Programs of Research Excellence. Dr Short is supported by the K12 Paul Calabresi Clinical Oncology Scholar Award and the American Society of Hematology Junior Faculty Scholar Award in Clinical Research. This study was supported in part by the Intramural Research Program of the National Heart, Lung, and Blood Institute of the National Institutes of Health.

Role of the Funder/Sponsor: The funding sources had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

References
1.
Döhner  H , Weisdorf  DJ , Bloomfield  CD .  Acute myeloid leukemia.   N Engl J Med. 2015;373(12):1136-1152. doi:10.1056/NEJMra1406184 PubMedGoogle Scholar
2.
Short  NJ , Rytting  ME , Cortes  JE .  Acute myeloid leukaemia.   Lancet. 2018;392(10147):593-606. doi:10.1016/S0140-6736(18)31041-9 PubMedGoogle Scholar
3.
Papaemmanuil  E , Gerstung  M , Bullinger  L ,  et al.  Genomic classification and prognosis in acute myeloid leukemia.   N Engl J Med. 2016;374(23):2209-2221. doi:10.1056/NEJMoa1516192 PubMedGoogle Scholar
4.
Grimwade  D , Hills  RK , Moorman  AV ,  et al; National Cancer Research Institute Adult Leukaemia Working Group.  Refinement of cytogenetic classification in acute myeloid leukemia: determination of prognostic significance of rare recurring chromosomal abnormalities among 5876 younger adult patients treated in the United Kingdom Medical Research Council trials.   Blood. 2010;116(3):354-365. doi:10.1182/blood-2009-11-254441 PubMedGoogle Scholar
5.
Döhner  H , Estey  E , Grimwade  D ,  et al.  Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel.   Blood. 2017;129(4):424-447. doi:10.1182/blood-2016-08-733196 PubMedGoogle Scholar
6.
Hourigan  CS , Karp  JE .  Minimal residual disease in acute myeloid leukaemia.   Nat Rev Clin Oncol. 2013;10(8):460-471. doi:10.1038/nrclinonc.2013.100 PubMedGoogle Scholar
7.
Schuurhuis  GJ , Heuser  M , Freeman  S ,  et al.  Minimal/measurable residual disease in AML: a consensus document from the European LeukemiaNet MRD Working Party.   Blood. 2018;131(12):1275-1291. doi:10.1182/blood-2017-09-801498 PubMedGoogle Scholar
8.
Hochhaus  A , Larson  RA , Guilhot  F ,  et al; IRIS Investigators.  Long-term outcomes of imatinib treatment for chronic myeloid leukemia.   N Engl J Med. 2017;376(10):917-927. doi:10.1056/NEJMoa1609324 PubMedGoogle Scholar
9.
Böttcher  S , Ritgen  M , Fischer  K ,  et al.  Minimal residual disease quantification is an independent predictor of progression-free and overall survival in chronic lymphocytic leukemia: a multivariate analysis from the randomized GCLLSG CLL8 trial.   J Clin Oncol. 2012;30(9):980-988. doi:10.1200/JCO.2011.36.9348 PubMedGoogle Scholar
10.
Brüggemann  M , Raff  T , Flohr  T ,  et al; German Multicenter Study Group for Adult Acute Lymphoblastic Leukemia.  Clinical significance of minimal residual disease quantification in adult patients with standard-risk acute lymphoblastic leukemia.   Blood. 2006;107(3):1116-1123. doi:10.1182/blood-2005-07-2708 PubMedGoogle Scholar
11.
Bassan  R , Spinelli  O , Oldani  E ,  et al.  Improved risk classification for risk-specific therapy based on the molecular study of minimal residual disease (MRD) in adult acute lymphoblastic leukemia (ALL).   Blood. 2009;113(18):4153-4162. doi:10.1182/blood-2008-11-185132 PubMedGoogle Scholar
12.
Berry  DA , Zhou  S , Higley  H ,  et al.  Association of minimal residual disease with clinical outcome in pediatric and adult acute lymphoblastic leukemia: a meta-analysis.   JAMA Oncol. 2017;3(7):e170580. doi:10.1001/jamaoncol.2017.0580 PubMedGoogle Scholar
13.
Pui  CH , Pei  D , Coustan-Smith  E ,  et al.  Clinical utility of sequential minimal residual disease measurements in the context of risk-based therapy in childhood acute lymphoblastic leukaemia: a prospective study.   Lancet Oncol. 2015;16(4):465-474. doi:10.1016/S1470-2045(15)70082-3 PubMedGoogle Scholar
14.
Vora  A , Goulden  N , Wade  R ,  et al.  Treatment reduction for children and young adults with low-risk acute lymphoblastic leukaemia defined by minimal residual disease (UKALL 2003): a randomised controlled trial.   Lancet Oncol. 2013;14(3):199-209. doi:10.1016/S1470-2045(12)70600-9 PubMedGoogle Scholar
15.
Buckley  SA , Wood  BL , Othus  M ,  et al.  Minimal residual disease prior to allogeneic hematopoietic cell transplantation in acute myeloid leukemia: a meta-analysis.   Haematologica. 2017;102(5):865-873. doi:10.3324/haematol.2016.159343 PubMedGoogle Scholar
16.
Terwijn  M , van Putten  WL , Kelder  A ,  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. 2013;31(31):3889-3897. doi:10.1200/JCO.2012.45.9628 PubMedGoogle Scholar
17.
Freeman  SD , Virgo  P , Couzens  S ,  et al.  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. doi:10.1200/JCO.2013.49.1753 PubMedGoogle Scholar
18.
Ivey  A , Hills  RK , Simpson  MA ,  et al; 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. doi:10.1056/NEJMoa1507471 PubMedGoogle Scholar
19.
Ravandi  F , Jorgensen  J , Borthakur  G ,  et al.  Persistence of minimal residual disease assessed by multiparameter flow cytometry is highly prognostic in younger patients with acute myeloid leukemia.   Cancer. 2017;123(3):426-435. doi:10.1002/cncr.30361 PubMedGoogle Scholar
20.
Balsat  M , Renneville  A , Thomas  X ,  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. 2017;35(2):185-193. doi:10.1200/JCO.2016.67.1875 PubMedGoogle Scholar
21.
Freeman  SD , Hills  RK , Virgo  P ,  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. 2018;36(15):1486-1497. doi:10.1200/JCO.2017.76.3425 PubMedGoogle Scholar
22.
Jongen-Lavrencic  M , Grob  T , Hanekamp  D ,  et al.  Molecular minimal residual disease in acute myeloid leukemia.   N Engl J Med. 2018;378(13):1189-1199. doi:10.1056/NEJMoa1716863 PubMedGoogle Scholar
23.
Short  NJ , Ravandi  F .  How close are we to incorporating measurable residual disease into clinical practice for acute myeloid leukemia?   Haematologica. 2019;104(8):1532-1541. doi:10.3324/haematol.2018.208454 PubMedGoogle Scholar
24.
Moher  D , Liberati  A , Tetzlaff  J , Altman  DG ; PRISMA Group.  Preferred Reporting Items for Systematic Reviews and Meta-analyses: the PRISMA statement.   PLoS Med. 2009;6(7):e1000097. doi:10.1371/journal.pmed.1000097 PubMedGoogle Scholar
25.
Parkin  B , Londoño-Joshi  A , Kang  Q , Tewari  M , Rhim  AD , Malek  SN .  Ultrasensitive mutation detection identifies rare residual cells causing acute myelogenous leukemia relapse.   J Clin Invest. 2017;127(9):3484-3495. doi:10.1172/JCI91964 PubMedGoogle Scholar
26.
Weber  S , Alpermann  T , Dicker  F ,  et al.  BAALC expression: a suitable marker for prognostic risk stratification and detection of residual disease in cytogenetically normal acute myeloid leukemia.   Blood Cancer J. 2014;4:e173. doi:10.1038/bcj.2013.71 PubMedGoogle Scholar
27.
Weber  S , Haferlach  T , Alpermann  T ,  et al.  Feasibility of BAALC gene expression for detection of minimal residual disease and risk stratification in normal karyotype acute myeloid leukaemia.   Br J Haematol. 2016;175(5):904-916. doi:10.1111/bjh.14343 PubMedGoogle Scholar
28.
Steinbach  D , Bader  P , Willasch  A ,  et al.  Prospective validation of a new method of monitoring minimal residual disease in childhood acute myelogenous leukemia.   Clin Cancer Res. 2015;21(6):1353-1359. doi:10.1158/1078-0432.CCR-14-1999 PubMedGoogle Scholar
29.
Guyot  P , Ades  AE , Ouwens  MJNM , Welton  NJ .  Enhanced secondary analysis of survival data: reconstructing the data from published Kaplan-Meier survival curves.   BMC Med Res Methodol. 2012;12(1):9. doi:10.1186/1471-2288-12-9 PubMedGoogle Scholar
30.
Berry  DA .  Bayesian clinical trials.   Nat Rev Drug Discov. 2006;5(1):27-36. doi:10.1038/nrd1927 PubMedGoogle Scholar
31.
Gelman  A , Carlin  JB , Stern  HS , Dunson  DB , Vehtari  A , Rubin  DB .  Bayesian Data Analysis. 3rd ed. Text in Statistical Science series. CRC press; 2013. doi:10.1201/b16018
32.
Higgins  J , Thomas  J , Chandler  J ,  et al Cochrane handbook for systematic reviews of interventions. Accessed September 1, 2019. http://www.training.cochrane.org/handbook
33.
Borenstein  M , Hedges  LV , Higgins  JP , Rothstein  HR .  Introduction to Meta-analysis. John Wiley & Sons; 2011.
34.
Fu  C , Zhou  S , Berry  DA . Evidence synthesis with reconstructed survival data. Pennsylvania State University Technical Report; 2020.
35.
Royston  P , Parmar  MK .  Restricted mean survival time: an alternative to the hazard ratio for the design and analysis of randomized trials with a time-to-event outcome.   BMC Med Res Methodol. 2013;13:152. doi:10.1186/1471-2288-13-152 PubMedGoogle Scholar
36.
Uno  H , Claggett  B , Tian  L ,  et al.  Moving beyond the hazard ratio in quantifying the between-group difference in survival analysis.   J Clin Oncol. 2014;32(22):2380-2385. doi:10.1200/JCO.2014.55.2208 PubMedGoogle Scholar
37.
Trinquart  L , Jacot  J , Conner  SC , Porcher  R .  Comparison of treatment effects measured by the hazard ratio and by the ratio of restricted mean survival times in oncology randomized controlled trials.   J Clin Oncol. 2016;34(15):1813-1819. doi:10.1200/JCO.2015.64.2488 PubMedGoogle Scholar
38.
San Miguel  JF , Vidriales  MB , López-Berges  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(6):1746-1751. doi:10.1182/blood.V98.6.1746 PubMedGoogle Scholar
39.
Sievers  EL , Lange  BJ , Alonzo  TA ,  et al.  Immunophenotypic evidence of leukemia after induction therapy predicts relapse: results from a prospective Children’s Cancer Group study of 252 patients with acute myeloid leukemia.   Blood. 2003;101(9):3398-3406. doi:10.1182/blood-2002-10-3064 PubMedGoogle Scholar
40.
Coustan-Smith  E , Ribeiro  RC , Rubnitz  JE ,  et al.  Clinical significance of residual disease during treatment in childhood acute myeloid leukaemia.   Br J Haematol. 2003;123(2):243-252. doi:10.1046/j.1365-2141.2003.04610.x PubMedGoogle Scholar
41.
Feller  N , van der Pol  MA , van Stijn  A ,  et al.  MRD parameters using immunophenotypic detection methods are highly reliable in predicting survival in acute myeloid leukaemia.   Leukemia. 2004;18(8):1380-1390. doi:10.1038/sj.leu.2403405 PubMedGoogle Scholar
42.
Weisser  M , Kern  W , Rauhut  S ,  et al.  Prognostic impact of RT-PCR-based quantification of WT1 gene expression during MRD monitoring of acute myeloid leukemia.   Leukemia. 2005;19(8):1416-1423. doi:10.1038/sj.leu.2403809 PubMedGoogle Scholar
43.
Weisser  M , Kern  W , Schoch  C , Hiddemann  W , Haferlach  T , Schnittger  S .  Risk assessment by monitoring expression levels of partial tandem duplications in the MLL gene in acute myeloid leukemia during therapy.   Haematologica. 2005;90(7):881-889.PubMedGoogle Scholar
44.
Perea  G , Lasa  A , Aventín  A ,  et al; Grupo Cooperativo para el Estudio y Tratamiento de las Leucemias Agudas y Miel.  Prognostic value of minimal residual disease (MRD) in acute myeloid leukemia (AML) with favorable cytogenetics [t(8;21) and inv(16)].   Leukemia. 2006;20(1):87-94. doi:10.1038/sj.leu.2404015 PubMedGoogle Scholar
45.
Lapillonne  H , Renneville  A , Auvrignon  A ,  et al.  High WT1 expression after induction therapy predicts high risk of relapse and death in pediatric acute myeloid leukemia.   J Clin Oncol. 2006;24(10):1507-1515. doi:10.1200/JCO.2005.03.5303 PubMedGoogle Scholar
46.
Laane  E , Derolf  AR , Björklund  E ,  et al.  The effect of allogeneic stem cell transplantation on outcome in younger acute myeloid leukemia patients with minimal residual disease detected by flow cytometry at the end of post-remission chemotherapy.   Haematologica. 2006;91(6):833-836.PubMedGoogle Scholar
47.
Langebrake  C , Creutzig  U , Dworzak  M ,  et al; MRD-AML-BFM Study Group.  Residual disease monitoring in childhood acute myeloid leukemia by multiparameter flow cytometry: the MRD-AML-BFM Study Group.   J Clin Oncol. 2006;24(22):3686-3692. doi:10.1200/JCO.2005.05.4312 PubMedGoogle Scholar
48.
Maurillo  L , Buccisano  F , Spagnoli  A ,  et al.  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. doi:10.3324/haematol.10432 PubMedGoogle Scholar
49.
Narimatsu  H , Iino  M , Ichihashi  T ,  et al.  Clinical significance of minimal residual disease in patients with t(8;21) acute myeloid leukemia in Japan.   Int J Hematol. 2008;88(2):154-158. doi:10.1007/s12185-008-0108-1 PubMedGoogle Scholar
50.
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(2):91-101. doi:10.1002/cyto.b.20444 PubMedGoogle Scholar
51.
Hess  CJ , Feller  N , Denkers  F ,  et al.  Correlation of minimal residual disease cell frequency with molecular genotype in patients with acute myeloid leukemia.   Haematologica. 2009;94(1):46-53. doi:10.3324/haematol.13110 PubMedGoogle Scholar
52.
Cilloni  D , Renneville  A , Hermitte  F ,  et al.  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 LeukemiaNet study.   J Clin Oncol. 2009;27(31):5195-5201. doi:10.1200/JCO.2009.22.4865 PubMedGoogle Scholar
53.
Guièze  R , Renneville  A , Cayuela  JM ,  et al.  Prognostic value of minimal residual disease by real-time quantitative PCR in acute myeloid leukemia with CBFB-MYH11 rearrangement: the French experience.   Leukemia. 2010;24(7):1386-1388. doi:10.1038/leu.2010.112 PubMedGoogle Scholar
54.
Buccisano  F , Maurillo  L , Spagnoli  A ,  et al.  Cytogenetic and molecular diagnostic characterization combined to postconsolidation minimal residual disease assessment by flow cytometry improves risk stratification in adult acute myeloid leukemia.   Blood. 2010;116(13):2295-2303. doi:10.1182/blood-2009-12-258178 PubMedGoogle Scholar
55.
Corbacioglu  A , Scholl  C , Schlenk  RF ,  et al.  Prognostic impact of minimal residual disease in CBFB-MYH11-positive acute myeloid leukemia.   J Clin Oncol. 2010;28(23):3724-3729. doi:10.1200/JCO.2010.28.6468 PubMedGoogle Scholar
56.
van der Velden  VH , van der Sluijs-Geling  A , Gibson  BE ,  et al.  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(9):1599-1606. doi:10.1038/leu.2010.153 PubMedGoogle Scholar
57.
Chou  WC , Hou  HA , Liu  CY ,  et al.  Sensitive measurement of quantity dynamics of FLT3 internal tandem duplication at early time points provides prognostic information.   Ann Oncol. 2011;22(3):696-704. doi:10.1093/annonc/mdq402 PubMedGoogle Scholar
58.
Inoue  D , Maruoka  H , Takahashi  T .  Clinical analysis and optimization of postremission therapy for acute myeloid leukemia patients with minimal residual disease as determined by flow cytometry.   Mediterr J Hematol Infect Dis. 2010;2(2):e2010020. doi:10.4084/mjhid.2010.020 PubMedGoogle Scholar
59.
Krönke  J , Schlenk  RF , Jensen  KO ,  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. 2011;29(19):2709-2716. doi:10.1200/JCO.2011.35.0371 PubMedGoogle Scholar
60.
Chen  Y , Cortes  J , Estrov  Z ,  et al.  Persistence of cytogenetic abnormalities at complete remission after induction in patients with acute myeloid leukemia: prognostic significance and the potential role of allogeneic stem-cell transplantation.   J Clin Oncol. 2011;29(18):2507-2513. doi:10.1200/JCO.2010.34.2873 PubMedGoogle Scholar
61.
Gray  JX , McMillen  L , Mollee  P ,  et al.  WT1 expression as a marker of minimal residual disease predicts outcome in acute myeloid leukemia when measured post-consolidation.   Leuk Res. 2012;36(4):453-458. doi:10.1016/j.leukres.2011.09.005 PubMedGoogle Scholar
62.
Terwijn  M , Kelder  A , Snel  AN ,  et al.  Minimal residual disease detection defined as the malignant fraction of the total primitive stem cell compartment offers additional prognostic information in acute myeloid leukaemia.   Int J Lab Hematol. 2012;34(4):432-441. doi:10.1111/j.1751-553X.2012.01416.x PubMedGoogle Scholar
63.
Loken  MR , Alonzo  TA , Pardo  L ,  et al.  Residual disease detected by multidimensional flow cytometry signifies high relapse risk in patients with de novo acute myeloid leukemia: a report from Children’s Oncology Group.   Blood. 2012;120(8):1581-1588. doi:10.1182/blood-2012-02-408336 PubMedGoogle Scholar
64.
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. doi:10.1182/blood-2012-06-435669 PubMedGoogle Scholar
65.
Inaba  H , Coustan-Smith  E , Cao  X ,  et al.  Comparative analysis of different approaches to measure treatment response in acute myeloid leukemia.   J Clin Oncol. 2012;30(29):3625-3632. doi:10.1200/JCO.2011.41.5323 PubMedGoogle Scholar
66.
Xu  XJ , Feng  JH , Tang  YM ,  et al.  Prognostic significance of flow cytometric minimal residual disease assessment after the first induction course in Chinese childhood acute myeloid leukemia.   Leuk Res. 2013;37(2):134-138. doi:10.1016/j.leukres.2012.11.002 PubMedGoogle Scholar
67.
Jourdan  E , Boissel  N , Chevret  S ,  et al; 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. doi:10.1182/blood-2012-10-462879 PubMedGoogle Scholar
68.
Zhang  L , Li  Q , Li  W ,  et al.  Monitoring of minimal residual disease in acute myeloid leukemia with t(8;21)(q22;q22).   Int J Hematol. 2013;97(6):786-792. doi:10.1007/s12185-013-1344-6 PubMedGoogle Scholar
69.
Hoyos  M , Nomdedeu  JF , Esteve  J ,  et al.  Core binding factor acute myeloid leukemia: the impact of age, leukocyte count, molecular findings, and minimal residual disease.   Eur J Haematol. 2013;91(3):209-218. doi:10.1111/ejh.12130 PubMedGoogle Scholar
70.
Shayegi  N , Kramer  M , Bornhäuser  M ,  et al; 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. doi:10.1182/blood-2012-10-461749 PubMedGoogle Scholar
71.
Marani  C , Clavio  M , Grasso  R ,  et al.  Integrating post induction WT1 quantification and flow-cytometry results improves minimal residual disease stratification in acute myeloid leukemia.   Leuk Res. 2013;37(12):1606-1611. doi:10.1016/j.leukres.2013.07.005 PubMedGoogle Scholar
72.
Rossi  G , Minervini  MM , Melillo  L ,  et al.  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. doi:10.1007/s00277-014-2029-9 PubMedGoogle Scholar
73.
Hubmann  M , Köhnke  T , Hoster  E ,  et al.  Molecular response assessment by quantitative real-time polymerase chain reaction after induction therapy in NPM1-mutated patients identifies those at high risk of relapse.   Haematologica. 2014;99(8):1317-1325. doi:10.3324/haematol.2014.104133 PubMedGoogle Scholar
74.
Wang  L , Gao  L , Xu  S ,  et al.  High prognostic value of minimal residual disease detected by flow-cytometry-enhanced fluorescence in situ hybridization in core-binding factor acute myeloid leukemia (CBF-AML).   Ann Hematol. 2014;93(10):1685-1694. doi:10.1007/s00277-014-2107-z PubMedGoogle Scholar
75.
Köhnke  T , Sauter  D , Ringel  K ,  et al.  Early assessment of minimal residual disease in AML by flow cytometry during aplasia identifies patients at increased risk of relapse.   Leukemia. 2015;29(2):377-386. doi:10.1038/leu.2014.186 PubMedGoogle Scholar
76.
Zhang  L , Cao  Z , Ruan  M ,  et al.  Monitoring the AML1/ETO fusion transcript to predict outcome in childhood acute myeloid leukemia.   Pediatr Blood Cancer. 2014;61(10):1761-1766. doi:10.1002/pbc.25109 PubMedGoogle Scholar
77.
Hirsch  P , Labopin  M , Viguié  F ,  et al.  Interest of cytogenetic and FISH evaluation for prognosis evaluation in 198 patients with acute myeloid leukemia in first complete remission in a single institution.   Leuk Res. 2014;38(8):907-912. doi:10.1016/j.leukres.2014.05.021 PubMedGoogle Scholar
78.
Lambert  J , Lambert  J , Nibourel  O ,  et al.  MRD assessed by WT1 and NPM1 transcript levels identifies distinct outcomes in AML patients and is influenced by gemtuzumab ozogamicin.   Oncotarget. 2014;5(15):6280-6288. doi:10.18632/oncotarget.2196 PubMedGoogle Scholar
79.
Yoon  JH , Kim  HJ , Kim  JW ,  et al.  Identification of molecular and cytogenetic risk factors for unfavorable core-binding factor-positive adult AML with post-remission treatment outcome analysis including transplantation.   Bone Marrow Transplant. 2014;49(12):1466-1474. doi:10.1038/bmt.2014.180 PubMedGoogle Scholar
80.
Terwijn  M , Zeijlemaker  W , Kelder  A ,  et al.  Leukemic stem cell frequency: a strong biomarker for clinical outcome in acute myeloid leukemia.   PLoS One. 2014;9(9):e107587. doi:10.1371/journal.pone.0107587 PubMedGoogle Scholar
81.
Pigazzi  M , Manara  E , Buldini  B ,  et al.  Minimal residual disease monitored after induction therapy by RQ-PCR can contribute to tailor treatment of patients with t(8;21) RUNX1-RUNX1T1 rearrangement.   Haematologica. 2015;100(3):e99-e101. doi:10.3324/haematol.2014.114579 PubMedGoogle Scholar
82.
Chen  X , Xie  H , Wood  BL ,  et al.  Relation of clinical response and minimal residual disease and their prognostic impact on outcome in acute myeloid leukemia.   J Clin Oncol. 2015;33(11):1258-1264. doi:10.1200/JCO.2014.58.3518 PubMedGoogle Scholar
83.
Buccisano  F , Maurillo  L , Piciocchi  A ,  et al.  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. doi:10.1007/s00277-015-2364-5 PubMedGoogle Scholar
84.
Shibasaki  Y , Seki  Y , Tanaka  T ,  et al.  The association of level of reduction of Wilms’ tumor gene 1 mRNA transcript in bone marrow and outcome in acute myeloid leukemia patients.   Leuk Res. 2015;39(6):667-671. doi:10.1016/j.leukres.2015.03.021 PubMedGoogle Scholar
85.
Klco  JM , Miller  CA , Griffith  M ,  et al.  Association between mutation clearance after induction therapy and outcomes in acute myeloid leukemia.   JAMA. 2015;314(8):811-822. doi:10.1001/jama.2015.9643 PubMedGoogle Scholar
86.
Zeijlemaker  W , Kelder  A , Oussoren-Brockhoff  YJ ,  et al.  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. doi:10.1038/leu.2015.255 PubMedGoogle Scholar
87.
Vidriales  MB , Pérez-López  E , Pegenaute  C ,  et al; PETHEMA Programa para el Estudio de la Terapéutica en Hemopatías Malignas Cooperative Study Group.  Minimal residual disease evaluation by flow cytometry is a complementary tool to cytogenetics for treatment decisions in acute myeloid leukaemia.   Leuk Res. 2016;40:1-9. doi:10.1016/j.leukres.2015.10.002 PubMedGoogle Scholar
88.
Willekens  C , Blanchet  O , Renneville  A ,  et al; French AML Intergroup.  Prospective long-term minimal residual disease monitoring using RQ-PCR in RUNX1-RUNX1T1-positive acute myeloid leukemia: results of the French CBF-2006 trial.   Haematologica. 2016;101(3):328-335. doi:10.3324/haematol.2015.131946 PubMedGoogle Scholar
89.
Malagola  M , Skert  C , Borlenghi  E ,  et al.  Postremission sequential monitoring of minimal residual disease by WT1 Q-PCR and multiparametric flow cytometry assessment predicts relapse and may help to address risk-adapted therapy in acute myeloid leukemia patients.   Cancer Med. 2016;5(2):265-274. doi:10.1002/cam4.593 PubMedGoogle Scholar
90.
Keino  D , Kinoshita  A , Tomizawa  D ,  et al.  Residual disease detected by multidimensional flow cytometry shows prognostic significance in childhood acute myeloid leukemia with intermediate cytogenetics and negative FLT3-ITD: a report from the Tokyo Children’s Cancer Study Group.   Int J Hematol. 2016;103(4):416-422. doi:10.1007/s12185-016-1937-y PubMedGoogle Scholar
91.
Kim  Y , Lee  GD , Park  J ,  et al.  Quantitative fragment analysis of FLT3-ITD efficiently identifying poor prognostic group with high mutant allele burden or long ITD length.   Blood Cancer J. 2015;5:e336. doi:10.1038/bcj.2015.61 PubMedGoogle Scholar
92.
Tierens  A , Bjørklund  E , Siitonen  S ,  et al.  Residual disease detected by flow cytometry is an independent predictor of survival in childhood acute myeloid leukaemia; results of the NOPHO-AML 2004 study.   Br J Haematol. 2016;174(4):600-609. doi:10.1111/bjh.14093 PubMedGoogle Scholar
93.
Othus  M , Wood  BL , Stirewalt  DL ,  et al.  Effect of measurable (“minimal”) residual disease (MRD) information on prediction of relapse and survival in adult acute myeloid leukemia.   Leukemia. 2016;30(10):2080-2083. doi:10.1038/leu.2016.120 PubMedGoogle Scholar
94.
Manara  E , Basso  G , Zampini  M ,  et al.  Characterization of children with FLT3-ITD acute myeloid leukemia: a report from the AIEOP AML-2002 study group.   Leukemia. 2017;31(1):18-25. doi:10.1038/leu.2016.177 PubMedGoogle Scholar
95.
Huang  S , Yang  H , Li  Y ,  et al.  Prognostic significance of mixed-lineage leukemia (MLL) gene detected by real-time fluorescence quantitative PCR assay in acute myeloid leukemia.   Med Sci Monit. 2016;22:3009-3017. doi:10.12659/MSM.900429 PubMedGoogle Scholar
96.
Buldini  B , Rizzati  F , Masetti  R ,  et al.  Prognostic significance of flow-cytometry evaluation of minimal residual disease in children with acute myeloid leukaemia treated according to the AIEOP-AML 2002/01 study protocol.   Br J Haematol. 2017;177(1):116-126. doi:10.1111/bjh.14523 PubMedGoogle Scholar
97.
Martínez-Laperche  C , Kwon  M , Franco-Villegas  AC ,  et al; Cooperative Group for Molecular Biology in Haematology (GBMH).  Wilms tumor 1 gene expression levels improve risk stratification in AML patients: results of a multicentre study within the Spanish Group for Molecular Biology in Haematology.   Br J Haematol. 2018;181(4):542-546. doi:10.1111/bjh.14635 PubMedGoogle Scholar
98.
Daver  N , Kantarjian  H , Garcia-Manero  G ,  et al.  Vosaroxin in combination with decitabine in newly diagnosed older patients with acute myeloid leukemia or high-risk myelodysplastic syndrome.   Haematologica. 2017;102(10):1709-1717. doi:10.3324/haematol.2017.168732 PubMedGoogle Scholar
99.
Frairia  C , Aydin  S , Audisio  E ,  et al.  Post-remissional and pre-transplant role of minimal residual disease detected by WT1 in acute myeloid leukemia: a retrospective cohort study.   Leuk Res. 2017;61:10-17. doi:10.1016/j.leukres.2017.08.008 PubMedGoogle Scholar
100.
Boddu  P , Jorgensen  J , Kantarjian  H ,  et al.  Achievement of a negative minimal residual disease state after hypomethylating agent therapy in older patients with AML reduces the risk of relapse.   Leukemia. 2018;32(1):241-244. doi:10.1038/leu.2017.285 PubMedGoogle Scholar
101.
Lacombe  F , Campos  L , Allou  K ,  et al; Groupe d’Etude Immunologique des Leucémies (GEIL).  Prognostic value of multicenter flow cytometry harmonized assessment of minimal residual disease in acute myeloblastic leukemia.   Hematol Oncol. 2018;36(2):422-428. doi:10.1002/hon.2488 PubMedGoogle Scholar
102.
Ferret  Y , Boissel  N , Helevaut  N ,  et al.  Clinical relevance of IDH1/2 mutant allele burden during follow-up in acute myeloid leukemia: a study by the French ALFA group.   Haematologica. 2018;103(5):822-829. doi:10.3324/haematol.2017.183525 PubMedGoogle Scholar
103.
Höllein  A , Jeromin  S , Meggendorfer  M ,  et al.  Minimal residual disease (MRD) monitoring and mutational landscape in AML with RUNX1-RUNX1T1: a study on 134 patients.   Leukemia. 2018;32(10):2270-2274. doi:10.1038/s41375-018-0086-0 PubMedGoogle Scholar
104.
Morita  K , Kantarjian  HM , Wang  F ,  et al.  Clearance of somatic mutations at remission and the risk of relapse in acute myeloid leukemia.   J Clin Oncol. 2018;36(18):1788-1797. doi:10.1200/JCO.2017.77.6757 PubMedGoogle Scholar
105.
Boddu  P , Gurguis  C , Sanford  D ,  et al.  Response kinetics and factors predicting survival in core-binding factor leukemia.   Leukemia. 2018;32(12):2698-2701. doi:10.1038/s41375-018-0158-1 PubMedGoogle Scholar
106.
Onecha  E , Linares  M , Rapado  I ,  et al.  A novel deep targeted sequencing method for minimal residual disease monitoring in acute myeloid leukemia.   Haematologica. 2019;104(2):288-296. doi:10.3324/haematol.2018.194712 PubMedGoogle Scholar
107.
Ok  CY , Loghavi  S , Sui  D ,  et al.  Persistent IDH1/2 mutations in remission can predict relapse in patients with acute myeloid leukemia.   Haematologica. 2019;104(2):305-311. doi:10.3324/haematol.2018.191148 PubMedGoogle Scholar
108.
Zhu  HH , Zhang  XH , Qin  YZ ,  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. 2013;121(20):4056-4062. doi:10.1182/blood-2012-11-468348 PubMedGoogle Scholar
109.
Hourigan  CS , Dillon  LW , Gui  G ,  et al.  Impact of conditioning intensity of allogeneic transplantation for acute myeloid leukemia with genomic evidence of residual disease.   J Clin Oncol. 2020;38(12):1273-1283. doi:10.1200/JCO.19.03011 PubMedGoogle Scholar
110.
Sockel  K , Wermke  M , Radke  J ,  et al.  Minimal residual disease-directed preemptive treatment with azacitidine in patients with NPM1-mutant acute myeloid leukemia and molecular relapse.   Haematologica. 2011;96(10):1568-1570. doi:10.3324/haematol.2011.044388 PubMedGoogle Scholar
111.
Platzbecker  U , Wermke  M , Radke  J ,  et al.  Azacitidine for treatment of imminent relapse in MDS or AML patients after allogeneic HSCT: results of the RELAZA trial.   Leukemia. 2012;26(3):381-389. doi:10.1038/leu.2011.234 PubMedGoogle Scholar
112.
Platzbecker  U , Middeke  JM , Sockel  K ,  et al.  Measurable residual disease-guided treatment with azacitidine to prevent haematological relapse in patients with myelodysplastic syndrome and acute myeloid leukaemia (RELAZA2): an open-label, multicentre, phase 2 trial.   Lancet Oncol. 2018;19(12):1668-1679. doi:10.1016/S1470-2045(18)30580-1 PubMedGoogle Scholar
113.
Ragon  BK , Daver  N , Garcia-Manero  G ,  et al.  Minimal residual disease eradication with epigenetic therapy in core binding factor acute myeloid leukemia.   Am J Hematol. 2017;92(9):845-850. doi:10.1002/ajh.24782 PubMedGoogle Scholar
114.
Gökbuget  N , Dombret  H , Bonifacio  M ,  et al.  Blinatumomab for minimal residual disease in adults with B-cell precursor acute lymphoblastic leukemia.   Blood. 2018;131(14):1522-1531. doi:10.1182/blood-2017-08-798322 PubMedGoogle Scholar
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