Acute myeloid leukemia (AML) is classified by risk groups according to a number of genetic mutations, which may occur alone or in combination with other mutations and chromosomal abnormalities. Prognosis and appropriate therapy can vary significantly based on a patient's genetic risk group, making mutation-informed decisions crucial to successful management. However, the presence of measurable residual disease (MRD) after induction and consolidation therapy, before hematopoietic cell transplant, and during posttransplant monitoring can be even more significant to patient prognosis than their genetic subtype. Clinicians must select MRD-monitoring methods most appropriate for a patient's genetic profile and a treatment regimen that considers both a patient's primary genetic subgroup and other risk factors, including MRD information. Recent clinical trial data and drug approvals, together with advances in the validation of MRD using next-generation sequencing, require a deeper understanding of the complex AML mutation and MRD matrix, enabling more insightful monitoring and treatment decisions for intensively treated AML patients. Here, we provide an overview on methods and clinical consequences of MRD monitoring in genetic subgroups of patients with AML. As treatment options become more personalized, on-treatment MRD monitoring will become even more important to effective AML care.

2.
Rausch
C
,
Rothenberg-Thurley
M
,
Dufour
A
, et al.
Validation and refinement of the 2022 European LeukemiaNet genetic risk stratification of acute myeloid leukemia
.
Leukemia
.
2023
;
37
(
6
):
1234
-
1244
.
3.
Döhner
H
,
Wei
AH
,
Appelbaum
FR
, et al.
Diagnosis and management of AML in adults: 2022 recommendations from an international expert panel on behalf of the ELN
.
Blood
.
2022
;
140
(
12
):
1345
-
1377
.
4.
Grob
T
,
Sanders
MA
,
Vonk
CM
, et al.
Prognostic value of FLT3-internal tandem duplication residual disease in acute myeloid leukemia
.
J Clin Oncol
.
2023
;
41
(
4
):
756
-
765
.
5.
Loo
S
,
Dillon
R
,
Ivey
A
, et al.
Pretransplant FLT3-ITD MRD assessed by high-sensitivity PCR-NGS determines posttransplant clinical outcome
.
Blood
.
2022
;
140
(
22
):
2407
-
2411
.
6.
Dillon
LW
,
Gui
G
,
Page
KM
, et al.
DNA sequencing to detect residual disease in adults with acute myeloid leukemia prior to hematopoietic cell transplant
.
JAMA
.
2023
;
329
(
9
):
745
-
755
.
7.
Dillon
LW
,
Gui
G
,
Ravindra
N
, et al.
Measurable residual FLT3 internal tandem duplication before allogeneic transplant for acute myeloid leukemia
.
JAMA Oncol
. [published online
2
May
2024
].
8.
Erba
HP
,
Montesinos
P
,
Kim
HJ
, et al
;
QuANTUM-First Study Group
.
Quizartinib plus chemotherapy in newly diagnosed patients with FLT3-internal-tandem-duplication-positive acute myeloid leukaemia (QuANTUM-First): a randomised, double-blind, placebo-controlled, phase 3 trial
.
Lancet
.
2023
;
401
(
10388
):
1571
-
1583
.
9.
Stone
RM
,
Mandrekar
SJ
,
Sanford
BL
, et al.
Midostaurin plus chemotherapy for acute myeloid leukemia with a FLT3 mutation
.
N Engl J Med
.
2017
;
377
(
5
):
454
-
464
.
10.
Mecklenbrauck
R
,
Heuser
M.
Resistance to targeted therapies in acute myeloid leukemia
.
Clin Exp Metastasis
.
2023
;
40
(
1
):
33
-
44
.
11.
Döhner
H
,
Weber
D
,
Krzykalla
J
, et al.
Midostaurin plus intensive chemotherapy for younger and older patients with AML and FLT3 internal tandem duplications
.
Blood Adv
.
2022
;
6
(
18
):
5345
-
5355
.
12.
Heuser
M
,
Freeman
SD
,
Ossenkoppele
GJ
, et al.
2021 update on MRD in acute myeloid leukemia: a consensus document from the European LeukemiaNet MRD Working Party
.
Blood
.
2021
;
138
(
26
):
2753
-
2767
.
13.
Paras
G
,
Morsink
LM
,
Othus
M
, et al.
Conditioning intensity and peritransplant flow cytometric MRD dynamics in adult AML
.
Blood
.
2022
;
139
(
11
):
1694
-
1706
.
14.
Othman
J
,
Potter
N
,
Mokretar
K
, et al.
FLT3 inhibitors as MRD-guided salvage treatment for molecular failure in FLT3 mutated AML
.
Leukemia
.
2023
;
37
(
10
):
2066
-
2072
.
15.
Jimenez-Chillon
C
,
Othman
J
,
Taussig
D
, et al.
Venetoclax-based low intensity therapy in molecular failure of NPM1-mutated AML
.
Blood Adv
.
2024
;
8
(
2
):
343
-
352
.
16.
Levis
MJ
,
Hamadani
M
,
Logan
B
, et al
;
BMT-CTN 1506/MORPHO Study Investigators
.
Gilteritinib as post-transplant maintenance for AML with internal tandem duplication mutation of FLT3
.
J Clin Oncol
.
2024
;
42
(
15
):
1766
-
1775
.
17.
Schlenk
R
,
Montesinos
P
,
Romero-Aguilar
A
, et al.
Impact of allogeneic hematopoietic cell transplantation in first complete remission in addition to FLT3 inhibition with quizartinib in acute myeloid leukemia with FLT3-internal tandem duplication: results from the QuANTUM-first trial
.
Blood
.
2022
;
140
(
suppl 1
):
2130
-
2132
.
18.
Burchert
A
,
Bug
G
,
Fritz
LV
, et al.
Sorafenib maintenance after allogeneic hematopoietic stem cell transplantation for acute myeloid leukemia with FLT3-internal tandem duplication mutation (SORMAIN)
.
J Clin Oncol
.
2020
;
38
(
26
):
2993
-
3002
.
19.
Xuan
L
,
Wang
Y
,
Huang
F
, et al.
Sorafenib maintenance in patients with FLT3-ITD acute myeloid leukaemia undergoing allogeneic haematopoietic stem-cell transplantation: an open-label, multicentre, randomised phase 3 trial
.
Lancet Oncol
.
2020
;
21
(
9
):
1201
-
1212
.
20.
Arber
DA
,
Orazi
A
,
Hasserjian
RP
, et al.
International Consensus Classification of myeloid neoplasms and acute leukemias: integrating morphologic, clinical, and genomic data
.
Blood
.
2022
;
140
(
11
):
1200
-
1228
.
21.
Khoury
JD
,
Solary
E
,
Abla
O
, et al.
The 5th edition of the World Health Organization Classification of Haematolymphoid Tumours: myeloid and histiocytic/dendritic neoplasms
.
Leukemia
.
2022
;
36
(
7
):
1703
-
1719
.
22.
Tsai
XC
,
Sun
KJ
,
Lo
MY
, et al.
Poor prognostic implications of myelodysplasia-related mutations in both older and younger patients with de novo AML
.
Blood Cancer J
.
2023
;
13
(
1
):
4
.
23.
Huber
S
,
Baer
C
,
Hutter
S
, et al.
AML classification in the year 2023: how to avoid a Babylonian confusion of languages
.
Leukemia
.
2023
;
37
(
7
):
1413
-
1420
.
24.
Attardi
E
,
Savi
A
,
Borsellino
B
, et al.
Applicability of 2022 classifications of acute myeloid leukemia in the real-world setting
.
Blood Adv
.
2023
;
7
(
17
):
5122
-
5131
.
25.
Huber
S
,
Baer
C
,
Hutter
S
, et al.
Risk assessment according to IPSS-M is superior to AML ELN risk classification in MDS/AML overlap patients defined by ICC
.
Leukemia
.
2023
;
37
(
10
):
2138
-
2141
.
26.
Lindsley
RC
,
Mar
BG
,
Mazzola
E
, et al.
Acute myeloid leukemia ontogeny is defined by distinct somatic mutations
.
Blood
.
2015
;
125
(
9
):
1367
-
1376
.
27.
Caprioli
C
,
Lussana
F
,
Salmoiraghi
S
, et al.
Clinical significance of chromatin- spliceosome acute myeloid leukemia: a report from the Northern Italy Leukemia Group (NILG) randomized trial 02/06
.
Haematologica
.
2021
;
106
(
10
):
2578
-
2587
.
28.
Gardin
C
,
Pautas
C
,
Fournier
E
, et al.
Added prognostic value of secondary AML-like gene mutations in ELN intermediate-risk older AML: ALFA-1200 study results
.
Blood Adv
.
2020
;
4
(
9
):
1942
-
1949
.
29.
Lachowiez
CA
,
Loghavi
S
,
Furudate
K
, et al.
Impact of splicing mutations in acute myeloid leukemia treated with hypomethylating agents combined with venetoclax
.
Blood Adv
.
2021
;
5
(
8
):
2173
-
2183
.
30.
McCarter
JGW
,
Nemirovsky
D
,
Famulare
CA
, et al.
Interaction between myelodysplasia-related gene mutations and ontogeny in acute myeloid leukemia
.
Blood Adv
.
2023
;
7
(
17
):
5000
-
5013
.
31.
Tazi
Y
,
Arango-Ossa
JE
,
Zhou
Y
, et al.
Unified classification and risk- stratification in acute myeloid leukemia
.
Nat Commun
.
2022
;
13
(
1
):
4622
.
32.
Mecklenbrauck
R
,
Borchert
N
,
Klement
P
, et al.
Prognostic impact of clonality of myelodysplasia-related gene mutations in AML
.
Blood
.
2023
;
142
(
suppl 1
):
817
.
33.
Bill
M
,
Eckardt
JN
,
Rausch
C
, et al.
Secondary-type mutations do not impact the favorable outcome of NPM1-mutated acute myeloid leukemia patients—results from a large cohort of intensively treated patients
.
Blood
.
2023
;
142
(
suppl 1
):
721
.
34.
Ngai
LL
,
Hanekamp
D
,
Kelder
A
, et al.
The Laip-based-Dfn approach is superior in terms of useful MRD results as compared to the Laip approach after cycle II in acute myeloid leukemia
.
Blood
.
2023
;
142
(
suppl 1
):
1572
.
35.
Zhang
C
,
Gu
R
,
Zhou
C
, et al.
Prognostic effect and clinical application of early measurable residual disease (MRD) by flow cytometry on de novo acute myeloid leukemia (AML)
.
Blood
.
2022
;
140
(
suppl 1
):
2030
-
2032
.
36.
Orvain
C
,
Ali
N
,
Othus
M
, et al.
Relative prognostic value of flow cytometric measurable residual disease before allogeneic hematopoietic cell transplantation for adults with MDS/AML or AML
.
Am J Hematol
.
2024
;
99
(
5
):
862
-
870
.
37.
Bader
M
,
Mahmuti
A
,
Leßmann
J
, et al.
Myelodysplasia-related gene mutations for NGS-based MRD assessment in acute myeloid leukemia
.
Blood
.
2023
;
142
(
suppl 1
):
2944
.
38.
Kim
HJ
,
Kim
Y
,
Kang
D
, et al.
Prognostic value of measurable residual disease monitoring by next-generation sequencing before and after allogeneic hematopoietic cell transplantation in acute myeloid leukemia
.
Blood Cancer J
.
2021
;
11
(
6
):
109
.
39.
Bischof
L
,
Ussmann
J
,
Grimm
J
, et al.
Prognostic impact of measurable residual clonal hematopoiesis in acute myeloid leukemia patients after allogeneic hematopoietic stem cell transplantation
.
Leukemia
.
2024
;
38
(
1
):
198
-
201
.
40.
Wienecke
CP
,
Heida
B
,
Venturini
L
, et al.
Clonal relapse dynamics in acute myeloid leukemia following allogeneic hematopoietic cell transplantation
.
Blood
.
2024
;
144
(
3
):
296
-
307
.
41.
Lancet
JE
,
Uy
GL
,
Newell
LF
, et al.
CPX-351 versus 7 + 3 cytarabine and daunorubicin chemotherapy in older adults with newly diagnosed high-risk or secondary acute myeloid leukaemia: 5-year results of a randomised, open- label, multicentre, phase 3 trial
.
Lancet Haematol
.
2021
;
8
(
7
):
e481
-
e491
.
42.
Wei
AH
,
Döhner
H
,
Pocock
C
, et al
;
QUAZAR AML-001 Trial Investigators
.
Oral azacitidine maintenance therapy for acute myeloid leukemia in first remission
.
N Engl J Med
.
2020
;
383
(
26
):
2526
-
2537
.
43.
Teich
K
,
Stadler
M
,
Gabdoulline
R
, et al.
MRD as biomarker for response to donor lymphocyte infusion after allogeneic hematopoietic cell transplantation in patients with AML
.
Cancers (Basel)
.
2023
;
15
(
15
):
3911
.
44.
Othman
J
,
Wilhelm-Benartzi
C
,
Dillon
R
, et al.
A randomized comparison of CPX-351 and FLAG-Ida in adverse karyotype AML and high-risk MDS: the UK NCRI AML19 trial
.
Blood Adv
.
2023
;
7
(
16
):
4539
-
4549
.
45.
Senapati
J
,
Urrutia
S
,
Loghavi
S
, et al.
Venetoclax abrogates the prognostic impact of splicing factor gene mutations in newly diagnosed acute myeloid leukemia
.
Blood
.
2023
;
142
(
19
):
1647
-
1657
.
46.
Chua
CC
,
Roberts
AW
,
Reynolds
J
, et al.
Chemotherapy and venetoclax in elderly acute myeloid leukemia trial (CAVEAT): a phase Ib dose-escalation study of venetoclax combined with modified intensive chemotherapy
.
J Clin Oncol
.
2020
;
38
(
30
):
3506
-
3517
.
47.
Burnett
AK
,
Hills
RK
,
Milligan
D
, et al.
Identification of patients with acute myeloblastic leukemia who benefit from the addition of gemtuzumab ozogamicin: results of the MRC AML15 trial
.
J Clin Oncol
.
2011
;
29
(
4
):
369
-
377
.
48.
Döhner
H
,
Weber
D
,
Krzykalla
J
, et al
;
German-Austrian AML Study Group
.
Intensive chemotherapy with or without gemtuzumab ozogamicin in patients with NPM1-mutated acute myeloid leukaemia (AMLSG 09-09): a randomised, open-label, multicentre, phase 3 trial
.
Lancet Haematol
.
2023
;
10
(
7
):
e495
-
e509
.
49.
Kapp-Schwoerer
S
,
Weber
D
,
Corbacioglu
A
, et al.
Impact of gemtuzumab ozogamicin on MRD and relapse risk in patients with NPM1-mutated AML: results from the AMLSG 09-09 trial
.
Blood
.
2020
;
136
(
26
):
3041
-
3050
.
50.
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
.
51.
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
.
52.
Lambert
J
,
Pautas
C
,
Terré
C
, et al.
Gemtuzumab ozogamicin for de novo acute myeloid leukemia: final efficacy and safety updates from the open- label, phase III ALFA-0701 trial
.
Haematologica
.
2019
;
104
(
1
):
113
-
119
.
53.
Dillon
R
,
Hills
R
,
Freeman
S
, et al.
Molecular MRD status and outcome after transplantation in NPM1-mutated AML
.
Blood
.
2020
;
135
(
9
):
680
-
688
.
54.
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
.
55.
Othman
J
,
Potter
N
,
Ivey
A
, et al.
Postinduction molecular MRD identifies patients with NPM1 AML who benefit from allogeneic transplant in first remission
.
Blood
.
2024
;
143
(
19
):
1931
-
1936
.
56.
Bataller
A
,
Oñate
G
,
Diaz-Beyá
M
, et al
;
Grupo Cooperativo Para el Estudio y Tratamiento de las Leucemias Agudas y Mielodisplasias (CETLAM)
.
Acute myeloid leukemia with NPM1 mutation and favorable European LeukemiaNet category: outcome after preemptive intervention based on measurable residual disease
.
Br J Haematol
.
2020
;
191
(
1
):
52
-
61
.
57.
Bouvier
A
,
Hamel
JF
,
Delaunay
J
, et al
;
French Innovative Leukemia Organization
.
Molecular classification and prognosis in younger adults with acute myeloid leukemia and intermediate-risk cytogenetics treated or not by gemtuzumab ozogamycin: final results of the GOELAMS/FILO acute myeloid leukemia 2006-intermediate-risk trial
.
Eur J Haematol
.
2021
;
107
(
1
):
111
-
121
.
58.
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
.
59.
Rücker
FG
,
Agrawal
M
,
Corbacioglu
A
, et al.
Measurable residual disease monitoring in acute myeloid leukemia with t(8;21)(q22;q22.1): results from the AML Study Group
.
Blood
.
2019
;
134
(
19
):
1608
-
1618
.
60.
Borthakur
G
,
Cortes
JE
,
Estey
EE
, et al.
Gemtuzumab ozogamicin with fludarabine, cytarabine, and granulocyte colony stimulating factor (FLAG-GO) as front-line regimen in patients with core binding factor acute myelogenous leukemia
.
Am J Hematol
.
2014
;
89
(
10
):
964
-
968
.
61.
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
.
62.
Krauter
J
,
Gorlich
K
,
Ottmann
O
, et al.
Prognostic value of minimal residual disease quantification by real-time reverse transcriptase polymerase chain reaction in patients with core binding factor leukemias
.
J Clin Oncol
.
2003
;
21
(
23
):
4413
-
4422
.
63.
Weisser
M
,
Haferlach
C
,
Hiddemann
W
,
Schnittger
S.
The quality of molecular response to chemotherapy is predictive for the outcome of AML1-ETO-positive AML and is independent of pretreatment risk factors
.
Leukemia
.
2007
;
21
(
6
):
1177
-
1182
.
64.
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
.
65.
Deotare
U
,
Shaheen
M
,
Brandwein
JM
, et al.
Predictive value of molecular remissions postconsolidation chemotherapy in patients with core binding factor acute myeloid leukemia (CBF-AML)—a single center analysis
.
Hematol Oncol
.
2017
;
35
(
4
):
810
-
813
.
66.
Puckrin
R
,
Atenafu
EG
,
Claudio
JO
, et al.
Measurable residual disease monitoring provides insufficient lead-time to prevent morphologic relapse in the majority of patients with core-binding factor acute myeloid leukemia
.
Haematologica
.
2021
;
106
(
1
):
56
-
63
.
67.
Marcucci
G
,
Geyer
S
,
Laumann
K
, et al.
Combination of dasatinib with chemotherapy in previously untreated core binding factor acute myeloid leukemia: CALGB 10801
.
Blood Adv
.
2020
;
4
(
4
):
696
-
705
.
68.
Paschka
P
,
Schlenk
RF
,
Weber
D
, et al.
Adding dasatinib to intensive treatment in core-binding factor acute myeloid leukemia—results of the AMLSG 11-08 trial
.
Leukemia
.
2018
;
32
(
7
):
1621
-
1630
.
69.
Freeman
SD
,
Thomas
A
,
Thomas
I
, et al.
Fractionated vs single-dose gemtuzumab ozogamicin with determinants of benefit in older patients with AML: the UK NCRI AML18 trial
.
Blood
.
2023
;
142
(
20
):
1697
-
1707
.
70.
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
.
71.
Röllig
C
,
Serve
H
,
Noppeney
R
, et al
;
Study Alliance Leukaemia
.
Sorafenib or placebo in patients with newly diagnosed acute myeloid leukaemia: long-term follow-up of the randomized controlled SORAML trial
.
Leukemia
.
2021
;
35
(
9
):
2517
-
2525
.
72.
Levis
MJ
,
Erba
HP
,
Montesinos
P
, et al.
P483: quantum-first trial: FLT3-ITD–specific measurable residual disease (MRD) clearance is associated with improved overall survival
.
Hemasphere
.
2023
;
7
(
suppl
):
e446548f
.
73.
Han
L
,
Li
Y
,
Wu
J
, et al.
Post-remission measurable residual disease directs treatment choice and improves outcomes for patients with intermediate-risk acute myeloid leukemia in CR1
.
Int J Hematol
.
2022
;
116
(
6
):
892
-
901
.
74.
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
.
75.
Tettero
JM
,
Ngai
LL
,
Bachas
C
, et al.
Measurable residual disease-guided therapy in intermediate-risk acute myeloid leukemia patients is a valuable strategy in reducing allogeneic transplantation without negatively affecting survival
.
Haematologica
.
2023
;
108
(
10
):
2794
-
2798
.
76.
Venditti
A
,
Piciocchi
A
,
Candoni
A
, et al.
GIMEMA AML1310 trial of risk-adapted, MRD-directed therapy for young adults with newly diagnosed acute myeloid leukemia
.
Blood
.
2019
;
134
(
12
):
935
-
945
.
77.
Lancet
JE
,
Uy
GL
,
Cortes
JE
, et al.
CPX-351 (cytarabine and daunorubicin) Liposome for injection versus conventional cytarabine plus daunorubicin in older patients with newly diagnosed secondary acute myeloid leukemia
.
J Clin Oncol
.
2018
;
36
(
26
):
2684
-
2692
.
78.
Rautenberg
C
,
Stölzel
F
,
Röllig
C
, et al.
Real-world experience of CPX-351 as first-line treatment for patients with acute myeloid leukemia
.
Blood Cancer J
.
2021
;
11
(
10
):
164
.
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