• Transplant outcomes in older patients with AML in first remission are primarily determined by characteristics present at diagnosis.

  • MRD in older patients with AML is associated with high-risk baseline features and does not affect LFS independent of baseline risk.

Older patients with acute myeloid leukemia (AML) have high relapse risk and poor survival after allogeneic hematopoietic cell transplantation (HCT). Younger patients may receive myeloablative conditioning to mitigate relapse risk associated with high-risk genetics or measurable residual disease (MRD), but older adults typically receive reduced-intensity conditioning (RIC) to limit toxicity. To identify factors that drive HCT outcomes in older patients, we performed targeted mutational analysis (variant allele fraction ≥2%) on diagnostic samples from 295 patients with AML aged ≥60 years who underwent HCT in first complete remission, 91% of whom received RIC, and targeted duplex sequencing at remission in a subset comprising 192 patients. In a multivariable model for leukemia-free survival (LFS) including baseline genetic and clinical variables, we defined patients with low (3-year LFS, 85%), intermediate (55%), high (35%), and very high (7%) risk. Before HCT, 79.7% of patients had persistent baseline mutations, including 18.3% with only DNMT3A or TET2 (DT) mutations and 61.4% with other mutations (MRD positive). In univariable analysis, MRD positivity was associated with increased relapse and inferior LFS, compared with DT and MRD-negative mutations. However, in a multivariable model accounting for baseline risk, MRD positivity had no independent impact on LFS, most likely because of its significant association with diagnostic genetic characteristics, including MDS-associated gene mutations, TP53 mutations, and high-risk karyotype. In summary, molecular associations with MRD positivity and transplant outcomes in older patients with AML are driven primarily by baseline genetics, not by mutations present in remission. In this group of patients, where high-intensity conditioning carries substantial risk of toxicity, alternative approaches to mitigating MRD-associated relapse risk are needed.

1.
Mrózek
K
,
Marcucci
G
,
Nicolet
D
, et al
.
Prognostic significance of the European LeukemiaNet standardized system for reporting cytogenetic and molecular alterations in adults with acute myeloid leukemia
.
J Clin Oncol.
2012
;
30
(
36
):
4515
-
4523
.
2.
Goldstone
AH
,
Burnett
AK
,
Wheatley
K
,
Smith
AG
,
Hutchinson
RM
,
Clark
RE
;
Medical Research Council Adult Leukemia Working Party
.
Attempts to improve treatment outcomes in acute myeloid leukemia (AML) in older patients: the results of the United Kingdom Medical Research Council AML11 trial
.
Blood.
2001
;
98
(
5
):
1302
-
1311
.
3.
Oran
B
,
Weisdorf
DJ
.
Survival for older patients with acute myeloid leukemia: a population-based study
.
Haematologica.
2012
;
97
(
12
):
1916
-
1924
.
4.
Lindsley
RC
,
Mar
BG
,
Mazzola
E
, et al
.
Acute myeloid leukemia ontogeny is defined by distinct somatic mutations
.
Blood.
2015
;
125
(
9
):
1367
-
1376
.
5.
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
.
6.
Leith
CP
,
Kopecky
KJ
,
Godwin
J
, et al
.
Acute myeloid leukemia in the elderly: assessment of multidrug resistance (MDR1) and cytogenetics distinguishes biologic subgroups with remarkably distinct responses to standard chemotherapy. A Southwest Oncology Group study
.
Blood.
1997
;
89
(
9
):
3323
-
3329
.
7.
Itzykson
R
,
Fournier
E
,
Berthon
C
, et al
.
Genetic identification of patients with AML older than 60 years achieving long-term survival with intensive chemotherapy
.
Blood.
2021
;
138
(
7
):
507
-
519
.
8.
Devine
SM
,
Owzar
K
,
Blum
W
, et al
.
Phase II study of allogeneic transplantation for older patients with acute myeloid leukemia in first complete remission using a reduced-intensity conditioning regimen: results from Cancer and Leukemia Group B 100103 (Alliance for Clinical Trials in Oncology)/Blood and Marrow Transplant Clinical Trial Network 0502
.
J Clin Oncol.
2015
;
33
(
35
):
4167
-
4175
.
9.
Ustun
C
,
Le-Rademacher
J
,
Wang
H-L
, et al
.
Allogeneic hematopoietic cell transplantation compared to chemotherapy consolidation in older acute myeloid leukemia (AML) patients 60-75 years in first complete remission (CR1): an alliance (A151509), SWOG, ECOG-ACRIN, and CIBMTR study
.
Leukemia.
2019
;
33
(
11
):
2599
-
2609
.
10.
Diaconescu
R
,
Flowers
CR
,
Storer
B
, et al
.
Morbidity and mortality with nonmyeloablative compared with myeloablative conditioning before hematopoietic cell transplantation from HLA-matched related donors
.
Blood.
2004
;
104
(
5
):
1550
-
1558
.
11.
Slavin
S
,
Nagler
A
,
Naparstek
E
, et al
.
Nonmyeloablative stem cell transplantation and cell therapy as an alternative to conventional bone marrow transplantation with lethal cytoreduction for the treatment of malignant and nonmalignant hematologic diseases
.
Blood.
1998
;
91
(
3
):
756
-
763
.
12.
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
.
13.
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
.
14.
Muffly
L
,
Pasquini
MC
,
Martens
M
, et al
.
Increasing use of allogeneic hematopoietic cell transplantation in patients aged 70 years and older in the United States
.
Blood.
2017
;
130
(
9
):
1156
-
1164
.
15.
Lindsley
RC
,
Saber
W
,
Mar
BG
, et al
.
Prognostic mutations in myelodysplastic syndrome after stem-cell transplantation
.
N Engl J Med.
2017
;
376
(
6
):
536
547
.
16.
Tyner
JW
,
Tognon
CE
,
Bottomly
D
, et al
.
Functional genomic landscape of acute myeloid leukaemia
.
Nature.
2018
;
562
(
7728
):
526
-
531
.
17.
Polprasert
C
,
Schulze
I
,
Sekeres
MA
, et al
.
Inherited and somatic defects in DDX41 in myeloid neoplasms
.
Cancer Cell.
2015
;
27
(
5
):
658
-
670
.
18.
Sébert
M
,
Passet
M
,
Raimbault
A
, et al
.
Germline DDX41 mutations define a significant entity within adult MDS/AML patients
.
Blood.
2019
;
134
(
17
):
1441
-
1444
.
19.
Kadono
M
,
Kanai
A
,
Nagamachi
A
, et al
.
Biological implications of somatic DDX41 p.R525H mutation in acute myeloid leukemia
.
Exp Hematol.
2016
;
44
(
8
):
745
-
754.e4
.
20.
Reilly
CR
,
Myllymäki
M
,
Redd
R
, et al
.
The clinical and functional effects of TERT variants in myelodysplastic syndrome
.
Blood.
2021
;
138
(
10
):
898
-
911
.
21.
Marsh
JCW
,
Gutierrez-Rodrigues
F
,
Cooper
J
, et al
.
Heterozygous RTEL1 variants in bone marrow failure and myeloid neoplasms
.
Blood Adv.
2018
;
2
(
1
):
36
-
48
.
22.
Boocock
GRB
,
Morrison
JA
,
Popovic
M
, et al
.
Mutations in SBDS are associated with Shwachman-Diamond syndrome
.
Nat Genet.
2003
;
33
(
1
):
97
-
101
.
23.
Nagata
Y
,
Narumi
S
,
Guan
Y
, et al
.
Germline loss-of-function SAMD9 and SAMD9L alterations in adult myelodysplastic syndromes
.
Blood.
2018
;
132
(
21
):
2309
-
2313
.
24.
Hahn
CN
,
Chong
C-E
,
Carmichael
CL
, et al
.
Heritable GATA2 mutations associated with familial myelodysplastic syndrome and acute myeloid leukemia
.
Nat Genet.
2011
;
43
(
10
):
1012
-
1017
.
25.
Pohlen
M
,
Groth
C
,
Sauer
T
, et al
.
Outcome of allogeneic stem cell transplantation for AML and myelodysplastic syndrome in elderly patients (≥60 years)
.
Bone Marrow Transplant.
2016
;
51
(
11
):
1441
-
1448
.
26.
Yanada
M
,
Fukuda
T
,
Tanaka
M
, et al
.
Long-term results of reduced-intensity conditioning allogeneic hematopoietic cell transplantation for older patients with acute myeloid leukemia: a retrospective analysis of 10-year follow-up data
.
Bone Marrow Transplant.
2020
;
55
(
10
):
2008
-
2016
.
27.
Isobe
M
,
Konuma
T
,
Masuko
M
, et al;
Adult Acute Myeloid Leukemia Working Group of the Japan Society for Hematopoietic Cell Transplantation
.
Single cord blood transplantation for acute myeloid leukemia patients aged 60 years or older: a retrospective study in Japan
.
Ann Hematol.
2021
;
100
(
7
):
1849
-
1861
.
28.
Armand
P
,
Gibson
CJ
,
Cutler
C
, et al
.
A disease risk index for patients undergoing allogeneic stem cell transplantation
.
Blood.
2012
;
120
(
4
):
905
-
913
.
29.
Sorror
ML
,
Logan
BR
,
Zhu
X
, et al
.
Prospective validation of the predictive power of the hematopoietic cell transplantation comorbidity index: a center for International Blood and Marrow Transplant Research Study
.
Biol Blood Marrow Transplant.
2015
;
21
(
8
):
1479
-
1487
.
30.
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
.
31.
Morita
K
,
Wang
F
,
Jahn
K
, et al
.
Clonal evolution of acute myeloid leukemia revealed by high-throughput single-cell genomics
[Nat Commun. 2020;11(1):5996].
Nat Commun.
2020
;
11
(
1
):
5327
.
32.
Miles
LA
,
Bowman
RL
,
Merlinsky
TR
, et al
.
Single-cell mutation analysis of clonal evolution in myeloid malignancies
.
Nature.
2020
;
587
(
7834
):
477
-
482
.
33.
Gibson
CJ
,
Lindsley
RC
,
Tchekmedyian
V
, et al
.
Clonal hematopoiesis associated with adverse outcomes after autologous stem-cell transplantation for lymphoma
.
J Clin Oncol.
2017
;
35
(
14
):
1598
-
1605
.
34.
Coombs
CC
,
Zehir
A
,
Devlin
SM
, et al
.
Therapy-related clonal hematopoiesis in patients with non-hematologic cancers is common and associated with adverse clinical outcomes
.
Cell Stem Cell.
2017
;
21
(
3
):
374
-
382.e4
.
35.
Bolton
KL
,
Ptashkin
RN
,
Gao
T
, et al
.
Cancer therapy shapes the fitness landscape of clonal hematopoiesis
.
Nat Genet.
2020
;
52
(
11
):
1219
-
1226
.
36.
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
.
37.
Tanaka
T
,
Morita
K
,
Loghavi
S
, et al
.
Clonal dynamics and clinical implications of postremission clonal hematopoiesis in acute myeloid leukemia
.
Blood.
2021
;
138
(
18
):
1733
-
1739
.
38.
Craddock
C
,
Jackson
A
,
Loke
J
, et al
.
Augmented reduced-intensity regimen does not improve postallogeneic transplant outcomes in acute myeloid leukemia
.
J Clin Oncol.
2021
;
39
(
7
):
768
-
778
.
39.
Sung
A
,
Koll
T
,
Gier
SH
, et al
.
Fried’s frailty phenotype predicts overall survival for older hematopoietic cell transplantation recipients [abstract]
.
Transplant Cell Ther.
2021
;
27
(
3
):
S53
-
S54
. Abstract 56.
40.
Freeman
S
,
Craddock
C
.
Less is not necessarily more: toward a rational selection of the conditioning regimen in acute myeloid leukemia
.
J Clin Oncol.
2020
;
38
(
12
):
1249
-
1251
.
41.
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
.
42.
Schlenk
RF
,
Weber
D
,
Fiedler
W
, et al;
German-Austrian AML Study Group
.
Midostaurin added to chemotherapy and continued single-agent maintenance therapy in acute myeloid leukemia with FLT3-ITD
.
Blood.
2019
;
133
(
8
):
840
-
851
.
43.
de Lima
M
,
Oran
B
,
Champlin
RE
, et al
.
CC-486 maintenance after stem cell transplantation in patients with acute myeloid leukemia or myelodysplastic syndromes
.
Biol Blood Marrow Transplant.
2018
;
24
(
10
):
2017
-
2024
.
44.
Sandmaier
BM
,
Khaled
S
,
Oran
B
,
Gammon
G
,
Trone
D
,
Frankfurt
O
.
Results of a phase 1 study of quizartinib as maintenance therapy in subjects with acute myeloid leukemia in remission following allogeneic hematopoietic stem cell transplant
.
Am J Hematol.
2018
;
93
(
2
):
222
-
231
.
45.
Bashey
A
,
Medina
B
,
Corringham
S
, et al
.
CTLA4 blockade with ipilimumab to treat relapse of malignancy after allogeneic hematopoietic cell transplantation
.
Blood.
2009
;
113
(
7
):
1581
-
1588
.
46.
Davids
MS
,
Kim
HT
,
Bachireddy
P
, et al;
Leukemia and Lymphoma Society Blood Cancer Research Partnership
.
Ipilimumab for patients with relapse after allogeneic transplantation
.
N Engl J Med.
2016
;
375
(
2
):
143
-
153
.
47.
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
.
48.
Liu
J
,
Wang
L
,
Zhao
F
, et al
.
Pre-clinical development of a humanized anti-CD47 antibody with anti-cancer therapeutic potential
.
PLoS One.
2015
;
10
(
9
):
e0137345
.
49.
Romee
R
,
Rosario
M
,
Berrien-Elliott
MM
, et al
.
Cytokine-induced memory-like natural killer cells exhibit enhanced responses against myeloid leukemia
.
Sci Transl Med.
2016
;
8
(
357
):
357ra123
.
50.
Zhou
Z
,
Nath
R
,
Cerny
J
, et al
.
Reduced intensity conditioning for acute myeloid leukemia using melphalan- vs busulfan-based regimens: a CIBMTR report [published correction appears in Blood Adv. 2021;5(13):2752]
.
Blood Adv.
2020
;
4
(
13
):
3180
-
3190
.
51.
Ciurea
SO
,
Kongtim
P
,
Varma
A
, et al
.
Is there an optimal conditioning for older patients with AML receiving allogeneic hematopoietic cell transplantation?
Blood.
2020
;
135
(
6
):
449
-
452
.
52.
Kanakry
CG
,
O’Donnell
PV
,
Furlong
T
, et al
.
Multi-institutional study of post-transplantation cyclophosphamide as single-agent graft-versus-host disease prophylaxis after allogeneic bone marrow transplantation using myeloablative busulfan and fludarabine conditioning
.
J Clin Oncol.
2014
;
32
(
31
):
3497
-
3505
.
53.
Kasamon
YL
,
Bolaños-Meade
J
,
Prince
GT
, et al
.
Outcomes of nonmyeloablative HLA-haploidentical blood or marrow transplantation with high-dose post-transplantation cyclophosphamide in older adults
.
J Clin Oncol.
2015
;
33
(
28
):
3152
-
3161
.
54.
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
.
55.
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
.
You do not currently have access to this content.

Sign in via your Institution