VOLUME
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30
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2012
JOURNAL OF CLINICAL ONCOLOGY
O R I G I N A L
R E P O R T
Impact of FLT3 Internal Tandem Duplication on the
Outcome of Related and Unrelated Hematopoietic
Transplantation for Adult Acute Myeloid Leukemia in
First Remission: A Retrospective Analysis
Salut Brunet, Myriam Labopin, Jordi Esteve, Jan Cornelissen, Gerard Socié, Anna P. Iori, Leo F. Verdonck,
Liisa Volin, Alois Gratwohl, Jorge Sierra, Mohamad Mohty, and Vanderson Rocha
Salut Brunet and Jorge Sierra, Hospital de
la Santa Creu i Sant Pau, Universitat
Autònoma de Barcelona; Jordi Esteve,
Institut d’investigacions Biomèdiques
August Pi i Sunyer, Hospital Clinic, Barcelona, Spain; Myriam Labopin, Université
Pierre et Marie Curie Paris 6, Hôpital Saint
Antoine; Gerard Socié and Vanderson
Rocha, Hôpital Saint-Louis, Paris; Mohamad
Mohty, Centre Hospitalier et Universitaire
de Nantes, Université de Nantes, and Institut National de la Santé et de la Recherche
Médicale, Nantes, France; Jan Cornelissen,
Erasmus Medical Center–Daniel den Hoed
Cancer Center, Rotterdam; Leo F.
Verdonck, Isala Kliniecken Zwolle, Zwolle,
the Netherlands; Anna P. Iori, Sapienza
Università di Roma, Rome, Italy; Liisa Volin,
Helsinki University Central Hospital,
Helsinki, Finland; Alois Gratwohl, University
Hospital, Basel, Switzerland; and Vanderson Rocha, Sirio-Libanes Hospital and Children’s Cancer Hospital, University of Sao
Paulo, Sao Paulo, Brazil.
Submitted May 31, 2011; accepted
December 5, 2011; published online ahead
of print at www.jco.org on January 30,
2012.
Written on behalf of the Acute Leukemia
Working Party of the European Group for
Blood and Marrow Transplantation.
Supported in part by Grants No. EC07/
90065, PI080672, PI080413, RD06/0020/
0101, and RD06/0020/0004 from Instituto
de Salud Carlos III, Madrid, and No. 2009SGR-1246 from the Agency for Administration of University and Research Grants,
Barcelona, Spain.
Authors’ disclosures of potential conflicts
of interest and author contributions are
found at the end of this article.
Corresponding author: Salut Brunet, MD,
Hematology Service, Hospital de la Santa
Creu i Sant Pau, Mas Casanovas 90, 08041
Barcelona, Spain; e-mail: sbrunet@
santpau.cat.
© 2012 by American Society of Clinical
Oncology
0732-183X/12/3007-735/$20.00
DOI: 10.1200/JCO.2011.36.9868
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Purpose
Patients with acute myeloid leukemia (AML) and FLT3/internal tandem duplication (FLT3/ITD) have
poor prognosis if treated with chemotherapy only. Whether this alteration also affects outcome
after allogeneic hematopoietic stem-cell transplantation (HSCT) remains uncertain.
Patients and Methods
We analyzed 206 patients who underwent HLA-identical sibling and matched unrelated HSCTs
reported to the European Group for Blood and Marrow Transplantation with a diagnosis of
AML with normal cytogenetics and data on FLT3/ITD (present: n ⫽ 120, 58%; absent: n ⫽ 86,
42%). Transplantations were performed in first complete remission (CR) after myeloablative conditioning.
Results
Compared with FLT3/ITD-negative patients, FLT3/ITD-positive patients had higher median leukocyte count at diagnosis (59 v 21 ⫻ 109/L; P ⬍ .001) and shorter interval from CR to transplantation
(87 v 99 days; P ⫽ .04). Other characteristics were similar in the two groups. At 2 years, relapse
incidence (RI; ⫾ standard deviation) was higher (30% ⫾ 5% v 16% ⫾ 5%; P ⫽ .006) and
leukemia-free survival (LFS) lower (58% ⫾ 5% v 71% ⫾ 6%; P ⫽ .04) in FLT3/ITD-positive compared with
FLT3/ITD-negative patients. In multivariate analyses, FLT3/ITD led to increased RI (hazard ratio [HR], 3.4;
95% CI, 1.46 to 7.94; P ⫽ .005), as did older age, female sex, shorter interval between CR and
transplantation, and higher number of chemotherapy courses before achieving CR. FLT3/ITD positivity was
associated with decreased LFS (HR, 0.37; 95% CI, 0.19 to 0.73; P ⫽ .002), along with older age and higher
number of chemotherapy courses before achieving CR.
Conclusion
FLT3/ITD adversely affected the outcome of HSCT in the same direction it does after chemotherapy; despite this, more than half of the patients harboring this mutation who received transplants
were alive and leukemia free at 2 years. To further improve the results, use of FLT3 inhibitors
before or after HSCT deserves investigation.
J Clin Oncol 30:735-741. © 2012 by American Society of Clinical Oncology
INTRODUCTION
Acute myeloid leukemia (AML) is clinically and
biologically heterogeneous.1 This reflects the diversity of pathophysiologic events in this disease,
including acquired gene mutations and/or deregulation of gene expression.2-6 It is well recognized
that cytogenetic abnormalities of leukemic cells at
diagnosis are the most important biologic prognostic factors in AML. In practice, patients with
AML are allocated to prognostic categories to
adapt postremission therapy according to cytogenetic risk.7-9 Nonetheless, 45% of patients with
AML have normal cytogenetics (NC-AML). In this
latter group, molecular techniques are useful to detect somatic mutations of several genes such as
internal tandem duplication of FLT3 (FLT3/ITD),
NPM1, CEBPA, or MLL with marked prognostic
relevance.1-3,5,10,11 Among them, the presence of
FLT3/ITD is the most powerful indicator of adverse
prognosis in NC-AML. This mutation, detected in
approximately one third of patients with NC-AML,
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735
Brunet et al
increases the risk of relapse and has a negative impact on
survival.10,12-15 The role of autologous and allogeneic hematopoietic
stem-cell transplantation (alloHSCT) for patients with FLT3/ITD
AML remains controversial.16-20 Many groups recommend allogeneic
transplantation in first complete remission (CR) in the presence of this
molecular abnormality,2,18,19,21 because this treatment has the most
powerful antileukemic effect. In contrast, other investigators argue
that evidence supporting this approach is still limited, and a neat
benefit after alloHSCT for this group of patients is not obtained.17
Importantly, it is unknown whether FLT3/ITD also affects the
outcome of allogeneic transplantation itself. This uncertainty is a
result of the relatively reduced number of allografted patients with
known FLT3 mutational status included in reported series. For this
reason, analyses of large databases including molecular information are of particular interest. Herein, we report the first international transplantation registry study, to our knowledge, on the
impact of FLT3/ITD on the outcome of patients with NC-AML. All
patients received myeloablative conditioning in the first CR of their
disease and received transplants between 2000 and 2008 from
either HLA-identical siblings or matched unrelated donors
(MUDs). Characteristics and outcomes were reported to the European Group for Blood and Marrow Transplantation (EBMT).
PATIENTS AND METHODS
Data Collection
EBMT is a voluntary organization including more than 500 transplantation centers. They are required to file annual reports of all consecutive SCTs
with follow-up performed by EBMT physicians. All centers reporting specific
disease questionnaires (Med-B forms) for patients with AML who underwent
alloSCTs and fulfilled the inclusion criteria were asked to contribute additional data.
Inclusion Criteria
Adult patients age 18 years or older were included in the study if all of the
following criteria were met: de novo AML, normal cytogenetics at diagnosis on
chromosome-banding analysis, myeloablative alloHSCT, either from peripheral or bone marrow; non– ex vivo T-cell depletion, HLA-identical sibling or
MUD (MUDs were defined as 8/8, with high-resolution typing for HLA-A, -B,
-C, -DRB1, and -DRB), transplantation performed from 2000 to 2008, and
analysis of FLT3/ITD at diagnosis available. Ultimately, we were able to analyze
206 patients with available molecular information on FLT3/ITD (FLT3/ITD
negative, 86; FLT3/ITD positive, 120) of 1,467 adult patients reported to
EBMT fulfilling the aforementioned criteria.
Cytogenetics and FLT3/ITD Molecular Studies
Cytogenetics and molecular FLT3/ITD analyses were performed by referring institutions at diagnosis. FLT3/ITD was studied according to local
standardized protocols. All participating transplantation centers had access to
experienced laboratories in molecular techniques.
End Points and Statistical Analysis
Descriptive statistics included the main characteristics at diagnosis and
transplantation, whereas end points considered were relapse incidence (RI),
nonrelapse mortality (NRM), and leukemia-free survival (LFS). Cumulative
incidences of relapse and NRM were calculated from the date of transplantation to date of relapse or death in remission, respectively, with competing risk
as the other event.22 LFS was defined as the interval from SCT to either relapse
or death in remission. These end points were calculated at 2 years. Follow-up
values reported correspond to patients alive when the analysis was performed.
Proportions were compared by means of the ␹2 method, whereas the
Mann-Whitney test was applied to detect differences between continuous
parameters. Univariate comparisons of time-dependent end points were per736
© 2012 by American Society of Clinical Oncology
formed by means of the log-rank test in the case of Kaplan-Meier LFS curves
and the Gray’s test for RI and NRM cumulative incidences.
Multivariable analyses were performed using the Cox proportional hazards model for LFS and Fine-Gray model for RI.23 Factors differing in terms of
distribution between the two groups and factors associated with a P value less
than .15 by univariate analysis were included in the model. Then, a stepwise
backward procedure was used with a cutoff significance level of .05 for deleting
factors in the model. For all prognostic analyses, continuous variables were
categorized, and the median was used as a cutoff point. All tests are two sided.
The type I error rate was fixed at 0.05 for determination of factors associated
with time-to-event outcomes. Statistical analyses were performed with SPSS
(SPSS, Chicago, IL) and Splus (MathSoft, Seattle, WA) software packages.
RESULTS
Patients and Disease Characteristics
Of 1,467 patients who met the eligibility criteria, we were able to
analyze 206 patients (14%) with FLT/ITD data. Table 1 lists the main
characteristics of patients according to FLT3/ITD status. Briefly, presence of FLT3/ITD was detected in 120 (58%) of 206 patients. FLT3/
ITD-positive patients presented with higher WBC counts at diagnosis
(59 v 21 ⫻ 109/L; P ⬍ .001) and underwent alloHSCT after having
achieved CR (84 v 99 days; P ⫽ .04). No statistical differences in age,
sex, French-American-British classification, number of chemotherapy cycles before achieving CR, or interval from diagnosis to HSCT
were found between the two groups. Median follow-up of survivors
was 19 months (range, 2 to 96 months) for FLT3/ITD-positive patients and 12 months (range, 1 to 92 months) in the FLT3/ITDnegative group.
Donor and Transplantation Characteristics
All grafts were T-cell replete, from HLA-identical siblings or
MUDs. Myeloablative conditioning regimen was based on total body
irradiation or busulfan combined with other drugs, mainly cyclophosphamide (Table 1). Graft-versus-host disease (GVHD) prophylaxis
was cyclosporine (CSA) combined with methotrexate in most cases,
whereas a minority received CSA plus mycophenolate mofetil or CSA
alone. No significant differences were observed between FLT3/ITDpositive and -negative groups in year of transplantation, donor type,
donor sex, female-to-male recipient, serologic cytomegalovirus status,
conditioning regimen, graft source, or GVHD prophylaxis.
Neutrophil Recovery
Most patients (99%) surviving at least 50 days after transplantation had a neutrophil count greater than 0.5 ⫻ 109/L; only two FLT3/
ITD-positive patients experienced primary engraftment failure, and
another patient who was FLT3/ITD negative experienced secondary
graft failure after an initial engraftment.
Acute and Chronic GVHD
The cumulative incidence of acute GVHD at 100 days (⫾ standard deviation) was 43% ⫾ 4% (FLT3/ITD positive, 36% ⫾ 5%;
FLT3/ITD negative, 53% ⫾ 5%; P ⫽ .04). In a multivariate analysis,
FLT3/ITD positivity was not associated with higher incidence of acute
GVHD (P ⫽ .42).
Data on chronic GVHD were available for 152 patients at risk,
without significant difference in incidence according to FLT3/ITD
mutational status. Cumulative incidence at 2 years was 49% ⫾ 4%
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Impact of FLT3/ITD in Allogeneic Transplantation
Table 1. Patient, Disease, and Transplantation Characteristics According
to FLT3/ITD Status
Characteristic
Patient
Age, years
Median
Range
Sex
Male
Female
Disease
FAB type
M0
M1
M2
M4
M5
WBC, ⫻ 109/L
Median
Range
No. of courses to CR1
1
⬎1
Interval from CR1 to transplantation,
days
Median
Range
Transplant
Year of SCT
2000-2004
2005-2008
Donor relation
HLA identical sibling
MUD
Donor sex
Male
Female
Female donor to male recipient
No
Yes
CMV donor-recipient serologic status
Negative-negative
Positive-negative
Negative-positive
Positive-positive
Conditioning regimen based on TBI
No
Yes
Source of stem cells
Bone marrow
Peripheral blood
Use of ATG/ALG
No
Yes
GVHD prophylaxis
CSA and MTX
Other
FLT3/ITD
Negative
(n ⫽ 86)
FLT3/ITD
Positive
(n ⫽ 120)
No.
No.
%
%
P
.31
42
19-59
41
18-60
.06
50
36
58
42
2
9
17
17
8
72
7
17
32
32
15
54
66
45
55
.07
21
0.8-240
0
0
26 35
22 30
14 19
12 16
106
59
0.7-373
⬍ .001
77
23
77
99
26-219
76
19
80
20
104
87
17-241
.04
.37
23
63
27
73
39
81
32
68
68
18
79
21
90
39
75
25
50
36
58
42
58
62
48
52
71
15
83
17
92
28
77
23
19
7
15
40
23
9
18
49
38
13
18
49
32
11
15
42
.5
.17
.31
.47
.37
42
44
49
51
51
69
42
58
.14
41
45
48
52
45
75
37
63
71
14
84
16
98
22
82
18
67
14
83
17
91
21
81
29
.73
.67
Abbreviations: ATG/ALG, antithymocyte or antilymhoglobulin; CMV, cytomegalovirus; CR1, first complete remission; CSA, cyclosporine; FAB, FrenchAmerican-British; FLT3/ITD, internal tandem duplication of FLT3 gene; GVHD,
graft-versus-host disease; MTX, methotrexate; MUD, matched unrelated
donor; SCT, stem-cell transplantation; TBI, total body irradiation.
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NRM
Two-year cumulative incidence of NRM (⫾ standard deviation)
was 13% ⫾ 2%. Presence of FLT3/ITD was not associated with cumulative incidence of NRM (Table 2). Additionally, none of the other
factors analyzed were associated with NRM.
RI
At 2 years, cumulative incidence of relapse for the whole population (⫾ standard deviation) was 24% ⫾ 5%, with a significant increased RI in the FLT3/ITD-positive group (30% ⫾ 5% v 16% ⫾ 5%;
P ⫽ .006; Fig 1A). This higher risk of relapse associated with FLT3/ITD
mutation was also confirmed in the multivariable analysis (HR, 3.4;
95% CI, 1.46 to 7.94; P ⫽ .005; Table 3). In addition, other factors such
as older age (ⱖ 42 years), more than one course of chemotherapy
before achieving CR, shorter interval from CR to transplantation, and
female sex were associated with a higher RI (Table 3; Fig 1A).
LFS
.6
49
15
(FLT3/ITD positive, 47% ⫾ 6%; FLT3/ITD negative, 52% ⫾ 6%;
P ⫽ .72).
Two-year LFS for the whole population (⫾ standard deviation)
was 64% ⫾ 3% (Table 2). When comparing unadjusted probabilities
of LFS between FLT3/ITD-positive and -negative patients, outcome
was worse in the former group (58% ⫾ 5% v 71% ⫾ 6%; P ⫽ .04;
Table 2; Fig 1B). In the multivariable analysis, after adjustment for
patient-, disease-, and transplantation-related variables, difference in
LFS according to FLT3/ITD status was confirmed (HR, 0.37; 95% CI,
0.19 to 0.73; Table 3). Other variables influencing LFS in the univariate
analysis were patient age and number of chemotherapy courses before
achieving CR, a finding that was confirmed in the multivariable analysis after adjustment for other variables (Tables 2 and 3). Thus,
younger patients (age ⬍ 42 years), with a borderline significance level
(74% ⫾ 5% v 54% ⫾ 5%; HR, 0.54; 95% CI, 0.3 to 0.99; P ⫽ .05) and
patients requiring only one course of chemotherapy before achieving
CR (71% ⫾ 5% v 30% ⫾ 11%; HR, 0.26; 95% CI, 0.14 to 0.48; P ⫽ .05)
showed a more favorable outcome. On the contrary, other variables
such as leukocyte count at diagnosis, time from CR to transplantation,
donor source, and donor-recipient relation did not have an impact on
LFS, either in the univariate or multivariable analysis.
DISCUSSION
This study is the largest analysis of the impact of FLT3/ITD mutation on the results of alloHSCT as treatment for patients with AML
with normal karyotype in first CR. The presence of FLT3/ITD led
to higher relapse risk and inferior LFS. Nonetheless, the observed
2-year LFS of 58% in patients with FLT3/ITD and the relapse risk of
30% favorably compares with the outcomes reported after postremission chemotherapy only. This suggests that alloHSCT has a relevant
role in the management of AML involving this genetic lesion, although
we acknowledge that some degree of selection bias in the series reported here cannot be ruled out. As an example, those patients who
relapsed before transplantation could not be included in the series
herein analyzed.
Definition of risk in AML has been historically based on age,
leukocyte count, and cytogenetics. Regarding the latter, treatment
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737
Brunet et al
Table 2. Main Results of Univariate Analysis of Prognostic Factors for LFS, RI, and NRM
LFS
Two-Year Outcome
%
SD
Overall
FLT3/ITD
Negative
Positive
Patient age, years
⬍ 42
ⱖ 42
Donor sex
Male
Female
WBC, ⫻ 109/L
⬍ 30
ⱖ 30
No. of courses to CR1
1
⬎1
Interval from diagnosis to SCT (median, 140 days)
⬍ Median
⬎ Median
Interval from CR1 to SCT (median, 93 days)
⬍ Median
⬎ Median
Year of SCT
ⱕ 2005
⬎ 2005
Donor-recipient relation
HLA identical sibling
MUD
Total body irradiation
No
Yes
Source of progenitor cells
Bone marrow
Peripheral cells
T-cell depleted in vivo
No
Yes
64
3
71
58
6
5
74
54
5
5
59
67
6
5
68
63
6
5
71
30
5
11
65
62
5
6
59
66
6
6
65
62
5
6
63
60
4
11
63
62
5
5
63
63
6
5
63
65
4
10
RI
P
%
SD
24
5
16
30
5
5
14
32
4
5
25
23
5
5
18
24
5
6
17
53
4
13
24
24
5
5
28
17
5
5
25
24
4
7
25
22
4
9
28
21
5
4
22
26
5
4
25
22
4
9
.04
NRM
P
%
SD
13
2
13
13
4
3
12
13
4
3
15
10
4
3
14
13
4
4
12
18
3
7
11
14
3
4
13
17
4
4
11
14
3
4
12
17
3
7
8
16
3
4
15
11
4
3
12
17
3
7
.006
.004
.72
.006
.57
.51
.78
.25
.23
.14
⬍ .001
.84
⬍ .001
.81
.25
.73
.32
.47
.03
.47
.3
.73
.96
.47
.48
.41
.36
.68
.98
.1
.33
.96
P
.24
.48
.36
Abbreviations: CR1, first complete remission; FLT3/ITD, internal tandem duplication of FLT3 gene; LFS, leukemia-free survival; MUD, matched unrelated donor;
NRM, nonrelapse mortality; RI, relapse incidence; SCT, stem-cell transplantation; SD, standard deviation.
results in the large subgroup of patients with intermediate-risk karyotype have been diverse, reflecting the heterogeneous nature of this
cytogenetic category. In recent years, it has become evident that the
identification of mutations or overexpression of several genes allows
for segregation of prognostic categories in the heterogeneous
intermediate-risk cytogenetic group. Among them, FLT3 mutations
resulting in an ITD of the juxtamembrane domain of this tyrosine
kinase receptor consistently confer an adverse prognosis.5,12-14
In the last few years, the impact of FLT3/ITD according to postremission strategy has been analyzed in some studies. Two reports
showed that autologous transplantation improved outcome compared with chemotherapy.19,24 Regarding alloHSCT, two consecutive
trials conducted by the Medical Research Council cooperative
group did not show a clear benefit from HLA-identical sibling
transplantation in AML with FLT3/ITD, although the relapse rate
was markedly reduced compared with that in other treatments.17
738
© 2012 by American Society of Clinical Oncology
In contrast, recently reported data indicate that allogeneic transplantation improves the outcome of these patients, as it does in
other high-risk AML groups.4,19,21
It may be argued that a caveat of this and other prognostic factor
analyses could be not taking into account certain important variables
with potential influence on transplantation outcome. Some of these
relevant variables are included in the EBMT score,25 which should be
considered in future prognostic factor studies in the transplantation
setting. This weakness of the present report is counterbalanced in part
by the fact that we analyzed a rather homogeneous population (ie,
early disease stage, only myeloablative conditioning, no ex vivo T-cell
depletion, HLA-matched donors, and treatment during recent years).
The key finding of this study was that patients with NC-AML in first
CR harboring FLT3/ITD had increased RI and consequently decreased
LFS compared with patients with FLT3/ITD-negative NC-AML. This
increase in relapse incidence was observed in FLT3/ITD-positive patients
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Impact of FLT3/ITD in Allogeneic Transplantation
A
Table 3. Results of Multivariable Analyses for LFS and RI (n ⫽ 158)
1.0
Cumulative Incidence of Relapse
(proportion)
Outcome
LFS
FLT3/ITD, positive v negative
Age ⱖ 42 years
⬎ One course to CR
RI
FLT3/ITD, positive v negative
Age ⱖ 42 years
Patient sex, female v male
Interval from CR to transplantation
⬎ 93 days
⬎ One course to CR
0.8
0.6
0.4
95% CI
P
0.37
0.54
0.26
0.19 to 0.73
0.3 to 0.99
0.14 to 0.48
.002
.05
⬍ .001
3.4
3.02
2.61
1.46 to 7.94
1.48 to 6.15
1.23 to 5.55
.005
.002
.013
0.46
3.72
0.21 to 0.98
1.71 to 8.09
.046
⬍ .001
Abbreviations: CR, complete remission; FLT3/ITD, internal tandem duplication of FLT3 gene; HR, hazard ratio; LFS, leukemia-free survival; RI, relapse
incidence.
0.2
0
HR
1
2
3
Time (years)
Leukemia-Free Survival
(proportion)
B
1.0
0.8
0.6
0.4
0.2
0
1
2
3
Time (years)
Fig 1. Outcome after allogeneic transplantation performed in first complete
remission for patients with acute myeloid leukemia and normal cytogenetics
according to the presence (dashed line) or absence (solid line) of internal tandem
duplication of FLT3 gene. (A) Estimated probability of 2 years of cumulative
incidence of relapse; (B) leukemia-free survival after transplantation at 2 years.
independently of other variables such as stem-cell source, donor type, and
the combination of female donor to male recipient. Moreover, this effect
does not seem to be related to a lower GVHD incidence or higher use of in
vivo T-cell depletion in the FLT3/ITD-positive group, thus confirming
the negative influence of this mutation in the alloHSCT setting as
well.26-28 Despite these findings, the adverse impact of FLT3/ITD
on transplantation outcome does not preclude indication of this
procedure in these patients if they have an HLA-identical sibling or
MUD, because we observed a remarkable 2-year LFS of 58% and
relapse incidence of 30%. These results seem by far better than
those obtained with chemotherapy, which has been followed by a
median survival of only 2.5 months.3,5,10,11,14,17,29 Whether the recent
introduction of FLT3 kinase inhibitors will significantly improve outcome after chemotherapy remains to be answered by ongoing clinical
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trials. These FLT3 inhibitors may in the future make unnecessary
allogeneic transplantation in first CR in a substantial fraction of patients with this molecular alteration. On the other hand, these inhibitors, if effective, may increase the proportion of patients with FLT3/
ITD who achieve CR and reach allografting in the best condition.
Therefore, the administration of FLT3 inhibitors before and/or after
allogeneic transplantation may be a strategy to be explored with the
aims of increasing transplantation feasibility and reducing relapse
incidence after the procedure.
The data herein reported suggest the existence of a strong antileukemic effect from myeloablative conditioning and graft–versus–
FLT3/ITD-positive AML reaction. Therefore, only prospective
randomized studies may definitively establish the best treatment option for this molecular group of AML. However, this type of study is
unlikely to be performed, because it has now been established that the
prognosis of patients with NC-AML harboring FLT3/ITD and treated
with chemotherapy only is poor.
We used the EBMT registry database with the acknowledgment
that this type of study may have the selection bias of excluding patients
who experience relapse before the procedure. This may particularly be
the case in AML with FLT3/ITD, because early relapse is frequent.
Despite this, investigating the outcome of patients with FLT3/ITD
AML who reach allogeneic transplantation remains of interest; it is
also worth knowing whether their results are worse than those
achieved in the absence of this molecular feature. Despite this selection
effect inherent to all studies based on transplantation registries,30 the
population of patients with FLT3/ITD AML included in this study had
typical features characteristic of this AML subtype, such as high median WBC count at diagnosis.5,10,12 As we have mentioned before,
prospective randomized studies are needed to establish definitively the
best treatment option for this molecular group of AML, although it
may be difficult to launch in this setting given the poor outcome
observed after chemotherapy-based postremission strategies. The
58% proportion of FLT3/ITD AML observed in this series of NCAML is much higher than that observed in the overall population
of patients with NC-AML. This finding likely reflects that FLT3/ITD is
in practice a criterion indicating alloHSCT in first remission, whereas
in the absence of this adverse molecular feature, patients with NCAML are frequently treated with postremission chemotherapy only.
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739
Brunet et al
Because the majority of patients with AML who are candidates
for allogeneic transplantation lack an HLA-identical sibling, the use of
MUDs is increasing.31-33 As recently reported by the EBMT group,34
the current indications of allogeneic transplantation for AML do not
differ according to type of donor, provided that an HLA match exists.
This recommendation is also supported by our study, which showed a
similar outcome in patients receiving transplants from HLA-identical
siblings and those receiving transplants from MUDs.
Another aspect that deserves attention is the fact that a substantial number of patients in this series received transplants from
MUDs for AML in first remission, despite normal karyotype and
absence of FLT3/ITD. Some groups claim that alloHSCT involving
a matched donor is the best option for all patients with NC-AML in
first remission, regardless of donor-recipient relation, unless a favorable molecular profile is present, such as NPM1 or CEBPA mutation. Furthermore, patients without FLT3/ITD could be also
candidates for allogeneic transplantation based on other high-risk
criteria, such as hyperleucocytosis at diagnosis or need of more than
one chemotherapy course to achieve CR.34 This latter variable also
adversely influences the outcome of FLT3/ITD-positive patients, and
in this circumstance, intensified conditioning regimens, preemptive
strategies based on close monitoring of minimal residual disease after
transplantation, and prophylactic use of donor lymphocyte infusions
are potential strategies.
Other aspects not analyzed in the present report that deserve
investigation are the possible influence on transplantation results of
FLT3/ITD allelic burden, duplication length, and location as well as
the possible impact of the coexistence of other gene mutations with
prognostic value, such as NPM1, WT1, IDH1 and IDH2, or DNMT3A.
In summary, the presence of FLT3/ITD correlated with a higher
risk of relapse and lower LFS after alloHSCT performed in first CR,
and our study confirms that this mutation defines a high-risk entity
even in the context of allogeneic transplantation. Nonetheless, the
relative favorably outcome observed after transplantation, with a relapse incidence and LFS of 30% and 58% at 2 years, respectively,
suggests that this procedure might have a relevant role for the management of this molecular entity. Tyrosine kinase inhibitors with
activity on FLT3 receptor have been developed and are currently
under clinical investigation.35,36 These agents may improve the outcome of patients with FLT3 mutations treated with chemotherapy and
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AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS
OF INTEREST
Although all authors completed the disclosure declaration, the following
author(s) indicated a financial or other interest that is relevant to the subject
matter under consideration in this article. Certain relationships marked
with a “U” are those for which no compensation was received; those
relationships marked with a “C” were compensated. For a detailed
description of the disclosure categories, or for more information about
ASCO’s conflict of interest policy, please refer to the Author Disclosure
Declaration and the Disclosures of Potential Conflicts of Interest section in
Information for Contributors.
Employment or Leadership Position: None Consultant or Advisory
Role: Jorge Sierra, Celgene (C), Genzyme (C) Stock Ownership: None
Honoraria: Jorge Sierra, Celgene, Genzyme Research Funding: Jorge
Sierra, Celgene, Novartis, Amgen Expert Testimony: None Other
Remuneration: None
AUTHOR CONTRIBUTIONS
Conception and design: Salut Brunet, Jordi Esteve, Jorge Sierra,
Mohamad Mohty, Vanderson Rocha
Financial support: Vanderson Rocha
Administrative support: Myriam Labopin, Mohamad Mohty,
Vanderson Rocha
Provision of study materials or patients: Salut Brunet, Jordi Esteve, Jan
Cornelissen, Gerard Socié, Anna P. Iori, Leo F. Verdonck, Liisa Volin,
Alois Gratwohl, Vanderson Rocha
Collection and assembly of data: Salut Brunet, Myriam Labopin, Jordi
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Data analysis and interpretation: Salut Brunet, Myriam Labopin, Jordi
Esteve, Jorge Sierra, Mohamad Mohty, Vanderson Rocha
Manuscript writing: All authors
Final approval of manuscript: All authors
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