Potent graft-versus-leukemia effect after reduced-intensity allogeneic SCT for intermediate-risk AML with FLT3-ITD or wild-type NPM1 and CEBPA without FLT3-ITD

Article · July 2012with23 Reads
DOI: 10.1016/j.bbmt.2012.06.012 · Source: PubMed
Abstract
To investigate the role of reduced-intensity allogeneic (RIC-allo) stem cell transplant (SCT) as postremission therapy in adult intermediate-risk patients with acute myelogenous leukemia (AML) with FLT3-ITD or wild-type NPM1 and CEBPA without FLT3-ITD, we conducted a single-center retrospective study between January 2001 and December 2010. Sixty-six patients were included: 37 treated with RIC-alloSCT and 29 with nonallogeneic SCT therapies. Both groups were comparable concerning age, WBC count at diagnosis, gender, karyotype, genotype, and number of courses of chemotherapy to reach complete remission (CR1). Median follow-up after CR1 was 37 months (range, 11-112 months) and 48 months (range, 9-83 months) in the allo and no-allo groups, respectively. In the allo versus no-allo groups, the 3-year cumulative incidence of relapse (CIR) rates were 25% ± 8% versus 61% ± 9%; P = .005. The 3-year nonrelapse mortality (NRM), overall survival (OS), and relapse-free survival (RFS) were 22% ± 7% versus 4% ± 4% (P = .005), 52% ± 9% versus 44% ± 10% (P = .75), and 53% ± 9% versus 35% ± 9% (P = .28), respectively. Multivariate analysis indicated that CIR was reduced by allo (hazard ratio [HR], 0.32; P = .01). A landmark analysis performed at day 185 after CR1 confirmed a lower CIR after allo. RIC-allo reduces the risk of relapse, suggesting a potent graft-versus-leukemia (GVL) effect in these patients at a high risk of relapse.
3 Figures
Potent Graft-versus-Leukemia Effect
after Reduced-Intensity Allogeneic SCT for
Intermediate-Risk AML with
FLT3-
ITD or Wild-Type
NPM1
and
CEBPA
without
FLT3-
ITD
Ga
elle Labour
e,
1
St
ephanie Dulucq,
2
Myriam Labopin,
3
Reza Tabrizi,
1
Estelle Gu
erin,
4
Arnaud Pigneux,
1,6
Xavier Lafarge,
5
Thibaut Leguay,
1
Krimo Bouabdallah,
1
Marie-Sarah Dilhuydy,
1
C
edric Duclos,
1
Axelle Lascaux,
1
G
erald Marit,
1,6
Franc
¸ois-Xavier Mahon,
2,6
Jean-Michel Boiron,
5,6
No
el Milpied,
1,6
St
ephane Vigouroux
1
To investigate therole of reduced-intensity allogeneic(RIC-allo) stemcell transplant(SCT) as postremission ther-
apy in adult intermediate-risk patients with acute myelogenous leukemia (AML) with FLT3-ITD or wild-type
NPM1 and CEBPA without FLT3-ITD, we conducted a single-center retrospective study between January 2001
and December 2010. Sixty-six patients were included: 37 treated with RIC-alloSCT and 29 with nonallogeneic
SCT therapies. Both groups were comparable concerning age, WBC count at diagnosis, gender, karyotype, ge-
notype, and number of courses of chemotherapy to reach complete remission (CR1). Median follow-up after
CR1 was 37 months (range, 11-112 months) and 48 months (range, 9-83 months)in the allo and no-allo groups,
respectively. In the allo versus no-allo groups, the 3-year cumulative incidence of relapse (CIR) rates were
25% 68% versus 61% 69%; P5.005. The 3-year nonrelapse mortality (NRM), overall survival (OS), and
relapse-free survival (RFS) were 22% 67% versus 4% 64% (P5.005), 52% 69% versus 44% 610%
(P5.75), and 53% 69% versus 35% 69% (P5.28), respectively. Multivariate analysis indicated that CIR
was reduced by allo (hazard ratio [HR], 0.32; P5.01). A landmark analysis performed at day 185 after CR1
confirmed a lower CIR after allo. RIC-allo reduces the risk of relapse, suggesting a potent graft-versus-
leukemia (GVL) effect in these patients at a high risk of relapse.
Biol Blood Marrow Transplant 18: 1845-1850 (2012) Ó2012 American Society for Blood and Marrow Transplantation
KEY WORDS: Acute myeloid leukemia, FLT3-ITD, NPM1, CEBPA, Reduced conditioning, Allogeneic stem
cell transplantation
INTRODUCTION
The role of allogeneic stem cell transplant (allo-
SCT) in adults with intermediate-risk acute myeloid
leukemia (IR-AML) in first complete remission
(CR1) is controversial and remains a domain of intense
investigation [1-4]. A recent meta-analysis of prospec-
tive clinical trials has reported a significant benefit of
myeloablative allo for relapse-free survival (RFS) and
overall survival (OS) [5]. The median age of patients
in most of these trials was in the 30s, and an equivalent
benefit in older patients remains uncertain. A
German-Austrian retrospective study has demon-
strated that genotypes defined by the mutational status
of FMS-like tyrosine kinase 3 (FLT3), nucleophos-
min1 (NPM1), and CCAAT/enhancer binding protein
a(CEBPA) genes were associated with the outcome
for cytogenetically normal AML [6]. The benefit of
allo was limited to the subgroup of patients with the
prognostically adverse genotype FLT3 internal
tandem duplication (FLT3-ITD) or the genotype con-
sisting of wild-type NPM1 and CEBPA without FLT3-
ITD (triple-negative). In these patients, allo improved
RFS. It must be emphasized that patients were under
From the
1
Service d’H
ematologie et de Th
erapie Cellulaire, CHU
Haut-L
ev^
eque, Bordeaux, France;
2
Service d’H
ematologie
Biologique, CHU Haut-L
ev^
eque, Bordeaux, France;
3
ALWP-EBMT, H^
opital Saint-Antoine, AP-HP, UPMC Univ
Paris 06, UMR-S 938, Paris, France;
4
Service d’H
ematologie Bi-
ologique, H^
opital Dupuytren, Limoges, France;
5
Etablissement
Franc
¸ais du Sang, Bordeaux, France; and
6
Universit
e Bordeaux
Segalen, Bordeaux, France.
Financial disclosure: See Acknowledgments on page 1850.
Correspondence and reprint requests: St
ephane Vigouroux, M.D.,
Service d’H
ematologie et de Th
erapie Cellulaire, H^
opital
Haut-L
ev^
eque - CHU de Bordeaux, 1 avenue de Magellan,
33600 Pessac, France (e-mail: stephane.vigouroux@
chu-bordeaux.fr).
Received March 28, 2012; accepted June 18, 2012
Ó2012 American Society for Blood and Marrow Transplantation
1083-8791/$36.00
http://dx.doi.org/10.1016/j.bbmt.2012.06.012
1845
60 years of age, and underwent transplantation with an
HLA matched-related donor (MRD) after a myeloa-
blative conditioning regimen. As a consequence, the
benefit of reduced-intensity allo (RIC-allo) as postre-
mission therapy in older patients with IR-AML and
FLT3-ITD or a triple-negative genotype remains un-
certain. In an effort to further explore the role of allo
in this setting, we performed a retrospective study of
patients treated with RIC-allo or nonallogeneic SCT
therapies in the absence of a suitable donor. Our aim
was to compare both postremission strategies.
MATERIALS AND METHODS
Selection of Patients
The selection criteria for inclusion in this study
were set to select a population of patients between
18 and 65 years of age, diagnosed with de novo
AML (except acute promyelocytic leukemia) between
January 2001 and December 2010 at our center. All
patient records were reviewed, and some patients
were excluded from the analysis as detailed in
Figure 1. AML with favorable or adverse karyotypes
were excluded. Patients transplanted in CR1 after
a myeloablative conditioning regimen were also
excluded, as were patients who never reached com-
plete remission (CR). Genetic-risk groups were de-
fined according to the recommendations from an
international expert panel [7]. Patients diagnosed be-
fore 2007 at our center were not genotypically defined
at diagnosis, and those with available frozen leukemic
cells were retrospectively analyzed. Thus, patients
with a normal karyotype and either FLT3-ITD or
triple-negative genotype (intermediate-I group) were
included in the present study, as were patients with cy-
togenetic abnormalities not classified as favorable or
adverse and either FLT3-ITD or triple-negative geno-
type (intermediate-II group). We have included pa-
tients with cytogenetic abnormalities not classified as
favorable or adverse when associated with an adverse
genotype because there is some evidence that FLT3-
ITD and triple-negative genotype adversely affect
the outcome of these patients [7-9] as they do for
patients with a normal karyotype [6]. Before 2007,
our therapeutic strategy was to pursue allo in CR1
for patients with cytogenetically defined IR-AML.
From 2007, the same strategy was applied for
patients with IR-AML with either FLT3-ITD or
triple-negative genotype. Patients with cytogenetic
abnormalities not classified as favorable or adverse
and a favorable genotype (mutated NPM1 without
FLT3-ITD or mutated CEBPA) were not included in
our comparative study because we always chose to
treat them with nonallogeneic SCT therapies in
CR1 without looking for a donor. As a consequence,
the unique reason for not performing allo in our study
was the absence of a suitable donor at the time of CR1.
From 2001 to 2006, patients underwent transplanta-
tion only with MRDs. From 2007, patients underwent
transplantation in priority with MRD, then matched-
unrelated donor, and finally mismatched-unrelated
donor (C or DQB1) in the absence of MRD or
matched-unrelated donor. Cord blood units were
used from 2008 in the absence of any related or unre-
lated donor. Finally, to minimize potential biases fa-
voring patients who underwent transplantation,
patients ineligible for allo because of a poor perfor-
mance status or a severe comorbidity were excluded,
as were patients deceased or in relapse before the me-
dian time between CR1 and allo.
Materials
Bone marrow samples were used whenever avail-
able. In all other cases, peripheral blood samples
were examined if the percentage of blasts in peripheral
blood was .25%. Genomic DNA was extracted from
mononuclear cells separated by Ficoll gradient. Geno-
mic DNA (gDNA) was extracted using a QIAamp
DNA Blood miniKit (Qiagen, Courtaboeuf, France),
according to the manufacturer’s protocol.
Figure 1. Selection of patients included in the study.
1846 Biol Blood Marrow Transplant 18:1845-1850, 2012G. Labour
e et al.
Detection of FLT3-ITD, NPM1, and CEBPA
Gene Mutations
The presence of FLT3-ITD and NPM1 gene mu-
tations was detected by capillary electrophoresis-
based fragment analysis after fluorescence labeled
PCR on gDNA. Primers 11F and 12R were used for
FLT3-ITD detection as previously described [10].
Forward primer 50-[HEX]TTCCATACATACTT
AAAACCAAGCA-30described by Boissel et al. [11]
and reverse primer 50-TTAACTCTCTGGTGGTA
GAATGAA-30described by Falini et al. [12] were
used for NPM1 exon 12 mutations. Mutations of the
CEBPA gene were detected by gDNA PCR and
direct sequencing according to the method previously
described [13].
Patients’ Characteristics
Sixty-six patients were included. After CR1, 37 were
treated with RIC-allo (allo group) and 29 with non-
allogeneic SCT therapies (no-allo group). The reasons
for choosing RIC instead of myeloablative conditioning
regimen were as follows: age $50 years (n 532), num-
ber of courses of chemotherapy before allo $3(n54),
and abnormal liver function tests (n 51). The median
age at diagnosis was 55 years (range, 19-64 years). There
were 33 male patients. Forty-three patients had a normal
karyotype and 23 had cytogenetic abnormalities not
classified as favorable or adverse. Forty-two patients
had a triple-negative genotype and 24 patients had the
FLT3-ITD. The median time between CR1 and allo
was 114 days (range, 24-295 days). Conditioning regi-
men combined fludarabine with an alkylating agent
(n 527) or TBI2Gy (n 510). The sources of stem cells
were peripheral blood (n 532), bone marrow (n 51), or
cord blood (n 54). Donors were matched-related
(n 518), matched-unrelated at the allele level (4 digits)
for HLA-A, B, C, DRB1, and DQB1 (n 511), or
mismatch-unrelated (C: n 52 and DQB1: n 52, all at
the antigen level).
Statistical Analysis
Patient-related and disease-related variables of the
2 groups (receiving or not allo) were compared using
the chi-square statistic for categorical and the
Mann-Whitney test for continuous variables. Vari-
ables considered were allo (yes versus no), patient age
at diagnosis ($55 versus \55 years, because this is
the median age of the whole cohort), WBC count at
diagnosis (.versus\30,000/mL) [14], karyotype (nor-
mal versus abnormal), genotype (FLT3-ITD versus
triple-negative), number of courses of chemotherapy
to reach CR1 (1 versus $2), and year of CR1 (.versus
#2006). RFS after CR1 was defined as survival without
evidence of relapse or progression. The nonrelapse
mortality (NRM) was defined as death while in CR.
Cumulative incidence curves were used for relapse
incidence (RI) and NRM in a competing risks setting,
death in CR being a competing event for relapse. The
Gray test was used for univariate comparisons [15].
Probabilities of OS and RFS were calculated using
the Kaplan-Meier estimate [16]; the log-rank test was
used for univariate comparisons. In order to take into
account for delay before allo, we performed a landmark
analysis at day 185 after CR1. All factors studied were
included in the Cox proportional hazards [17] for OS
and RFS, and in a Fine-Gray model for RI and
NRM [18]. Given the retrospective design of the study,
and in order to minimize all possible biases, we decided
to adjust the comparison between the 2 groups (allo
versus no-allo) on all potential prognostic factors
even if not significant in our population. All tests
were 2-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 the SPSS version 19 (IBM, Chicago, IL) and R
2.13.2 software packages (R Development Core
Team, Vienna, Austria).
RESULTS
Comparison of Patients’ Characteristics
between Allo and No-Allo Groups
As shown in Table 1, both groups were comparable
concerning age, gender, WBC at diagnosis, propor-
tion of normal/abnormal karyotypes, proportion of
FLT3-ITD/triple-negative genotypes, and number of
courses of chemotherapy to reach CR1.
Relapse and Survival
The median follow-up after CR1 was 37 months
(range, 11-112 months) in the allo group and 48
months (range, 9-83 months) in the no-allo group. In
the allo group, the median follow-up after transplanta-
tion was 30 months (range, 7-108 months). In the allo
versus no-allo groups, the 3-year OS were 52% 69%
versus 44% 610%, P5.75, and the 3-year RFS were
53% 69% versus 35% 69%, P5.28 (Figure 2).
Nineteen patients have died in the allo group from dis-
ease (n 59), infections (n 57; bacterial septic shock:
n53; bacterial pneumonia: n 53; cytomegalovirus
colitis: n 51, with 5 patients having extensive chronic
graft-versus-host disease [GVHD] and 1 acute
[aGVHD] at the time of infection), aGVHD (n 52),
or suicide (n 51). Fourteen patients have died in the
no-allo group from disease (n 513) or infection
(n 51). Neither OS nor RFS were significantly influ-
enced by any of the studied variables in univariate or
multivariate analyses. In the allo versus no-allo groups,
the 3-year cumulative incidence of relapse (CIR) rates
were 25% 68% versus 61% 69%, P5.005
(Figure 3). In the allo group, 10 patients have relapsed
Biol Blood Marrow Transplant 18:1845-1850, 2012 1847Reduced-Intensity Allogeneic SCT for AML
at a median time of 8 months (range, 4-39 months)
after CR1. In the no-allo group, 18 patients have re-
lapsed at a median time of 8 months (range, 4-44
months) after CR1. Six of them were treated with
allo in CR2. The other patients did not undergo trans-
plantation mainly because of inability to reach CR2
(n 57), absence of a donor (n 54), or ineligibility
by age .65 years at relapse (n 51). In the allo versus
no-allo groups, the 3-year NRMs were 22% 67%
versus 4% 64%, P5.005. Univariate analyses indi-
cated that CIR was reduced only by allo in CR1. Mul-
tivariate analysis for CIR indicated that allo was
associated with a reduced risk of relapse (hazard ratio
[HR], 0.32; 95% confidence interval [CI]: 0.14-0.76;
P5.01; Table 2). Univariate and multivariate analyses
indicated that NRM was increased only by allo in CR1.
Multivariate analysis for NRM is shown in Table 2.
One patient only has undergone transplantation af-
ter day 185 after achievement of CR1, and 6 patients re-
lapsed or died before this date (3 in the allo group and 3
in the no-allo group). By a landmark analysis 185 days
after achievement of CR1, the 3-year CIRs were
19% 67% in the allo group versus 57% 611% in
the no-allo group (P5.003). NRM was 23% 68%
in the allo group versus 4% 64% in the no-allo group
(P5.005). The 3-year OS was 57% 69% versus
49% 611% (P5.70) and 3-year RFS was
58% 69% versus 39% 610% (P5.30) in the allo
and no-allo groups, respectively. By multivariate analy-
sis with landmark at day 185, CIR was reduced in the
allo group compared with the no-allo group (HR,
0.23; 95% CI: 0.09-0.59; P5.003), and NRM was
higher in the allo group compared with the no-allo
group (HR, 9.9; 95% CI: 1.22-80; P5.03).
Graft-versus-Host Disease
The 2-year cumulative incidence rates of aGVHD
grade II to IV, aGVHD grade III to IV, and extensive
chronic GVHD were 40% 68%, 16% 66%, and
25% 67%, respectively.
DISCUSSION
In the present study, we report a reduced CIR after
RIC-allo as postremission therapy in patients with de
novo IR-AML and an unfavorable genotype. The
high incidence of relapse observed in our study in the
no-allo group is comparable to incidence rates re-
ported in previous studies [6,8,9]. Moreover, the
NRM observed in our study in the allo group is also
comparable to NRM reported in studies focusing on
RIC-allo in myeloid malignancies [19]. During the
most recent years of the study, data on allo with
Figure 2. Overall survival (OS) and relapse-free survival (RFS) in allogeneic (allo) and no-allo groups.
Table 1. Characteristics of Patients Included in the Study
Separated into Allo and No-Allo Groups
Variables
Allo
Group
n537
No-Allo
Group
n529 PValue
Age at diagnosis, years
Median (range) 56 (31-64) 54 (19-64) .50
Gender .08
Male 22 11
Female 15 18
WBC count >30,000/mL at diagnosis 11/37 11/29 .50
Karyotype .30
Normal 22 21
Abnormal 15 8
Genotype .20
FLT3-ITD 11 13
Triple-negative 26 16
Courses of chemotherapy to
reach CR1 (n)
1 versus $2
1 22 21 .30
2128
330
Courses of chemotherapy
after CR1 (n)*
NA
080
1153
2116
$308
1 + autoSCT 3 8
2 + autoSCT 0 4
Allo indicates allogeneic; autoSCT, autologous stem cell transplantation;
NA, not applicable.
*Before allogeneic SCT in the allo group.
1848 Biol Blood Marrow Transplant 18:1845-1850, 2012G. Labour
e et al.
unrelated donors have emerged, as well as clinical trials
with cord blood, accounting for a higher number of
allo in recent years, and consequently a slightly shorter
follow-up in the allo group. Because only RIC regimes
were used in our study, the reduced incidence of re-
lapse suggests a potent graft-versus-leukemia (GVL)
effect. This benefit did not translate into a difference
in survival because allo was associated with a higher
NRM and because some successful allo procedures
were performed in CR2 in the no-allo group.
The cytogenetic analysis at diagnosis provides
the most powerful independent prognostic factor in
AML [14]. The prognosis has been refined in recent
years by analysis of gene mutations in FLT3,NPM1,
and CEBPA [8,9,20,21]. These efforts have led to the
characterization of IR-AML with a normal karyotype
or cytogenetic aberrations not classified as favorable or
adverse, associated with FLT3-ITD, or triple-negative
genotype [6-9]. The majority of these patients reach
a CR, but a high number rapidly relapse after usual
consolidation therapy with high-dose cytarabine,
accounting for a significant impact on relapse risk and
OS. This adverse effect is more striking in the presence
of a high FLT3-ITD allele ratio indicative of a homozy-
gous mutation [9]. However, this last data has not
been incorporated into the standardized reporting
system for genetic abnormalities recently recommended
from an international expert panel [7].Naturally,these
observations raise the questionof the optimal postremis-
sion therapy, but prospective studies are lacking. Koreth
et al. [5] reported the results of a systematic review and
meta-analysis of prospective trials evaluating allo versus
non-allogeneic SCT therapies for AML in CR1, based
on donor availability. The risk groups were cytogeneti-
cally defined. They reported that allo had significant
RFS and OS benefit for IR-AML. Most patients were
young, with median ages in the 30s, and underwent
transplantations with an MRD after a myeloablative
conditioning regimen. To further refine the analysis,
Schlenk et al. [6] evaluated the associations of the muta-
tions of the NPM1, FLT3, CEBPA, MLL,andNRAS
genes with clinical outcomes in 872 adults younger
than 60 years of age with cytogenetically normal AML.
In that study, RFS was significantly longer in patients
who underwent transplantation in the subgroup of pa-
tients with the prognostically adverse genotypes
FLT3-ITD or triple-negative. Patients underwent
transplantation with an MRD after a myeloablative con-
ditioning regimen. Additionally, Dezern et al. [22] re-
ported the outcome of allo in adult patients under 60
years of age with AML and FLT3-ITD. The study in-
cluded 133 patients. Among them, 31 harbored an
FLT3-ITD mutation at diagnosis. The OS for the
patients with FLT3-ITD was comparable to the 102 pa-
tients with wild-type FLT3 over the same 4-year time
period. Historically, OS for patients with FLT3-ITD
AML was significantly worse than for patients with
AML lacking this mutation. The authors hypothesized
that the difference that might have contributed to the
surprisingly favorable outcomes for the FLT3-ITD
group was their aggressive pursuit of allo. Altogether,
and despite the lack of prospective data, these studies
suggest that younger patients with FLT3-ITD or
triple-negative IR-AML benefit from myeloablative
allo as postremission therapy. Unfortunately, the avail-
able data do not indicate if this benefit is mostly due to
the antileukemic activity of the conditioning regimen,
or the existence of a potent GVL effect, or both.
A beneficial effect of RIC-allo in older patients
with IR-AML remains uncertain. As summarized in
a recent review article by Storb [19], several authors
have demonstrated the feasibility of RIC-allo in older
Figure 3. Cumulative incidence of relapse (CIR) in allogeneic (allo) and
no-allo groups.
Table 2. Results of Multivariate Analyses for CIR and NRM
Variables
CIR NRM
HR (95% CI) PValue HR (95% CI) PValue
Allo (yes versus no) 0.32 (0.14-0.76) .01 9.71 (1.18-80) .04
WBC at diagnosis (> versus <30,000/mL) 1.27 (0.45-3.57) .65 0.8 (0.17-3.73) .77
Karyotype (normal versus abnormal) 1.25 (0.6-2.59) .56 0.73 (0.23-2.25) .58
Genotype (FLT3-ITD versus triple-negative) 1.1 (0.4-3.17) .85 0.74 (0.13-4.22) .73
Age at diagnosis ($versus <55 years) 1.85 (0.83-4.12) .13 1.41 (0.32-6.13) .65
Courses of chemotherapy to reach CR1 (1 versus $2) 0.64 (0.28-1.49) .30 1.47 (0.42-5.17) .54
Year of CR1 (> versus #2006) 0.87 (0.35-2.2) .77 0.75 (0.23-2.39) .62
CIR indicates cumulative incidence of relapse; NRM, nonrelapse mortality; HR, hazard ratio; CI, confidence interval; Allo, allogeneic.
Biol Blood Marrow Transplant 18:1845-1850, 2012 1849Reduced-Intensity Allogeneic SCT for AML
patients using related or unrelated donors, with
reasonable outcomes. That review indicated that 2 to
5-year survival rates of 25% to 64% could be expected,
with similar survival for recipients of related and unre-
lated HLA-matched grafts. Relapse rates ranged from
16% to 53%, and the major issue was NRM ranging
from 16% to 39%. No RIC regimen has proven its
superiority, and fludarabine combined with either
low-dose TBI or an alkylating agent usually leads to
comparable outcome [19]. It must be emphasized
that no study has explored the outcome of RIC-allo
in the specific population of patients with FLT3-ITD
or triple-negative IR-AML. As a consequence, the
benefit of RIC-allo in these patients remains uncertain
to a large extent.
It must be acknowledged that the retrospective na-
ture of our study precludes the declaration of any firm
conclusions. The absence of difference in OS and RFS
must indeed be interpreted with caution given the
modest size of the study. However, we report that
RIC-allo reduces the risk of relapse in patients with
FLT3-ITD or triple-negative IR-AML in CR1, sug-
gesting a potent GVL effect. This finding can be dis-
cussed in light of a recent article suggesting that the
FLT3-ITD-mutated receptor is hyper-responsive to
its cognate ligand rather than autonomously activated
[23]. As chemotherapy leads to high levels of cognate
ligand during the period of recovery and during con-
solidation, the author raises the provocative hypothesis
that successive courses of consolidation chemotherapy
could promote relapse. If this hypothesis is confirmed,
and considering the GVL effect suggested in our
study, the best postremission strategy in patients
with FLT3-ITD could be to proceed as rapidly as pos-
sible to allo once remission is achieved. A strategy of
early allo might also permit the decrease of NRM
and thus improve the outcome of these patients.
ACKNOWLEDGMENTS
Financial disclosure: The authors have nothing to
declare.
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e et al.
  • [Show abstract] [Hide abstract] ABSTRACT: Acute myeloid leukemia (AML) is a molecularly heterogeneous disease. Based on cytogenetics and FISH, AML patients are stratified into three major risk categories: favourable, intermediate and unfavourable. However, prognostic stratification and treatment decision for the intermediate risk category, that mostly comprises AML patients with normal cytogenetics (CN-AML), has been difficult due to the clinical heterogeneity and scarce knowledge of the molecular alterations underlying this large AML subgroup. During the past decade, the identification of several mutations associated with CN-AML has resulted into important advances in the AML field. In this review, we address the biological features of the main mutations associated with CN-AML and the impact of next generation sequencing studies in expanding our knowledge of the molecular landscape of CN-AML. In addition, we outline the prognostic value of mutations for risk stratification of CN-AML patients and discuss the potential of mutations discovery process for developing new molecular targeted therapies.
    Article · Dec 2012
  • [Show abstract] [Hide abstract] ABSTRACT: Patients with acute myeloid leukemia (AML) traditionally classified as having an intermediate cytogenetic risk [mostly cytogenetically normal AML (CN-AML)] really include a significant proportion of cases with a poor outcome. This is based on the molecular findings at diagnosis, mainly the presence of internal tandem duplication in the FMS-like tyrosine kinase 3 gene(s) (FLT3/ITD). Optimal postremission therapy for these high-risk molecular cases is not well established; as the prognosis is adverse hematopoietic cell transplantation (HCT), mainly allogeneic HCT (allo-HCT), is the most widely accepted strategy. As a rule, patients with FLT3/ITD have a poor outcome with conventional chemotherapy alone. Only patients with an associated nucleophosmin 1 (NPM1) mutation and those with a low mutated-to-wild-type allelic ratio of FLT3/ITD have less unfavorable outcome. Most studies show an advantage of allo-HCT in first complete remission (CR1), with higher 3-5 year disease-free survival and lower relapse risk than with chemotherapy or autologous transplantation (auto-HCT). Regarding allo-HCT proceeding early after reaching CR1 seems to improve survival, rather than after several courses of consolidation chemotherapy. Patients with intermediate-risk cytogenetics AML and FLT3/ITD, especially NPM1-wild cases and those NPM1 mutated with a high allelic ratio, should proceed to allo-HCT if possible early after achieving CR1.
    Article · Mar 2013
  • [Show abstract] [Hide abstract] ABSTRACT: Abstract Internal tandem duplications of the FMS-like tyrosine kinase 3 (FLT3) gene are one of the most frequent gene mutations in acute myeloid leukemia (AML) and are associated with poor clinical outcome. The remission rate is high with intensive chemotherapy, but most of the patients eventually relapse. During the last decade, FLT3 mutations have emerged as an attractive target for a molecularly-specific treatment strategy. Targeting FLT3 receptor tyrosine kinases in AML has shown encouraging results in the treatment of FLT3 mutated AML, but in most of the patients responses are incomplete and not sustained. Newer, more specific compounds seem to have a higher potency and selectivity against FLT3. During therapy with FLT3 tyrosine kinase inhibitors (TKIs) the induction of acquired resistance has emerged as a clinical problem. Therefore, optimization of the targeted therapy and potential treatment options to overcome resistance is currently the focus of clinical research. In this review we discuss the use and limitations of TKIs as a therapeutic strategy for the treatment of FLT3 mutated AML, including mechanisms of resistance to TKIs as well as possible novel strategies to improve FLT3 inhibitor therapy.
    Article · Apr 2013
  • [Show abstract] [Hide abstract] ABSTRACT: Patients with acute myeloid leukemia who harbor an FMS-like tyrosine kinase 3 (FLT3) mutation present several dilemmas for the clinician. The results of an FLT3 mutation test, which can be influenced by several variables, need to be interpreted according to the clinical setting and there is a need for internationally standardized FLT3 mutation assays. Because of the lack of prospective studies, the role of allogeneic transplantation as consolidation therapy is still somewhat controversial, but the preponderance of evidence suggests that transplantation in first remission, if possible, is probably the best option. Clinically useful FLT3 inhibitors are hopefully on the near horizon and are being studied in the context of current treatment paradigms.
    Article · Dec 2013
  • [Show abstract] [Hide abstract] ABSTRACT: Acute myeloid leukemia (AML) is the most common form of acute leukemia affecting adults. Although it is a complex disease driven by numerous genetic and epigenetic abnormalities, nearly 50% of patients exhibit a normal karyotype (CN-AML) with an intermediate cytogenetic risk. However, a widespread genomic analysis has recently shown the recurrence of genomic aberrations in this category (mutations of FLT3, CEBPA, NPM1, RUNX1, TET2, IDH1/2, DNMT3A, ASXL1, MLL and WT1) thus revealing its marked genomic heterogeneity. In this perspective, a global gene expression analysis of AML patients provides an independent prognostic marker to categorize each patient into clinic-pathologic subgroups based on its molecular genetic defects. Consistently such classification, taking into account the uniqueness of each AML patient, furnishes an individualized treatment approach leading a step closer to personalized medicine. Overall the genome-wide analysis of AML patients, by providing novel insights into biology of this tumor, furnishes accurate prognostic markers as well as useful tools for selecting the most appropriate treatment option. Moreover it provides novel therapeutic targets useful to enhance efficacy of the current anti-AML therapeutics. Here we describe the prognostic relevance of such new genetic data and discuss how this approach can be used to improve survival and treatment of AML patients.
    Article · Mar 2014
  • [Show abstract] [Hide abstract] ABSTRACT: FMS-like tyrosine kinase 3 (FLT3) is the most frequently mutated gene in AML. Thirty percent of patients with acute myeloid leukemia (AML) harbor activating mutations in FLT3, either internal tandem duplication mutations in the juxtamembrane domain (FLT3-ITD) or point mutations in the tyrosine kinase domain (FLT3 TKD). Small molecule FLT3 inhibitors have emerged as an attractive therapeutic option in patients with FLT3 mutations; however, the clinical activity of early inhibitors was limited by a lack of selectivity, potency and unfavorable pharmacokinetic properties. Newer agents such as quizartinib have improved potency and selectivity associated with much higher bone marrow response rates; however, response duration is limited by the development of secondary resistance. We will review here a number of FLT3 inhibitors that have been evaluated in clinical trials and discuss challenges facing the use of these agents in AML.
    Article · Mar 2014
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January 2015 · Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation · Impact Factor: 3.40
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