Allogeneic stem cell transplantation in adult patients with acute myeloid leukaemia and 17p abnormalities in first complete remission: a study from the Acute Leukemia Working Party (ALWP) of the European Society for Blood and Marrow Transplantation (EBMT)
Poiré et al. Journal of Hematology & Oncology
Allogeneic stem cell transplantation in adult patients with acute myeloid leukaemia and 17p abnormalities in first complete remission: a study from the Acute Leukemia Working Party (ALWP) of the European Society for Blood and Marrow Transplantation (EBMT)
Xavier Poiré 0
Jan J. Cornelissen
0 Section of Hematology, Department of Medicine, Cliniques Universitaires Saint-Luc , 10, avenue Hippocrate, 1200 Brussels , Belgium
Background: Acute myeloid leukaemia (AML) with 17p abnormalities (abn(17p)) carries a very poor prognosis due to high refractoriness to conventional chemotherapy, and allogeneic stem cell transplantation (allo-SCT) appears as the only potential curative option. Methods: To address outcomes after allo-SCT in patients with abn(17p), we retrospectively analysed de novo or secondary AML undergoing SCT between 2000 and 2013 from the EBMT registry. Results: One hundred thirty-nine patients with confirmed abn(17p) have been selected. At the time of transplant, one hundred twenty-five were in first remission (CR1). Median age was 54 years old. Abn(17p) was associated with a monosomal karyotype in 83% of patients, complex karyotype in 91%, monosomy 5 or 5q deletion (-5/5q-) in 55%, monosomy 7 (-7) in 39% and both -5/5q and -7 in 27%. Seventy-three patients (59%) had a reduced-intensity conditioning regimen. The 2-year overall survival (OS) and leukaemia-free survival (LFS) were 28 and 24%, respectively. The 2-year non-relapse mortality (NRM) was 15%, and 2-year relapse incidence (RI) was 61%. The cumulative incidence of grade II to IV acute graft-versus-host disease (GvHD) was 24% and that of chronic GvHD was 21%. In multivariate analysis, the presence of a -5/5q- in addition to abn(17p) was significantly and independently associated with worse OS, LFS and higher RI. Age and donor types did not correlate with outcome. Conditioning intensity was not statistically associated with OS, LFS and NRM when adjusted for patients' age. Conclusions: In contrast to the dismal prognosis reported for AML patients harbouring abn(17p) undergoing conventional chemotherapy, allogeneic SCT provides responses in about 25% of those patients transplanted in CR1.
Acute myeloid leukaemia; 17p abnormalities; Stem cell transplantation; Survival; First remission
Allogeneic stem cell transplantation (allo-SCT) is now a
standard approach recommended for patients with
highrisk acute myeloid leukaemia (AML) in remission [1, 2].
High-risk AML is mainly defined by the presence of
determined poor-risk cytogenetic abnormalities at
diagnosis together with specific mutational events [3–6]. In
general, conventional post-remission high-dose
chemotherapy is not capable to eradicate the initiating stem
cell leukemic clone of high-risk AML, harbouring strong
chemoresistance mechanisms , and only the potent
graft-versus-leukaemia arising after allo-SCT may
overcome the poor prognosis of these high-risk AML
subtypes . Indeed, several reports have confirmed the
significant advantage of allo-SCT in high-risk AML,
especially when performed early in the course of the
disease [9–11]. Among the heterogeneous group of
high-risk AML, prognosis can be further stratified based
on specific genetic abnormalities, and the potential
benefit of allo-SCT differs between these diverse AML
subtypes [12–16]. While, it is still questionable if distinct
genetic abnormalities with a known worse outcome like
complex karyotype (CK) and monosomal karyotype
(MK) AML will get the same benefit from allo-SCT .
TP53 is located in 17p13 chromosomal region and is
one of the major tumour suppressor genes, often
inactivated by deletion and/or mutation in many tumours
. It has been described in 10 to 15% of AML
patients, with an increased frequency in elderly patients
and secondary AML . TP53 inactivation is associated
in AML with a significantly lower response to intensive
chemotherapy, translating into a poor outcome .
Although TP53 mutations/deletions show a high
correlation with complex karyotype in AML [21–23], TP53
mutations and/or loss have emerged as a strong and
independent prognostic marker of very poor outcomes
regardless of associated cytogenetic abnormalities [24, 25].
Thus, long-term disease control is observed in less than
5% of the patients harbouring the TP53 mutations with
conventional chemotherapy [25, 26]. Molecular
screening for TP53 mutations is not routinely performed, and
loss or disruption of 17p13 (17p abnormalities,
abn(17p)) is usually identified by FISH analysis . In
this context, the potential capability of allo-SCT to
overcome the dismal prognosis of abn(17p) AML is of great
interest, scarcely explored until now. A first report from
Mohr et al. described the outcome of 47 allografted
patients and did not show a different outcome compared
to non-transplanted patients, raising the hypothesis of a
lack of sensitivity of this entity to the potential benefit of
graft-versus-leukaemia effect . This detrimental
effect of abn(17p) on allo-SCT outcomes has been
confirmed in another report with an event-free survival
(EFS) of only 11% due to a very high incidence of relapse
. A recent report from Middeke et al. described 201
patients with abn(17p) AML transplanted during the
past decade, showing an overall EFS of only 12%, with a
slight better outcome among the 84 patients allografted
in first complete remission (3-year EFS 18 vs 7%) p <
0.001) . The purpose of the current study was to
explore the potential role of early-phase allo-SCT in
abn(17p) AML in the multicenter, registry context of
EBMT, with the aim to identify specific subsets of
patients who could benefit from the procedure.
Data collection and patient selection
The data on patients over 18 years of age with a
diagnosis of de novo or secondary AML transplanted with a
related or unrelated donor were available from the EBMT
registry. The latter is a voluntary working group of more
than 450 transplant centres reporting regularly on their
transplant activity. Only patients having available
cytogenetics and transplanted between 1 January 2000 and
31 December 2013 have been selected. Patients with
second allo-SCT have been excluded as well as those
receiving a haplo-identical transplantation. Audits are
routinely performed to insure the quality of the reported
data. All patients provided informed consent on the use
of their data in retrospective studies. The Review Board
of EBMT approved this study. We identified a dataset of
10,799 patients with 5495 patients displaying an
abnormal karyotype. All cytogenetic abnormalities have been
carefully reviewed by two physicians (Xavier Poiré and
Lucienne Michaux). Most centres report conventional
karyotype and a few report also FISH results.
Cytogenetic results found in the registry are complete or often
partial depending on the reporting center. Based on
available data, we kept for further analysis only patients
for whom data were sufficient to confirm the presence
of abn(17p). Abn(17p) were defined as loss of 17p13
(TP53 locus) such as monosomy 17, deletion (17p),
isochromosome 17q (i(17q)), addition (17p) or other
abnormalities that disrupt the 17p13 locus. Only one center
reported a patient with TP53 mutation. Those selected
patients have been further categorised as CK, MK,
presence of monosomy 7, presence of loss of 5q and/or
presence of a inversion of chromosome 3 (inv(3)). CK has
been defined as the presence of 3 or more cytogenetic
abnormalities. MK has been defined as two or more
autosomal monosomies or one autosomal monosomy in
combination with at least one structural chromosomal
abnormality. A total of 139 patients from 78 centres met
the criteria and have been selected for further analysis.
Myeloablative conditioning (MAC) has been defined as a
regimen including total body irradiation (TBI) of more than
8 Gy or a busulfan dose of more than 10 mg/kg. Reducedintensity conditioning (RIC) includes intermediate doses of
alkylating agents such as 8–10 mg/kg busulfan, 80–
140 mg/m2 melphalan, 600–1200 mg/m2
cyclophosphamide or 5–10 mg/kg thiotepa, and/or low-dose TBI
(<3 Gy). The following variables have been selected and
included in the analysis: year of transplantation, age, gender,
status at transplantation, time to diagnosis to complete
remission, time to complete remission to allo-SCT, number
of induction courses, type of conditioning regimen, in vivo
T cell depletion, type of T cell depletion, cytomegalovirus
(CMV) status of donor and recipient, donor type, source of
stem cells, Karnofsky performance status at transplantation,
engraftment, presence of acute and chronic
graft-versushost disease (GvHD), grade of acute GvHD, presence of
CK, MK, monosomy 7, loss of 5q and/or inv(3), cause of
death. HLA typing was determined at 10 loci (A, B, C,
DRB1, DQB1) by high-resolution techniques, although not
all the centres report complete data on HLA. All unrelated
donors were defined as HLA matched (10/10) or
mismatched at 1 locus (9/10). Additional data have been
collected on the therapy of relapsing patients when available.
HLA data on cord blood (CB) were not captured in this
study. Methods and definitions were similar to other
studies performed by the Acute Leukemia Working Party of the
Statistical analysis and endpoint definitions
Endpoints included leukaemia-free survival (LFS),
relapse incidence (RI), non-relapse mortality (NRM),
overall survival (OS), acute and chronic GVHD and
GVHD-free/relapse-free survival (GRFS). All outcomes
were measured from the time of stem cell infusion. LFS
was defined as survival without relapse; patients alive
without relapse were censored at the time of last
contact. OS was based on death from any cause. NRM was
defined as death without previous relapse. GRFS was
defined as survival without grade 3–4 acute GVHD,
extensive chronic GVHD, relapse or death. Surviving
patients were censored at the time of last contact. The
probabilities of OS and LFS were calculated by the
Kaplan-Meier test, and those of acute and chronic
GVHD, NRM, and relapse by the cumulative incidence
estimator to accommodate competing risks. Results are
expressed with a 95% confidence interval (CI). For
NRM, relapse was the competing risk, and for relapse,
the competing risk was NRM. For acute and chronic
GVHD, death without the event and relapse were the
For all prognostic analyses, continuous variables were
categorised and the median was used as a cut-off point.
A Cox proportional hazards model was used for
multivariate regression. Factors associated with a p value less
than 0.05 by univariate analysis were included in the
model. Results were expressed as hazard ratio (HR) with
95% confidence interval
All tests were two-sided. The type 1 error rate was
fixed at 0.05 for determination of factors associated with
time to event outcomes. Statistical analyses were
performed with SPSS 19 (SPSS Inc./IBM, Armonk, NY) and
R 3.0.1 (R Development Core Team, Vienna, Austria)
A total of 139 patients with abn(17p) have been
identified. There were 125 patients transplanted in first
complete remission (CR1), while only 14 patients
were transplanted in second remission (CR2). Because
of the small number of patients transplanted in CR2,
further analysis has been focused on CR1 patients. A
detailed table of the different abn(17p) is available as
a Additional file 1: Table S1.
A total of 125 patients with abn(17p) transplanted in
CR1 have been analysed in November 2015. The median
follow-up of the cohort was 21 months (ranging 3–
146 months). The median age at transplantation was
54 years old (ranging 18–69 years old). The median year
of transplantation was 2009 (ranging 2000–2013). The
median time from diagnosis to CR1 was 57 days
(ranging 18–170 days), and median time from CR1 to
transplantation was 82 days (ranging 11–286 days). For 81
patients, we had information about the number of
induction courses to reach CR1. Fifty-two had just one
course, 27 had 2 and 3 needed 3 rounds of
chemotherapy. Most patients were de novo AML (85%) and only
19 patients corresponded to secondary AML, seven of
them arising from an antecedent myelodysplastic
syndrome. The majority of patients were male (57%) and
were transplanted with a Karnofsky performance status
of more than 90% (70%). A sibling donor was used in
48% and an unrelated donor in 43% (10/10: N = 23
(64%); 9/10: N = 13 (33%), missing: N = 36) whereas a
cord blood was used in 10 patients. Source of stem cell
was mostly peripheral blood (76%). CMV status was
positive in 68% of the patients and also 68% of the
donors. Fifty-one patients received a MAC and 74 patients
a RIC. In patients less than 50 years old, only 14 patients
(26.4%) received a RIC but this number increased up to
60 (83.3%) in patients over 50 years old (p < 10−5). Most
frequent MAC were the combination of
cyclophosphamide and busulfan (N = 19) followed by the association
of total body irradiation (TBI) with cyclophosphamide
(N = 14). Most RIC were fludarabine and TBI (N = 25)
closely followed by fludarabine and busulfan (N = 24).
Seven patients received the sequential FLAMSA-RIC
approach . In vivo T cell depletion has been used in 64
patients. Among those, 47 patients received
antithymocyte globulin (ATG) and 17 patients
alemtuzumab. Regarding associated cytogenetic categories, most
patients carried also a CK (N = 98) or a MK (N = 86). An
inv(3) was present in only 3 patients. Monosomy 7 (-7)
was seen in 41 patients and a monosomy 5 or a loss of
5q (-5/5q-) in 58 patients. Both -7 and -5/5q- were
present together in 28 patients. Table 1 summarises the
Table 1 Patients’ characteristics (N = 125)
Median age at SCT (range)
Median follow-up (range)
Interval between diagnosis and CR1 (range)
Intervals from CR1 to SCT (range)
Median year of SCT
Secondary AML, N (%)
CMV+ patient, N (%)
CMV+ donor, N (%)
Karnofsky >90% at SCT, N (%)
Donor type, N (%)
Source of SC, N (%)
Conditioning regimen, N (%)
In vivo T cell depletion, N (%)
Monosomal karyotype, N (%)
Complex karyotype, N (%)
53.6 years old (18–69)
21 months (3.3–146)
56.5 days (18–170)
81.5 days (11–286)
Engraftment and graft-versus-host disease
Engraftment was successful in 117 patients (94%). Six
patients showed a graft failure and 1 patient lost his
graft. The cumulative incidence of grade II to IV acute
GvHD was 24%. The 2-year cumulative incidence of
chronic GvHD was only 21% [95% CI 14.2–29.5]
(Fig. 1). This low incidence is explained because many
patients relapsed before developing chronic GvHD. A
Cox proportional hazards model including age, donor
type, use of ATG during the conditioning regimen,
source of stem cells and conditioning intensity has
been performed for cGvHD (Table 2). Only the use of
ATG during the conditioning regimen was
significantly associated with less chronic GvHD (HR 0.33,
95% CI 0.11–0.97; p = 0.04), whereas donor other than
an HLA-matched sibling showed just a trend towards
more chronic GvHD (p = 0.07).
Non-relapse mortality and relapse incidence
The 2-year cumulative incidence of NRM was 15% [95%
CI 8.9–21.8] as illustrated in Fig. 2a. None of the
analysed variables (i.e. conditioning intensity, in vivo T cell
depletion, use of ATG, age, donor or patient gender,
female donor to male recipient, Karnofsky performance
status, donor type, number of induction course, CK,
MK, -7, -5/5q- or both -7 and -5/5q-) were significantly
associated with NRM neither in univariate analysis nor
in multivariate analysis.
Seventy-six patients relapsed at a median interval of
4 months from allo-SCT (range 0.2–92.8 months)
translating into a 2-year cumulative incidence of relapse of
61.3% [95% CI 51.5–69.7] as illustrated in Fig. 2b. The 2
factors significantly associated with a higher RI were
conditioning intensity and presence of -5/5q-. On the
Both -7 and -5/5q-, N (%)
Abbreviations; N number, CR1 first complete remission, SCT stem cell
transplantation, AML acute myeloid leukaemia, CMV cytomegalovirus, BM bone
marrow, PB peripheral blood, CB cord blood, MAC myeloablative conditioning,
RIC reduced-intensity conditioning, ATG anti-thymocyte globulin
Fig. 1 Cumulative incidence of chronic GvHD. The 2-year cumulative
incidence of chronic GvHD was 21% [95% CI 14.2–29.5]
Table 2 Multivariate analysis using a Cox proportional hazards
model, N = 96. Chronic GvHD
Age ≥50 years old
Donor other than MSD
Abbreviations: MSD matched sibling donor, ATG anti-thymocyte globulins, PB
peripheral blood, BM bone marrow, RIC reduced-intensity conditioning, MAC
myeloablative conditioning, HR hazard ratio, CI confidence interval
contrary, in vivo T cell depletion was not associated with
higher relapse rate. The relapse incidence was 53% [95%
CI 37–66.2] after a MAC and 68% [95% CI 55.2–78.2]
when a RIC was used (p = 0.01). The presence of
-5/5qwas associated with a significant higher RI (70% [95% CI
Fig. 2 Non-relapse mortality (NRM) (a) and relapse incidence (RI) (b).
The 2-year cumulative incidence of NRM was 15% [95% CI 8.9–21.8]
(a) and the 2-year cumulative incidence of relapse was 61.3% [95%
CI 51.5–69.7] (b)
55.4–80.9]) compared to patients without -5/5q- (51%
[95% CI 35.4–65.4], p = 0.03). Patients’ age above 50 years
old and MK showed only a trend towards a higher RI (p
= 0.06 and p = 0.05, respectively). The number of
induction courses to reach CR1 did not impact on relapse
rate. In multivariate analysis, only the presence of
-5/5qkept its significant impact on RI (p = 0.03) while
conditioning intensity, age and MK did not show a significant
impact on relapse risk (Table 3). Among the 56 relapsed
patients with available information, 16 patients received
donor leukocyte infusion (DLI). Thirteen of them
received a second allo-SCT thereafter and 2 additional
patients received a second allo-SCT as the only cell-based
therapy for relapse. The 2-year probabilities of OS were
8.4% after DLI [95% CI 0–24.1] and 20% after second
allo-SCT [95% CI 0–55.1].
The 2-year probability of OS was 28% [95% CI 19.7–
37.1] (Fig. 3a). In univariate analysis, factors significantly
associated with a worse OS were RIC, older age, MK
and presence of -5/5q-. Monosomy 7 showed only a
trend towards a decreased OS (p = 0.06 and p = 0.08,
respectively). Thus, the 2-year probability of OS was 40%
[95% CI 25–55] after a MAC and 21% after a RIC [95%
CI 10–31] (p < 0.005). Patients above 50 years old had a
worse OS (22%, [95% CI 12–36]) than younger patients
(39%, [95% CI 23–54], p < 0.005). Given the strong
interaction between use of RIC and older age, as previously
described, conditioning intensity did not show any
impact on OS when adjusted for age. Concerning
associated cytogenetic categories, patients harbouring a MK
had a decreased 2-year OS (19%, [95% CI 17–36])
compared to patients without this cytogenetic abnormality
Table 3 Multivariate analysis using a Cox proportional hazards
model, N = 90. Only variables with p < 0.05 in univariate analysis.
LFS, OS and RI
Age ≥50 years old
Age ≥50 years old
Age ≥50 years old
Abbreviations: N number, LFS leukaemia-free survival, OS overall survival, RI
relapse incidence, HR hazard ratio, CI confidence interval, MAC myeloablative
conditioning, RIC reduced-intensity conditioning, MK monosomal karyotype
Fig. 3 Overall survival (OS) (a) and leukaemia-free survival (LFS) (b).
In the whole cohort, the 2-year probability of OS was 28% [95% CI
19.7–37.1] (a) and the 2-year probability of LFS was 24% [95% CI
(58%, [95% CI 34–82], p = 0.005) as well as patient with
concomitant -5/5q- (12%, [95% CI 2–22] vs 44%, [95%
CI 28–59], p < 0.005). Taking together -7 and -5/5q-
status, absence of -5/5q- was associated to a better
outcome (2-year OS 47% [95% CI 30–65] and 31% [95% CI
0–63] in patients without and with concomitant -7,
respectively) compared to the subset of patients
harbouring -5/5q- (2-year OS 16% [95% CI 1–31] and 10% [95%
CI 0–22], according to simultaneous -7 or not,
respectively) (Fig. 4a). Thus, in multivariate analysis, the
presence of -5/5q- was significantly associated with a
decreased OS (HR 2.02; 95% CI 1.2–3.5, p = 0.01),
whereas RIC was associated with a trend towards a
worse OS (p = 0.07) (Table 3). Causes of death were
disease related in 63 patients, infections in 13, GvHD in 11,
haemorrhage in 1 and others in 2 patients.
The 2-year probability of LFS was 24% [95% CI
15.7–31.9] as illustrated in Fig. 3b. In univariate
Fig. 4 Overall survival (OS) (a) and leukaemia-free survival (LFS) (b)
by cytogenetics subgroup. Mono5 refers as the presence of
monosomy 5 or loss of 5q and mono7 refers as the presence of
monosomy 7. Absence of Mono5 was associated to a better OS (2-year OS
47% [95% CI 30–65] and 31% [95% CI 0–63] in patients without and
with mono7, respectively) compared to the subset of patients
harbouring mono5 (2-year OS: 16% [95% CI 1–31] and 10% [95% CI 0–
22], according to simultaneous mono7 or not, respectively) (a). The
deleterious impact of mono5 on LFS was independent of presence
of additional mono7, with a 2-year LFS of 11% [95% CI 0–23]
(mono5 without mono7) and 13% [95% CI 0–27] (mono5 with
mono7) vs 38% [95% CI 9–67] (absence of mono5 with mono7) and
37% [95% CI 20–53] (absence of both abnormalities, p = 0.007) (b)
analysis, decreased LFS was significantly associated
with RIC (2-year LFS of 20% [95% CI 8–29] and 30%
[95% CI 16–44] after RIC and MAC allo-SCT,
respectively, p = 0.01), age above 50 years old (2-year LFS:
20% [95% CI 10–30] vs 29% [95% CI 15–43], p <
0.005), MK (2-year LFS 17% [95% CI 8–25] vs 49%
[95% CI 25–72], p = 0.02), and presence of -5/5q-).
The deleterious impact of 5q loss was independent of
presence of additional -7, with a 2-year LFS of 11%
[95% CI 0–23] (-5/5q- without -7) and 13% [95% CI
0–27] (-5/5q- with -7) vs 38% [95% CI 9–67] (absence
of -5/5q- with -7) and 37% [95% CI 20–53] (absence
of both abnormalities, p = 0.007; Fig. 4b). In vivo T cell
depletion and the use of ATG were not significantly
associated with worse LFS. In multivariate analysis,
only the presence of -5/5q- remained significantly
associated with a decreased LFS (p = 0.02) (Table 3).
The presence of chronic GvHD was associated with
significantly decreased risk of RI, but resulted in higher
NRM, and worse OS and LFS (p < 0.005) (Table 4). The
2-year probability of GvHD and relapse-free survival
(GRFS) was 16% [95% CI 9–23]. Among the 10 patients
transplanted with CB, we found similar 2-year OS and
LFS of 27% [95% CI 0–56] and 27% [95% CI 2–58],
respectively. No significant differences were found with
the other patients (p = 0.95 and p = 0.81, respectively). In
this small cohort, four out of them showed the
combination of abn(17p) and -5/5q-.
P53 loss of function resulting from chromosomal losses
of 17p region and TP53 gene mutations result in marked
chemorefractoriness and very poor prognosis, with
virtually incurability for most patients treated with
conventional AML chemotherapy [24, 25, 28, 29]. The present
study focused on the capability of allo-SCT to
circumvent this dismal prognosis. In patients allografted in
CR1, LFS at 2 years was 24%, suggesting the potential
curability of a proportion of these patients with this
approach, and the existence of a potent
graft-versustumour effect capable to sustain response. Our cohort
might correspond to a highly selected patient
population, with some degree of chemosensitivity sufficient to
achieve an initial response, and is therefore not
representative of the whole abn(17p) AML. However, these
results confirm the role of allo-SCT as a reasonable
option for the subset of patients achieving sufficient
cytoreduction at the time of transplantation. Abn(17p) are
highly represented in overlapping cytogenetically very
high-risk AML, such as MK and CK, and might
participate in the underlying mechanisms responsible of the
their refractoriness to standard intensive AML therapy.
Table 4 Multivariate analysis using a Cox proportional hazards
model. Impact of cGvHD on outcomes (time-dependant
Abbreviations: N number, LFS leukaemia-free survival, OS overall survival,
RI relapse incidence, NRM non-relapse mortality, HR hazard ratio, CI
Nonetheless, the study provides evidences of the urgent
unmet need to develop novel strategies for these
patients. Different transplant modalities, concerning donor
source or conditioning regimen, did not have a major
impact on transplant outcome in our study, and future
improvement attempts must explore pre- and
posttransplant interventions, together with innovative
modifications of allo-SCT conditioning regimen.
Our results are quite comparable to those reported by
Middeke et al. . The 2-year LFS and OS of 24 and
28%, respectively, in our cohort are more favourable
compared to the previous retrospective study from Mohr
et al., based on 47 transplanted patients, which did not
show any advantage compared to conventional therapy,
with a 4-year probability of survival for the entire cohort
of only 4% . Relapse was the main cause of treatment
failure, achieving 70% at 2 years after RIC conditioning,
and these relapses occurred at a median interval from
transplant of 4 months, indicating the need of
implementing early interventions in the post-transplant period
to prevent relapse. Notably, the current results in
patients with AML harbouring abn(17p) are similar to
those observed with MK and CK AML. In those studies,
an independent effect of abn(17p) has not been found
[13–15]. In fact, genomic losses of 17p, together with
losses of 5q and 7q, and gains 11q and 8q, are the most
frequent cytogenetic abnormalities described in CK .
Nevertheless, our study cohort represents a more
homogeneous population than the one addressed in the
studies evaluating MK and CK AML. On the other hand, we
were not able to find a significant effect of the presence
of MK, probably because 83% of patients displayed MK
NRM was only 17%, probably reflecting the positive
selection effect in this population, enriched with
responsive patients to previous chemotherapy. In fact, these
139 patients represent only 1.3% of 10,799 patients with
an available karyotype in the EBMT database, a lower
proportion than the expected rate of 5–10% in general
AML population . These 1.3% of patients refer only
to the proportion of abn(17p) AML patients who were
in remission and fit enough to survive until the
transplantation procedure. Lower intensity conditioning
regimens were associated to a higher relapse risk, up to
70%, in the univariate analysis, an association not
confirmed in the multivariate analysis adjusted for other
variable such as concomitant presence of 5q loss and
age. Nonetheless, the effect of different regimens aimed
to enhance antitumour effect without increasing toxicity
must also be explored in the next future.
Presence of chronic GvHD, analysed as
timedependant variable, was independently associated with a
lower relapse risk (HR 0.76), supporting the existence of
a genuine and potent graft-versus-leukaemia. This
antitumour effect of chronic GvHD, nonetheless, did not
result in a neat benefit due to its association to a higher
NRM translating into worse OS and LFS. Recognition of
a potential graft-versus-leukaemia effect in abn(17p)
AML would give the basis to develop strategies aimed to
harness this alloimmune effect in the early
posttransplant period, such as early withdrawal of
immunosuppression or administration of prophylactic donor
leukocyte infusion [35, 36]. Post-transplant
administration azacytidine might contribute to stimulate the
antitumour donor graft effect by enhancing the expression
of tumour and minor histocompatibility antigens, with
the theoretical added advantage of avoiding an increased
GvHD rate by expansion of T regulatory cell population.
Several studies have demonstrated feasibility of
azacytidine during the post-transplant period, and the
correlation of the expansion determined cytotoxic T cell
subsets against tumour antigens with a lower relapse
incidence, but the clinical benefit of such strategy should
be further proven [37–40]. Other innovative donor cell
strategies such as NK cell infusion or Cytokine-induced
killer population, with a theoretical lower potential of
GvHD induction, must be of high interest in this setting
[41–43]. Anyhow, based on the very short median time
to relapse, post-transplantation interventions should be
given early as a prophylactic or maintenance strategy.
Vosaroxin [44, 45] is a quinolone derivative reported to
be TP53 independent and shows some clinical benefit in
combination with high-dose cytarabine in relapsed
patients. Currently, it is completely unknown if this agent,
administered prior to allo-SCT, might result into
improved outcome after allo-SCT, but it might constitute a
model to bring abn(17p) AML with better response to
Additional chromosomal 5q loss conferred an even
worse outcome in this cohort of patients, with an
increased relapse risk and 2-year OS and LFS of only 10
and 11%, respectively, regardless the presence of
concomitant monosomy 7. It was the only independent
prognostic factor in this patient population. While the
biological basis accounting for this combined deleterious
effect is mostly unknown, TP53 mutations have been
frequently observed in association with loss of 5q, up to
80% of cases in some series, suggesting cooperation
between TP53 mutations and loss of putative tumour
suppressor genes localised in 5q region [46–48]. Previous
reports supported this hypothesis that multiple
candidate genes localised on 5q cooperate with TP53
mutations in the pathogenesis of myelodysplastic syndrome
or AML [49–51]. Many genes on 5q have been
proposed, but recently, haploinsufficiency of ERG1 and APC
in combination with the early acquisition of TP53
mutations have emerged as a potential mechanism leading to
the development of a leukemic clone resistant to
apoptosis and with increased genomic instability .
This translates into chemoresistance and worse
outcomes confirmed in our study with patients harbouring
both abn(17p) and -5/5q-. In this subgroup of patients,
the benefit of allo-SCT appears very limited and new
therapeutic strategies are strongly warranted. On the
contrary, patients with abn(17p) without -5/5q- showed
a relative good outcome after allo-SCT with a 2-year
probability of LFS of 37–38%.
Allo-SCT arises as the best therapeutic option to
improve survival in selected patients harbouring abn(17p)
and achieving CR after frontline chemotherapy,
especially in the absence of -5/5q-. Nonetheless, clinical
benefit of allo-HCT remains very limited, followed by a
high relapse incidence. Recognition of a potential
graftversus-leukaemia effect preventing relapse in some
patients gives the rationale basis for the development of
early chemotherapy-based or cell-based strategies to
prevent relapse and therefore to increase the potential
benefit of allo-SCT in these patients.
Additional file 1: Table S1. (DOCX 13 kb)
-5/5q-: Monosomy 5 or loss of 5q-; -7: Monosomy 7; Abn(17p): 17p
abnormalities; Allo-SCT: Allogeneic stem cell transplantation; AML: Acute
myeloid leukaemia; ATG: Anti-thymocyte globulin; CB: Cord blood;
CI: Confidence interval; CK: Complex caryotype; CMV: Cytomegalovirus;
CR1: First complete remission; CR2: Second complete remission; DLI: Donor
leukocyte infusion; EBMT: European Society of Blood and Marrow
Transplantation; EFS: Event-free survival; GRFS: GvHD-free/relapse-free
survival; GvHD: Graft-versus-host disease; HLA: Human leukocyte antigen;
HR: Hazard ratio; Inv(3): Inversion of chromosome 3; LFS: Leukaemia-free
survival; MAC: Myeloablative conditioning; MK: Monosomal karyotype;
NRM: Non-relapse mortality; OS: Overall survival; RI: Relapse incidence;
RIC: Reduced-intensity conditioning; TBI: Total body irradiation
Availability of data and materials
The dataset analysed in the present study is avalaible in the EBMT registry.
XP designed the study. XP and LM reviewed the cytogenetic data. XP, ML, JE
and AN analysed the data. XP wrote the paper. JE, MM and AN reviewed the
paper. JM, IYA, DB, NI, GS, TGD, NS, JC, SV and JS provide the data. JM, IYA,
DB, NI, GS, TGD, NS, JC, SV and JS approved the manuscript. All authors read
and approved the final manuscript.
Consent for publication
All patients included in the EBMT registry database have previously
consented to be part anonymously to the registry.
1. Koreth J , Schlenk R , Kopecky KJ , et al. Allogeneic stem cell transplantation for acute myeloid leukemia in first complete remission: systematic review and meta-analysis of prospective clinical trials . JAMA . 2009 ; 301 : 2349 - 61 .
2. Cornelissen JJ , van Putten WL , Verdonck LF , et al. Results of a HOVON/SAKK donor versus no-donor analysis of myeloablative HLA-identical sibling stem cell transplantation in first remission acute myeloid leukemia in young and middle-aged adults: benefits for whom? Blood . 2007 ; 109 : 3658 - 66 .
3. Dohner H , Estey EH , Amadori S , et al. Diagnosis and management of acute myeloid leukemia in adults: recommendations from an international expert panel, on behalf of the European LeukemiaNet . Blood . 2010 ; 115 : 453 - 74 .
4. Grimwade D , Hills RK , Moorman AV , et al. Refinement of cytogenetic classification in acute myeloid leukemia: determination of prognostic significance of rare recurring chromosomal abnormalities among 5876 younger adult patients treated in the United Kingdom Medical Research Council trials . Blood . 2010 ; 116 : 354 - 65 .
5. Dohner H , Weisdorf DJ , Bloomfield CD . Acute myeloid leukemia . N Engl J Med . 2015 ; 373 : 1136 - 52 .
6. Grimwade D , Ivey A , Huntly BJ . Molecular landscape of acute myeloid leukemia in younger adults and its clinical relevance . Blood . 2016 ; 127 : 29 - 41 .
7. Schoch C , Kern W , Kohlmann A , et al. Acute myeloid leukemia with a complex aberrant karyotype is a distinct biological entity characterized by genomic imbalances and a specific gene expression profile . Genes Chromosomes Cancer . 2005 ; 43 : 227 - 38 .
8. Baron F , Labopin M , Niederwieser D , et al. Impact of graft-versus-host disease after reduced-intensity conditioning allogeneic stem cell transplantation for acute myeloid leukemia: a report from the Acute Leukemia Working Party of the European group for blood and marrow transplantation . Leukemia . 2012 ; 26 : 2462 - 8 .
9. Schlenk RF , Dohner K , Mack S , et al. Prospective evaluation of allogeneic hematopoietic stem-cell transplantation from matched related and matched unrelated donors in younger adults with high-risk acute myeloid leukemia: German-Austrian trial AMLHD98A . J Clin Oncol . 2010 ; 28 : 4642 - 8 .
10. Stelljes M , Beelen DW , Braess J , et al. Allogeneic transplantation as post-remission therapy for cytogenetically high-risk acute myeloid leukemia: landmark analysis from a single prospective multicenter trial . Haematologica . 2011 ; 96 : 972 - 9 .
11. Versluis J , Hazenberg CL , Passweg JR , et al. Post-remission treatment with allogeneic stem cell transplantation in patients aged 60 years and older with acute myeloid leukaemia: a time-dependent analysis . Lancet Haematol . 2015 ; 2 : e427 - 36 .
12. Ferrant A , Labopin M , Frassoni F , et al. Karyotype in acute myeloblastic leukemia: prognostic significance for bone marrow transplantation in first remission: a European Group for Blood and Marrow Transplantation study . Acute Leukemia Working Party of the European Group for Blood and Marrow Transplantation (EBMT). Blood . 1997 ; 90 : 2931 - 8 .
13. Cornelissen JJ , Breems D , van Putten WL , et al. Comparative analysis of the value of allogeneic hematopoietic stem-cell transplantation in acute myeloid leukemia with monosomal karyotype versus other cytogenetic risk categories . J Clin Oncol . 2012 ; 30 : 2140 - 6 .
14. Fang M , Storer B , Estey E , et al. Outcome of patients with acute myeloid leukemia with monosomal karyotype who undergo hematopoietic cell transplantation . Blood . 2011 ; 118 : 1490 - 4 .
15. Kayser S , Zucknick M , Dohner K , et al. Monosomal karyotype in adult acute myeloid leukemia: prognostic impact and outcome after different treatment strategies . Blood . 2012 ; 119 : 551 - 8 .
16. Brands-Nijenhuis AV , Labopin M , Schouten HC , et al. Monosomal karyotype as an adverse prognostic factor in patients with acute myeloid leukemia treated with allogeneic hematopoietic stem-cell transplantation in first complete remission: a retrospective survey on behalf of the ALWP of the EBMT . Haematologica. 2016 ; 101 : 248 - 55 .
17. Middeke JM , Beelen D , Stadler M , et al. Outcome of high-risk acute myeloid leukemia after allogeneic hematopoietic cell transplantation: negative impact of abnl(17p) and -5/5q . Blood. 2012 ; 120 : 2521 - 8 .
18. Harris CC , Hollstein M. Clinical implications of the p53 tumor-suppressor gene . N Engl J Med . 1993 ; 329 : 1318 - 27 .
19. Fenaux P , Preudhomme C , Quiquandon I , et al. Mutations of the P53 gene in acute myeloid leukaemia . Br J Haematol . 1992 ; 80 : 178 - 83 .
20. Wattel E , Preudhomme C , Hecquet B , et al. p53 mutations are associated with resistance to chemotherapy and short survival in hematologic malignancies . Blood . 1994 ; 84 : 3148 - 57 .
21. Fenaux P , Preudhomme C , Lai JL , et al. Cytogenetics and their prognostic value in de novo acute myeloid leukaemia: a report on 283 cases . Br J Haematol . 1989 ; 73 : 61 - 7 .
22. Haferlach C , Dicker F , Herholz H , et al. Mutations of the TP53 gene in acute myeloid leukemia are strongly associated with a complex aberrant karyotype . Leukemia . 2008 ; 22 : 1539 - 41 .
23. Schiffer CA , Lee EJ , Tomiyasu T , et al. Prognostic impact of cytogenetic abnormalities in patients with de novo acute nonlymphocytic leukemia . Blood . 1989 ; 73 : 263 - 70 .
24. Bowen D , Groves MJ , Burnett AK , et al. TP53 gene mutation is frequent in patients with acute myeloid leukemia and complex karyotype, and is associated with very poor prognosis . Leukemia . 2009 ; 23 : 203 - 6 .
25. Seifert H , Mohr B , Thiede C , et al. The prognostic impact of 17p (p53) deletion in 2272 adults with acute myeloid leukemia . Leukemia . 2009 ; 23 : 656 - 63 .
26. Grossmann V , Schnittger S , Kohlmann A , et al. A novel hierarchical prognostic model of AML solely based on molecular mutations . Blood . 2012 ; 120 : 2963 - 72 .
27. Middeke JM , Herold S , Rucker-Braun E , et al. TP53 mutation in patients with high-risk acute myeloid leukaemia treated with allogeneic haematopoietic stem cell transplantation . Br J Haematol . 2016 ; 172 : 914 - 22 .
28. Mohr B , Schetelig J , Schafer-Eckart K , et al. Impact of allogeneic haematopoietic stem cell transplantation in patients with abnl(17p) acute myeloid leukaemia . Br J Haematol . 2013 ; 161 : 237 - 44 .
29. Middeke JM , Fang M , Cornelissen JJ , et al. Outcome of patients with abnl(17p) acute myeloid leukemia after allogeneic hematopoietic stem cell transplantation . Blood . 2014 ; 123 : 2960 - 7 .
30. Rubio MT , Savani BN , Labopin M , et al. The impact of HLA-matching on reduced intensity conditioning regimen unrelated donor allogeneic stem cell transplantation for acute myeloid leukemia in patients above 50 years-a report from the EBMT acute leukemia working party . J Hematol Oncol . 2016 ; 9 : 65 .
31. Ruggeri A , Battipaglia G , Labopin M , et al. Unrelated donor versus matched sibling donor in adults with acute myeloid leukemia in first relapse: an ALWP-EBMT study . J Hematol Oncol . 2016 ; 9 : 89 .
32. Saraceni F , Labopin M , Gorin NC , et al. Matched and mismatched unrelated donor compared to autologous stem cell transplantation for acute myeloid leukemia in first complete remission: a retrospective, propensity scoreweighted analysis from the ALWP of the EBMT . J Hematol Oncol . 2016 ; 9 : 79 .
33. Schmid C , Schleuning M , Hentrich M , et al. High antileukemic efficacy of an intermediate intensity conditioning regimen for allogeneic stem cell transplantation in patients with high-risk acute myeloid leukemia in first complete remission . Bone Marrow Transplant . 2008 ; 41 : 721 - 7 .
34. Rucker FG , Bullinger L , Schwaenen C , et al. Disclosure of candidate genes in acute myeloid leukemia with complex karyotypes using microarray-based molecular characterization . J Clin Oncol . 2006 ; 24 : 3887 - 94 .
35. Schmid C , Schleuning M , Ledderose G , et al. Sequential regimen of chemotherapy, reduced-intensity conditioning for allogeneic stem-cell transplantation, and prophylactic donor lymphocyte transfusion in high-risk acute myeloid leukemia and myelodysplastic syndrome . J Clin Oncol . 2005 ; 23 : 5675 - 87 .
36. Yan CH , Liu DH , Liu KY , et al. Risk stratification-directed donor lymphocyte infusion could reduce relapse of standard-risk acute leukemia patients after allogeneic hematopoietic stem cell transplantation . Blood . 2012 ; 119 : 3256 - 62 .
37. Bally C , Ades L , Renneville A , et al. Prognostic value of TP53 gene mutations in myelodysplastic syndromes and acute myeloid leukemia treated with azacitidine . Leuk Res . 2014 ; 38 : 751 - 5 .
38. Goodyear OC , Dennis M , Jilani NY , et al. Azacitidine augments expansion of regulatory T cells after allogeneic stem cell transplantation in patients with acute myeloid leukemia (AML) . Blood . 2012 ; 119 : 3361 - 9 .
39. Platzbecker U , Wermke M , Radke J , et al. Azacitidine for treatment of imminent relapse in MDS or AML patients after allogeneic HSCT: results of the RELAZA trial . Leukemia . 2012 ; 26 : 381 - 9 .
40. Craddock C , Labopin M , Robin M , et al. Clinical activity of azacitidine in patients who relapse after allogeneic stem cell transplantation for acute myeloid leukemia . Haematologica . 2016 ; 101 ( 7 ): 879 - 83 .
41. Lim O , Jung MY , Hwang YK , et al. Present and future of allogeneic natural killer cell therapy . Front Immunol . 2015 ; 6 : 286 .
42. Pittari G , Filippini P , Gentilcore G , et al. Revving up natural killer cells and cytokine-induced killer cells against hematological malignancies . Front Immunol . 2015 ; 6 : 230 .
43. Stern M , Passweg JR , Meyer-Monard S , et al. Pre-emptive immunotherapy with purified natural killer cells after haploidentical SCT: a prospective phase II study in two centers . Bone Marrow Transplant . 2013 ; 48 : 433 - 8 .
44. Hotinski AK , Lewis ID , Ross DM . Vosaroxin is a novel topoisomerase-II inhibitor with efficacy in relapsed and refractory acute myeloid leukaemia . Expert Opin Pharmacother . 2015 ; 16 : 1395 - 402 .
45. Walsby EJ , Coles SJ , Knapper S , et al. The topoisomerase II inhibitor voreloxin causes cell cycle arrest and apoptosis in myeloid leukemia cells and acts in synergy with cytarabine . Haematologica . 2011 ; 96 : 393 - 9 .
46. Castro PD , Liang JC , Nagarajan L. Deletions of chromosome 5q13.3 and 17p loci cooperate in myeloid neoplasms . Blood . 2000 ; 95 : 2138 - 43 .
47. Kulasekararaj AG , Smith AE , Mian SA , et al. TP53 mutations in myelodysplastic syndrome are strongly correlated with aberrations of chromosome 5, and correlate with adverse prognosis . Br J Haematol . 2013 ; 160 : 660 - 72 .
48. Stoddart A , Fernald AA , Wang J , et al. Haploinsufficiency of del(5q) genes, Egr1 and Apc, cooperate with Tp53 loss to induce acute myeloid leukemia in mice . Blood . 2014 ; 123 : 1069 - 78 .
49. Bejar R , Stevenson K , Abdel-Wahab O , et al. Clinical effect of point mutations in myelodysplastic syndromes . N Engl J Med . 2011 ; 364 : 2496 - 506 .
50. Shih AH , Chung SS , Dolezal EK , et al. Mutational analysis of therapy-related myelodysplastic syndromes and acute myelogenous leukemia . Haematologica . 2013 ; 98 : 908 - 12 .
51. Walter MJ , Shen D , Shao J , et al. Clonal diversity of recurrently mutated genes in myelodysplastic syndromes . Leukemia . 2013 ; 27 : 1275 - 82 .