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Comparative outcome of reduced intensity and myeloablative conditioning regimen
in HLA identical sibling allogeneic haematopoietic stem cell transplantation for patients
older than 50 years of age with acute myeloblastic leukaemia: a retrospective survey
from the Acute Leukemia Working Party (ALWP) of the European group for Blood and
Marrow Transplantation (EBMT)
M Aoudjhane
1
, M Labopin
1
, NC Gorin
1
, A Shimoni
1
, T Ruutu
1
, H-J Kolb
1
, F Frassoni
1
, JM Boiron
1
, JL Yin
1
, J Finke
1
, H Shouten
1
,
D Blaise
1
, M Falda
1
, AA Fauser
1
, J Esteve
1
, E Polge
1
, S Slavin
1
, D Niederwieser
1
, A Nagler
1
and V Rocha
1
on behalf of the Acute
Leukemia Working Party of EBMT
2
1
EA1638 Universite
´
Paris 6, Acute Leukemia Working Party and European Group of Blood and Marrow Transplant Office Paris,
Paris, France
Results of reduced intensity conditioning regimen (RIC) in the
HLA identical haematopoietic stem cell transplantation (HSCT)
setting have not been compared to those after myeloablative
(MA) regimen HSCT in patients with acute myeloblastic
leukaemia (AML) over 50 years of age. With this aim, outcomes
of 315 RIC were compared with 407 MA HSCT recipients. The
majority of RIC was fludarabine-based regimen associated to
busulphan (BU) (53%) or low-dose total body irradiation (24%).
Multivariate analyses of outcomes were used adjusting for
differences between both groups. The median follow-up was 13
months. Cytogenetics, FAB classification, WBC count at
diagnosis and status of the disease at transplant were not
statistically different between the two groups. However, RIC
patients were older, transplanted more recently, and more
frequently with peripheral blood allogeneic stem cells as
compared to MA recipients. In multivariate analysis, acute
GVHD (II–IV) and transplant-related mortality were significantly
decreased (P ¼ 0.01 and Po10
4
, respectively) and relapse
incidence was significantly higher (P ¼ 0.003) after RIC trans-
plantation. Leukaemia-free survival was not statistically differ-
ent between the two groups. These results may set the grounds
for prospective trials comparing RIC with other strategies of
treatment in elderly AML.
Leukemia (2005) 19, 2304–2312. doi:10.1038/sj.leu.2403967;
published online 29 September 2005
Keywords: acute myelocytic leukaemia; genoidentical
haematopoietic stem cell transplants; reduced intensity preparative
regimen
Introduction
In patients with an available HLA identical sibling or unrelated
donor, allogeneic haematopoietic stem cell transplantation
(HSCT) for the treatment of acute myeloblastic leukaemia
(AML) has, for decades, remained limited by patient age and
physical condition. Indeed, the best results in terms of
leukaemia-free survival (LFS) have essentially concerned young-
er patients. In patients over 50 years of age, HSCT has resulted in
an unacceptable transplantation-related mortality (TRM) both
due to the toxicity of the myeloablative (MA) regimen used as
conditioning and the high incidence and severity of graft-versus-
host disease (GVHD).
1
Following studies in animal models, a new modality ‘non-MA
transplant or reduced intensity conditioning (RIC) regimen’ has
been developed
2–12
for older patients and patients with high risk
of TRM, with the argument that a less intense preparative
regimen would produce less organ damage, and still enable
engraftment and occurrence of graft-versus-tumour effect. In the
past 6 years, this approach has proved feasible and the induction
of graft-versus-tumour effect has indeed generated a high rate of
responses. It remains, however, unclear, whether the reduction
in antitumour activity secondary to the decrease in intensity of
the preparative regimen is compensated by the graft-versus-
tumour effect, which in this approach is the key antitumour
tool.
13
There has recently been a trend to use RIC even in patients
who, a few years ago, would have been candidates for a
conventional allogeneic HSCT. However, results of RIC reported
have usually mixed various diseases
14
at different stages and the
follow-up has remained short. Only recently a specific analysis
of RIC and conventional transplants in patients with a single
haematological malignancy, that is, multiple myeloma, has
been reported by the European Blood and Marrow Transplant
(EBMT) group.
15
In a retrospective analysis of 95 patients with AML analysed
through a donor vs no donor genetic randomization, RIC
transplant has been shown to be superior to chemotherapy,
16
but there has so far been no specific comparison of RIC to
conventional transplants.
17
In order to compare mainly TRM and other outcomes, we
analysed retrospectively the data on HLA identical sibling HSCT
using RIC, and compared the outcome with HLA identical
sibling HSCT using conventional MA transplants in adult
patients over 50 years of age with AML reported to EBMT
registry.
Materials and methods
Data collection
Data of HLA identical HSCT recipients older than 50 years
receiving either a reduced intensity regimen or a conventional
conditioning regimen were provided by the Acute Leukemia
Working Party (ALWP) of the EBMT group. EBMT registry is a
voluntary working group of more than 450 transplant centres,
participants of which are required once a year to report all
consecutive haematopoietic stem cell transplantations and
follow-up.
Received 30 May 2005; accepted 23 August 2005; published online
29 September 2005
Correspondence: Dr V Rocha, Acute Leukemia Working Party–
European Group of Blood and Marrow Transplant, Ho
ˆ
pital Saint-
Louis and Ho
ˆ
pital Saint-Antoine, Universite
´
de Paris 7 and Universite
´
de Paris 6, 27, Rue de Chaligny, 75012 Paris, France;
E-mail: vanderson.rocha@sls.ap-hop-paris.fr
2
Other authors are listed in the Appendix
Leukemia (2005) 19, 2304–2312
& 2005 Nature Publishing Group All rights reserved 0887-6924/05 $30.00
www.nature.com/leu
Criteria of selection
The study included patients receiving HLA identical sibling
HSCT who (1) were aged X50 years at time of transplant; (2)
had de novo acute myeloid leukaemia; (3) were transplanted
between 1 January 1997 and 31 December 2003; (4) had
received a reduced intensity regimen defined as the use of
fludarabine associated with low-dose total body irradiation (TBI)
(o3 Gy), or busulphan (total dose p8 mg/kg), or other non-MA
drugs; (5) had received a MA-based preparative regimen with
TBIX10 or busuphfan (48 mg/kg) associated with other drugs;
(6) were patients whose clinical data on outcomes were
adequate.
All patients receiving previous autologous transplantation
were excluded from this analysis.
A total of 315 RIC and 407 MA HSCT recipients from 182
transplant centres met these eligibility criteria.
Patients
The registry contained information on a total of 722 patients of
whom 407 received an MA and 315 RIC. The patient-, disease-
and transplant-related factors and differences between the two
groups of patients are given in Table 1. Interestingly, the
majority of patients was transplanted in CR1 (245 MA and 171
RIC). RIC patients were older (median 57 vs 54 years) – as were
their donors (57 vs 52 years) – and more frequently male (61 vs
51%). They were also transplanted more recently (median year
2001 vs 2000). As a source of stem cells, peripheral blood was
used in the majority for both transplant modalities, but was more
frequently used for RIC (90 vs 69%). Regarding GVHD
prophylaxis, RIC patients more often received cyclosporin A
alone without methotrexate or a combination of cyclosporin A
with mycophenolate mofetil (MMF). There was no other
detectable difference: in particular, the FAB classification and
the cytogenetics (in the populations where the information was
available) were evenly split in the overall population and when
stratifying by status at transplant.
The follow-up was 13 months (1–84) for the patients who
received an MA regimen and 14 months (1–67) for those who
received an RIC.
Statistical analysis
Patient-, disease-, and transplant-related variables of both
groups were compared, using the w
2
statistic for categorical
and the Mann–Whitney test for continuous variables. Variables
considered were recipient age and sex; disease characteristics
(FAB classification, cytogenetics, white blood count at the time
of diagnosis); donor characteristics (age, sex); disease status at
transplant (CR1, CR2 or more advanced disease); transplant
characteristics including year of transplant and GVHD prophy-
laxis. Factors differing in distribution between the two groups
with a P-value less than 0.10 and factors known to influence
outcomes (such as status at transplant) were included in the final
models. In order to test for a centre effect, we introduced a
random effect or frailty for each centre into the model.
18,19
Cumulative incidence curves were used in a competing risks
setting, death being treated as a competing event to calculate
probabilities of chronic GVHD (cGVHD), TRM and relapse.
20
Probabilities of survival and LFS were calculated using the
Kaplan–Meier estimate; the log-rank test was used for univariate
comparisons. Associations of graft type with outcomes were
evaluated in multivariate analyses, using Cox proportional
hazards for LFS and survival, logistic regression for acute GVHD
(aGVHD), and proportional subdistribution hazard regression
model of Fine and Gray
21
for other outcomes.
All P-values are two-sided with type I error rate fixed at 0.05.
Statistical analyses were performed with SPSS (Inc., Chicago)
and Splus (MathSoft, Inc, Seattle) software packages.
Results
Table 2 indicates the unadjusted outcomes post-transplant
according to disease status at transplants and according to MA
or RIC.
Graft-versus-host disease
aGVHD grade II–IV was observed in 114 patients receiving an
MA transplant (63 patients with grade II, 28 with grade III and 23
with grade IV) and in 64 patients receiving an RIC transplant (38
patients with grade II, 14 with grade III and 12 with grade IV).
Incidence of grade II–IV aGVHD was significantly lower after
RIC: 22% compared to 31% after MA HSCT (P ¼ 0.003) but not
grade III–IV (8 vs 12%, respectively) (P ¼ 0.12) (Table 2).
In a multivariate analysis, after statistical adjustment for
relevant risk factors, risk of grade II–IV aGVHD was significantly
lower after RIC than after MA transplant. The relative risk of
grade II–IV aGVHD with RIC vs MA was 0.60 (95% CI ¼ 0.4–
0.88, P ¼ 0.01). Other variables associated with lower aGVHD
risk are listed in Table 3. Multivariate analysis for grade III–IV
Table 1 Characteristics of patients, disease and transplants of
patients over 50 years of age with AML transplanted with an HLA
identical sibling donor according to type of conditioning used
(myeloablative vs reduced intensity)
Characteristics MA (n ¼ 407) RIC (n ¼ 315) P
Median WBC at diagnosis
10
9
/l (range)
5.7 (0.3–203) 6.9 (0.4–648) 0.41
FAB%
M0–2/M4–7 54/43 (M3:3) 58/42 NS
M0–4/M5–7 81/19 (M3:3) 78/21 0.27
Cytogenetics %
a
Good/inter/poor 13/75/12 9/75/16 0.37
Patient age (Years) 54 (50–64) 57 (50–73) 0.0001
Patient sex (Male%) 51 61 0.004
Donor age (Years) 52 (34–71) 57 (32–79) 0.001
Donor sex (Male%) 57 54 0.28
Median year of
transplant (range)
2000
(1997–2003)
2001
(1997–2003)
0.0001
Status at transplant n (%)
CR1 245 (60) 171 (54)
CR2 52 (13) 52 (17)
Advanced 110 (27) 92 (30)
GVHD
Cyclosporin % 13 37 0.0001
Prophylaxis
Cyclo+Metho % 85 44
Cyclo+MMF % 2 19
a
Good ¼ inv(16); t(8;21) and t(15;17); Poor ¼ abn 5 or 7 and 11q23.
Comparative outcome of RIC and MA regimen
M Aoudjhane et al
2305
Leukemia
aGVHD was not performed due to the small number of events
observed in both groups.
The 2-year cumulative incidences of cGVHD were 48% after
RIC compared with 56% after MA (P ¼ 0.64). In multivariate
analysis, the risk of chronic GVHD was lower following RIC
(RR ¼ 0.69; 95% CI ¼ 0.51–0.94, P ¼ 0.02).
Transplantation-related mortality
In univariate analysis, there was higher TRM after MA than after
RIC regimen in patients transplanted in CR1, CR2 and advanced
phase of the disease (Table 2). Cumulative incidence of TRM at
2 years for all patients was 32% after MA transplant compared to
18% after RIC transplant (Po0.001, Figure 1a). In a multivariate
analysis, the risk of mortality was statistically significantly higher
for patients receiving an MA transplantation than for those
receiving an RIC transplantation (Table 3).
Relapse
In univariate analysis, not adjusted for differences between the
two groups, the cumulative incidence of relapse was higher after
RIC transplant: 41% compared to 24% after MA transplant
(Po0.0001) (Figure 1b). According to the disease status at
transplant, relapse was also statistically significantly higher after
RIC in patients transplanted in remission (CR1 or CR2) than in
patients receiving an MA transplant (Table 2). For those patients
transplanted in the advanced phase of the disease, there was a
trend for higher relapse rate also in RIC recipients (P ¼ 0.06). In a
multivariate analysis, after adjustment for risk factors, relapse
was increased in RIC recipients compared to those receiving an
MA transplant. Other covariable associated with relapse
incidence was the advanced phase of the disease at transplant
(Table 3).
Overall survival and LFS
Unadjusted 2-year probability of LFS and overall survival (OS)
were 40 and 47%, (Figure 1c) and 44 and 46% (Figure 1d), in
the RIC and MA cohorts, respectively. Table 2 lists results of
unadjusted 2-year OS and LFS probability in each transplant
cohort according to diagnosis and status of the disease at
transplant. There was no significant difference for LFS and OS
for patients receiving either MA or RIC HSCT whatever the status
of the disease at transplant (Table 2). Results of multivariate
analysis comparing LFS and OS after RIC and MA transplants are
shown in Table 3. Similarly to the univariate analysis, there was
no significant difference in OS or LFS between both groups.
Causes of death
A total of 157 MA recipients and 137 RIC recipients died.
Persistent or recurrent leukaemia caused 69 (44%) deaths in the
MA group and 86 (64%) in RIC recipients. Table 4 lists causes of
death in both groups. Of note, in the RIC group, there were
Table 2 Nonadjusted outcomes of patients over 50 years of age
with AML transplanted with an HLA identical sibling donor according
to type of conditioning (myeloablative vs reduced intensity)
Outcomes Disease
status
MA
(N ¼ 407)
RIC
(N ¼ 315)
P-value
Acute GVHD (II–IV)
a
All status 31% 22% 0.003
Acute GVHD (III–IV)
a
All status 12% 8% 0.12
Chronic GVHD
b
All status 56734873 0.64
TRM
b
All status 32721872 o10
4
CR1 30732273 0.01
CR2 34781676 0.04
Advanced 34741473 0.002
RI
b
All status 24724173 o10
4
CR1 16733374 o10
4
CR2 18762876 0.04
Advanced 45756475 0.06
LFS
c
All status 44734073 0.8
CR1 54734475 0.26
CR2 47785577 0.81
Advanced 21742375 0.19
OS
c
All status 46734773 0.43
CR1 56745375 0.8
CR2 50786077 0.76
Advanced 23752776 0.1
GVHD: graft-versus-host disease; LFS: leukaemia-free survival;
OS: overall survival; RI: relapse incidence; TRM: transplant-related
mortality.
a
Incidence calculated at day 100.
b
Two years cumulative incidences using death as a competing event.
c
Two years Kaplan–Meier estimates.
Table 3 Multivariate analyses for outcomes of patients over 50
years of age with AML transplanted with an HLA identical sibling
donor according to type of conditioning (myeloablative vs reduced
intensity)
P-value RR
a
95.0% CI
Acute GVHD (II–IV)
b
RIC vs MA 0.01 0.6 0.4–0.88
Chronic GVHD
c
RIC vs MA 0.02 0.69 0.51–0.94
Transplant-related mortality
d
RIC vs MA 0.00006 0.48 0.33–0.68
Relapse
e
RIC vs MA 0.0003 1.78 1.3–2.43
Leukaemia-free survival
f
RIC vs MA 0.24 1.15 0.9–1.47
Overall survival
g
RIC vs MA 0.08 1.26 0.98–1.63
a
Relative risk with RIC vs MA transplants.
b
Other significant covariates: patient’s age RR ¼ 0.67 (95% CI ¼ 0.45–
0.99); P ¼ 0.04; peripheral blood vs bone marrow cells, RR ¼ 1.7 (95%
CI ¼ 1.05–2.7) P ¼ 0.03.
c
Other significant covariates: peripheral blood vs bone marrow cells,
RR ¼ 1.83 (95% CI ¼ 1.23–2.7) P ¼ 0.003.
d
No other covariate was selected in the multivariate model.
e
Other significant covariates: advanced status of the disease
RR ¼ 0.50 (95% CI ¼ 1.90–3.45); P ¼ o0.0001.
f
Other significant covariates: advanced status of the disease RR ¼ 0.46
(95% CI ¼ 0.36–0.58); P ¼ o0.0001.
g
Other significant covariates: advanced status of the disease
RR ¼ 0.42 (95% CI ¼ 0.33–0.55); P ¼ o0.0001.
Comparative outcome of RIC and MA regimen
M Aoudjhane et al
2306
Leukemia
28 (20%) deaths from GVHD, and 29 (18%) in the MA group.
Deaths related to toxicity other than GVHD were more common
in MA recipients.
Discussion
This retrospective study concerns a large series of patients older
than 50 years of age and transplanted for AML with an HLA
identical sibling, following either an MA or an RIC regimen.
It shows that following RIC, the TRM was lower than after a
conventional transplant and the relapse incidence was higher.
The reduction in TRM after RIC was expected since RIC was
originally designed precisely in an effort to reduce TRM; indeed,
recent studies comparing TRM in RIC and MA have further
documented this reduction in non-GVHD toxicity
22,23
:asa
particular example, RIC patients conditioned with 2 Gy TBI have
a lower reduction in 1-s forced expiratory volume (FEV1), forced
vital capacity, total lung capacity, residual volume and carbon
monoxide diffusion capacity than MA patients receiving TBI at
10 Gy.
24
GVHD is the other major component of TRM in HSCT
and at the same time is associated with GVL effect: following
allogeneic transplants using standard preparative regimen, the
overall incidence of aGVHD grade II–IV is around 40% and the
incidence of cGVHD around 60%, but it is known to be
increased in older patients, where it contributes to poorer
outcome.
1
The International Bone Marrow Transplant Registry
(IBMTR) has shown 15 years ago that the relapse incidence was
reduced in patients with aGVHD and/or cGVHD.
25
A study
from EBMT has further indicated that the highest LFS after
allogeneic bone marrow transplantation was seen in patients
with grade I aGVHD.
26
Less is known on the incidence and
severity of GVHD and the GVL effect following RIC in which the
distinction between aGVHD and cGVHD is often more difficult
with late onset (after 100 days) occurring aGVHD.
27
In this
regard, using a specific definition, the Seattle team analysed
retrospectively 171 consecutive patients, who had related or
unrelated RIC HCT, for various haematologic malignancies for
the development of serious aGVHD or cGVHD.
28
A total of 43
(25%) patients had serious GVHD, of whom 20 had grade III–IV
aGVHD, and 30 had extensive chronic GVHD. To this were
added seven patients with grade III aGVHD and 84 with
extensive cGVHD that did not meet criteria for serious GVHD,
indicating in the end an incidence of aGVHD IIIFIV, of 16%,
and a very high incidence of chronic extensive GVHD, of 72%.
In another study from the same team,
29
of a total of 221 patients
with various haematological malignancies receiving an RIC,
grade II–IV aGVHD had no significant impact on the risk of
relapse or progression but was associated with an increased risk
of nonrelapse mortality and a decreased probability of progres-
sion-free survival (PFS). Conversely, extensive cGVHD was
associated with decreased risk of relapse or progression and
increased probability of PFS. In this context, it is of interest in
0123
0.0
0.2
0.4
0.6
0.8
1.0
years
3210
1.0
0.8
0.6
0.4
0.2
0.0
years
3210
1.0
0.8
0.6
0.4
0.2
0.0
y
ears
a
c
d
0123
0.0
0.2
0.4
0.6
0.8
1.0
years
b
MA
MA
MA
MA
RIC
RIC
RIC
RIC
Figure 1 Unadjusted cumulative incidence of TRM (a), relapse (b),
LFS (c) and OS (d) for patients over 50 years of age with AML receiving
an MA transplant or RIC after HLA identical sibling HSCT.
Table 4 Causes of death in both groups of patients
Causes of death MA RIC
Original disease 69 (44%) 86 (64%)
GVHD 29 (18%) 28 (20%)
Cardiac toxicity 2 (1.3%) 0
Haemorrhage 2 (1.3%) 1 (1%)
Failure/rejection 1 (0.6%) 0
Veno-occlusive disease 6 (4%) 0
Interstitial pneumonitis 5 (3%) 2 (1.5%)
Infection 37 (24%) 19 (14%)
Second malignancy 1 (0.6%) 1 (0.7%)
Other 5 (3%) 0
Total 157 137
Comparative outcome of RIC and MA regimen
M Aoudjhane et al
2307
Leukemia
our study, which is restricted to AML and genoidentical
transplants in patients older than 50 years of age, to note that
the incidence of aGVHD and cGVHD was lower following RIC
than MA HSCT. Our finding on the lower incidence of grade
II–IV aGVHD and cGVHD confirms the previous report by MD
Anderson
30
on 137 transplanted patients where the actuarial
rate of grade II–IV aGVHD was significantly higher in patients
receiving MA regimens (36%) than in the RIC group (12%). In
this report also, the cumulative incidence of cGVHD was higher
in the ablative group (40%) than in the RIC group (14%).
Unfortunately, due to the small number of patients presenting
grade III–IV in both groups, a multivariate analysis was not
possible to confirm the no statistical difference observed in the
unadjusted univariate analysis for grade III–IV GVHD. However,
GVHD remained the major cause of nonleukemic death after
RIC probably because the other causes of death were
considerably reduced (such as infections, liver VOD, interstitial
pneumonitis).
The literature on RIC is considerable but specific studies of
RIC on AML are limited:
31
previous retrospective reports on RIC
for any given haematological malignancy,
32,33
and most of all
for AML, have usually concerned small series of patients from
single institutions. Most retrospective studies, in fact have
pooled various diseases. In a series of 36 patients from 55 to
66 years of age receiving an RIC transplant from an unrelated
donor for various haematological malignancies, Shimoni et al
34
have reported a disease-free survival (DFS) of 43% at 1 year with
an incidence of aGVHD grade II–IV and cGVHD of 31 and 45%
with somewhat better outcome in patients with myeloid
malignancies. They concluded that unrelated donor SCT is
feasible in elderly patients, with outcomes that are similar to
younger patients. The Boston team has compared 71 patients
over 50 years of age receiving a non-MA transplant with 81
patients over 50 years of age who received an MA transplant
during the period from 1997 to 2002. They concluded in similar
outcome, with more relapses in RIC and lower TRM, but the
patient population was very heterogeneous with various
haematological malignancies (AML, ALL, myelodysplastic syndro-
mes, CLL, myelomas, lymphomas and other). In this study, only
34 AML patients were transplanted, 21 with RIC and 13 with a
conventional transplant. Moreover, this study also included
related and unrelated transplants.
The value of RIC in AML therefore is unclear and yet, several
teams have already taken the step at the institution policy level,
to use RIC rather than MA transplants in patients over 50 years of
age and, further, some have even proposed this scheme to
younger patients and in first complete remission. Such a policy
may at the moment be premature in view of the paucity of data
and the still short follow-up. There has so far been no
randomized study addressing the question of the comparison
of RIC with MA transplants, although some are being planned.
The ALWP of the EBMT registry, because it contained
information on a total of 721 patients with AML older than 50
years of age given an HLA identical sibling HSCT, was felt to be
an interesting tool to approach two major questions; that is, first
the outcome of older patients with AML receiving an RIC and
second, its value as compared with MA HSCT. The present study
shows that patients receiving an RIC had, at 2 years, a DFS of
4073% and an OS of 4773%, which is not different from the
figures of 4473 and 4673%, respectively, following an MA
HSCT. This was achieved despite a significant increase in
relapse incidence with RIC but thanks to a significant decrease
in TRM. Interestingly, these findings are reminiscent of the
retrospective studies from EBMT, a decade ago, which
compared conventional allogeneic stem cell transplantation
with autologous stem cell transplantation and similarly showed
for the latter a significant increase in relapse incidence
counterbalanced by a significant decrease in TRM.
35
EBMT
studies in progress are presently comparing RIC to autologous
HSCT in elderly patients with AML.
The present study suffers from the usual limitations of
retrospective and multicentre studies despite the fact that the
two patient populations were similar in several characteristics,
and patients receiving an RIC were older and were transplanted
more recently. RIC is still an emergent transplant modality and
not all centres perform both transplant modalities; 154 patients
who received a conventional transplant were reported from 59
centres performing only conventional transplants; 104 patients
who received an RIC were reported from 47 centres performing
only RIC and 464 patients were reported from 76 centres
performing both modalities. In these centres, the choice of the
modality, in the absence of randomization, has probably relied
on the patient performance status and physiological age, RIC
being proposed to the more fragile patients in addition to the
older as indicated above. By taking into account the centre
effect
36
with the frailty model we, of course, try to erase some
but not all the potential biases.
Finally, it is of interest that The Chronic Leukaemia Working
Party of EBMT has recently reported results of a study similar to
ours, but concerning patients with multiple myeloma;
15
the
results were strikingly similar to ours, namely more relapses with
RIC but lower TRM, in the end leading to similar DFS and OS
following both transplant modalities.
In conclusion, this analysis shows that RIC in patients with
AML older than 50 years of age is feasible and that in
comparison with conventional transplants, it is associated with
more relapses but less transplant toxicity. Since LFS and OS
were not statistically different with the two modalities, albeit
with a short follow-up, a randomized study in this high-risk
population seems warranted.
Acknowledgements
We thank all data managers from EBMT and National registries
who collect, check and contribute data for the ALWP.
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Appendix
List of EBMT transplant centres contributing data for this
study:
CIC:
: 119: Galieni P, Mazzoni Hospital Haematology Service
Ascoli Piceno, Italy
132: Petrini M, Dipartimento di Oncologia, dei trapianti e
delle nuove tecnologie in medicina Divisione di Ematologia,
Pisa, Italy
152: Schlimok G, II Medizinische Klinik, Postfach 10 19 20,
Augsburg, Germany
160: Buzyn A, Ho
ˆ
pital Necker Service Hematologie Adulte,
Paris, France
170: Ovali E, Karadeniz Technical University Faculty of
Medicine, Trabzon, Turkey
202: Gratwohl A, Division of Hematology Kantonsspital,
Basel, Switzerland
203: Willemze R, BMT Centre Leiden Leiden University
Hospital, Leiden, The Netherlands
204: Bunjes D, Abteilung Innere Medizin III Medizinische
Klinik und Poliklinik, Ulm, Germany
205: Goldman JM, Department of Haematology Hammer-
smith Hospital at London, United Kingdom
Comparative outcome of RIC and MA regimen
M Aoudjhane et al
2309
Leukemia
206: Jacobsen N, BMT Unit Department of Hematology L
4042 Blegdamsvey 9, Copenhagen, Denmark
207: Gluckman E, Deptartmentof Hematology – BMT –
Hopital St Louis, Paris, France
208: Schanz U, Department of Medicine, University Hospital,
Zurich, Switzerland
209: Boogaerts MA, Department of Hematology, University
Hospital, Gasthuisberg, Leuven, Belgium
212: Ljungman P, Department of Hematology, Huddinge
University Hospital, Huddinge, Sweden
214: Montserrat E, Institute of Hematology & Oncology,
Department of Hematology, Hospital Clinic, Barcelona,
Spain
215: Bron D, Experimental Hematology Institut Jules Bordet,
Brussels, Belgium
216: Potter M, Department of Hematology, Royal Free
Hospital and School of Med., London, United Kingdom
217: Bacigalupo A, Department of Hematology, Ospedale
San Martino, Genova, Italy
218: Powles R, Leukaemia Myeloma Units Royal Marsden
Hospital, Sutton, United Kingdom
222: Rio B, Service d’Hematologie Hotel Dieu, Paris, France
223: Kanz L, Medizinische Klinik Abteilung II, Tu
¨
bingen,
Germany
224: Goldstone AH, Department of Haematology, University
College London Hospital, London, United Kingdom
225: Remes K, Turku University Central Hospital BMT Unit,
Department of Medicine,Turku, Finland
227: Greinix HT, AKH und Universitaetskliniken Wien Klink
fuer Innere I, Vienna, Austria
228: Davies JM, Department of Hematology, Western
General Hospital, Edinburgh, United Kingdom
230: Blaise D, Institut Paoli Calmettes. 232 Boulevard de Ste.
Marguerite, Marseille, France
231: Falda M, Centro Trapianti Midollo Azienda Ospedaliera
S. Giovanni, Torino, Italy
232: Mandelli F, Dipartimento di Biotecnologie Cellulari e
Ematologia, University ‘La Sapienza’, Rome, Italy
233: Cahn JY, Service d’He
´
matologie Hopital, Jean Minjoz
Besancon, France
234: Ferrant A, Department of Haematology, Cliniques
Universitaires St. Luc, Brussels, Belgium
235: Brinch L, Department of Medicine, Rikshospitalet, Oslo,
Norway
236: Ferna
´
ndez-Ranada JM, Department of Hematology,
Hospital de la Princesa, Madrid, Spain
238: Torres Gomez A, Department of Hematology, Co
´
rdoba
Hospital, Co
´
rdoba, Spain
239: Verdonck LF, University Medical Centre, Department of
Haematology, Utrecht, The Netherlands
240: Baccarani M, Institute of Hematology and Medical
Oncology Sera
´
gnoli, Hospital San Orsola, Bologna, Italy
242: Iriondo A, Hospital Universitario ‘Marque
´
s de Valde-
cilla’, Santander, Spain
244: Franklin I, Department of Medicine, Glasgow Royal
Infirmary, Glasgow, United Kingdom
245: Rizzoli V, Cattedra di Ematologia – University of Parma
Centro Trapianti Midollo Osseo, Parma, Italy
246: Cornelissen JJ, Erasmus MC-Daniel den Hoed Cancer
Centre, PO Box 5201 Rotterdam The Netherlands
247, Van den Berg H, Academisch Ziekenhuis bij deUniver-
siteit van Amsterdam, Emma Kinderziekenhuis, Amsterdam, The
Netherlands
252: Cordonnier C, Sve d’ Hematologie Ho
ˆ
pital Henri
Mondor, Creteil, France
253: Harousseau JL, Department de Hematologie Hotel Dieu,
Nantes, France
254: Barnard DL, Bone Marrow Transplant Unit Level 8,
Gledhow Wing, Leeds, United Kingdom
255: Littlewood T, Clinical Haematology, The Oxford
Radcliffe Hospital, Oxford, United Kingdom
256: Horst HA, BMT University/Department of Internal Med.
II Christian-Albrechts-University, Kiel, Germany
257: McCann S, Department of Hematology, St James
Hospital Trinity College, Dublin, Ireland (Rep)
258: Slavin S, Department of Bone Marrow Transplantation,
Hadassah University Hospital, Jerusalem, Israel
259: Schaefer UW, Department of Bone Marrow Transplanta-
tion, University Hospital, Essen, Germany
260: Sierra J, Clinical Hematology, Division Hospital Santa
Creu i Sant Pau, Barcelona, Spain
261: Chapuis B, Division d’He
´
matologie, Hopital Cantonal
Universitaire, Geneva, Switzerland
262: Leblond V, Pitie-Salpetriere 47, boulevard de l’Hopital,
Paris, France
264: Guilhot F, Clinical Hematology, Head of the Bone
Marrow Transplant Unit, Poitiers, France
265: Lambertenghi Deliliers G, Ospedale Maggiore di Milano
IRCCS, Milano, Italy
266: Simonsson B, Department of Medicine, University
Hospital, Uppsala, Sweden
267: Reiffers J, CHU Bordeaux Ho
ˆ
pital Haut-leveque, Pessac,
France
270: Sotto JJ, Department of Hematology Hopital A Michal-
lon, Grenoble, France
271: Gastl G, University Hospital Innsbruck, Division of
Hematology and Oncology, Innsbruck, Austria
273: Bay JO, Fe
´
de
´
ration de Greffe de Moelle et de The
´
rapie
Cellulaire d’Auvergne, Clermont-Ferrand, France
276: Jackson GL, Department of Hematology, Royal Victoria
Infirmary, Newcastle upon Tyne, United Kingdom
282: Garcı´a-Conde J, Hospital Clı´nico Universitario Servicio
de Hematologia y Oncologia, Valencia, Spain
283: Lenhoff S, Department of Hematology, University
Hospital, Lund, Sweden
286: Alessandrino EP, Department of Hematology, BMT unit
Policlinico San Matteo, Pavia, Italy
287: Majolino I, Department of Hematology and BMT
Ospedale S Camillo-Forlanini, Rome, Italy
288: Izzi T, Department of Medicine Spedali Civili – Brescia,
Brescia, Italy
289: Brune M, Center for Hematopoietic Cell Transplantation
(CHECT), Goeteborg, Sweden
291: Pimentel P, Inst. Portugues Oncologia Centro do Porto –
BMT Unit, Porto, Portugal
293: Siegert W, Campus Charite
´
Mitte Medizinische Klinik
und Poliklinik II, Berlin, Germany
294: Morra E, Hematology Department, Ospedale di Niguar-
da Ca’ Granda, Milano, Italy
295: Hertenstein B, Department of Hematology/Oncology
Medical School of Hannover, Hannover, Germany
297: Hoelzer D, Department Hematology, Zentrum Inn
Medizin, Universita
¨
t Frankfurt, Frankfurt, Germany
299: Coser P, Department of Hematology – BMT Unit
Hospital San Maurizio, Bolzano, Italy
300: Abecasis M, Inst. Portugues Oncologia, BMT Unit,
Lisboa, Portugal
302: Labar B, Department of Medicine/BMT Unit
(Haematology), University Hospital Centre – Rebro, Zagreb,
Croatia
Comparative outcome of RIC and MA regimen
M Aoudjhane et al
2310
Leukemia
303: Burnett AK, Department of Haematology, College of
Medicine, Cardiff, United Kingdom
304: Bosi A, BMT Unit, Department of Hematology, Ospedale
di Careggi, Firenze, Italy
307: Leone G, Istituto Semeiotica Medica, Ematologia
Universita Cattolica S Cuore, Rome, ITALY
308: Linkesch W, Karl-Franzens-University-Graz Department
of Internal Medicine, Graz, Austria
311: Schwerdtfeger R, Deutsche Klinik fu
¨
r Diagnostik KMT
Zentrum, Wiesbaden, Germany
321: Lauria F, Department of Hematology, Policlinico Le
Scotte, Siena, Italy
331: Martinelli G, European Institute of Oncology, Milano,
Italy
332: Mazza P, Institute of Haematology Hospedale, Nord
Taranto, Italy
339: Zache
´
e P, AZ Stuivenberg Lange Beeldekensstraat, 267
Antwerp, Belgium
344: Culligan DJ, Grampian University Hospitals Trust,
Department of Haematology, Aberdeen, United Kingdom
345: Rowe JM, Department of Hematology & BMT Rambam
Medical Center, Haifa, Israel
372: Arpaci F, GATA BMT Center, Gu
¨
lhane Military Medical
Academy, Ankara, Turkey
374: De Souza CA, University Est. de Campinas/TMO/
UNICAMP Cidade Universitaria ‘Zeferino Vaz’, Campinas,
Brazil
378: Saglio G, Ospedale San Luigi Orbassano Medicina
Interna II SEZ 5A, Torino, Italy
387: Craddock C, Department of Haematology, University
Hospital Birmingham, NHS Trust, Birmingham, United Kingdom
389: Niederwieser D, University Leipzig, Division of Internal
Med. II, Dapartment of Haematology/Oncology, Leipzig,
Germany
390: Haas R, Klinik fu
¨
rHa
¨
mat, Onkol, Klin. Immun. Heinrich
Heine Universita
¨
t, Du
¨
sseldorf, Germany
392: Scime
`
R, Div. di Ematologia e Unita
`
Trapianti Ospedale
V. Cervello, Palermo, Italy
501: Clark RE, Royal Liverpool University Hospital, Depart-
ment of Haematology, Liverpool, United Kingdom
504: Poros A, Department Hematol & BMT Unit National
Medical Centre, Budapest, Hungary
513: Kolb HJ, Med. Klinik III Klinikum Grosshadern,
Mu
¨
nchen, Germany
515: Ruutu T, Department of Medicine, Helsinki University
Central Hospital, Helsinki, Finland
523: Gratecos N, Hematologie Clinique Ho
ˆ
pital de l’ARCHET
I, Nice, France
524: Ho AD, University of Heidelberg Medizinische Klinik u.
Poliklinik V, Heidelberg, Germany
526: Carella AM, IRCCS, Casa Sollievo della Sofferenza Unit
of Hematology and San Giovanni, Rotondo, Italy
529: Visani G, Department of Hematology, Pesaro Hospital,
Pesaro, Italy
530: Doelken G, Medizinische Universita
¨
tsklinik C Ernst-
Moritz-Arndt-Univer. Greifswald, Greifswald, Germany
539: Marsh JCW, Department of Cellular & Molecular
Sciences St George’s Hospital, Medical School, London, United
Kingdom
544: Pogliani EM, University di Milano-Bicocca Ospedale S.
Gerardo, Monza, Italy
558: Peschel C, III Med Klinik der TU Klinkum Rechts der Isar,
Mu
¨
nchen, Germany
561: Fassas A, Haematology Department/BMT Unit, The
George Papanicolaou General, Thessaloniki, Greece
565: Schouten H, Department Internal Med. Hematology/
Oncology, University Hospital Maastricht, Maastricht, The
Netherlands
566: Marcus R, Department of Haematology, Addenbrookes
Hospital, Box 234, Cambridge, United Kingdom
574: Indra
´
k K, Department of Haemato-oncology University
Hospital, Olomouc, Czech Repub
587: Iacopino P, Azienda Ospedaliera Bianchi-Melacrino-
Morelli Reggio, Calabria, Italy
588: Ossenkoppele GJ, Free University Hospital Amsterdam,
Department of Hematology, BR 240 Amsterdam, The Netherlands
590: Knauf W, Innere Medizin/Ha
¨
matologie/Onkologie Klin.
Benjamin Franklin, FU Berlin, Berlin, Germany
592: Fauser AA, Klinik fu
¨
r Knochenmarktransplantation und
Ha
¨
matologie/Onkologie GmbH Idar-Oberstein, Germany
594: Lutz D, Elisabethinen-Hospital I. Internal Department,
Linz, Austria
595: Schwarer AP, Alfred Hospital, BMT Programme Com-
mercial RD, Melbourne, Australia
597: Vorlicek J, University Hospital Brno Department of
Internal Med. – Hematooncology, Brno, Czech Repub
601: Liu Yin J, Manchester Royal Infirmary Haematology,
Manchester
607: Ferrara F, Division of Hematology, Cardarelli Hospital,
Napoli, Italy
610: Mistrik M, Clinic of Hematology & Transfusiology
University Hospital, Bratislava, Slovakian Republic
612: Leon Lara A, Hospital del SAS Department of Hemato-
logy, Ca
´
diz, Spain
613: Ribera Santasusana JM, Hospital Universitari Germans
Trias i Pujol, Barcelona, Spain
614: Zander AR, University Hospital Eppendorf Bone Marrow
Transplantation Centre, Hamburg, Germany
617: Gurman G, Department of Hematology, Ankara
University Medical School, Ankara, Turkey
622: Harhalakis N, Division of Hematology, BMT Unit
Evangelismos Hospital, Athens, Greece
623: Benedetti F, Divisione di Ematologia, Unita
`
di TMO
Policlinico G.B. Rossi, Verona, Italy
624: Attal M, CHU Department Hematologie Hopital de
Purpan, Toulouse, France
625: Wandt H, 5. Medizinische Klinik, BMT-Unit Klinikum
Nu
¨
rnberg, Nu
¨
rnberg, Germany
640: Pretnar J, Department of Hematology University Med.
Center, Ljubljana, Slovenia
645: Neubauer A, Klinik fuer Haematologie, Onkologie und
Immunologie, Marburg, Germany
646: Demuynck H, Heilig Hartziekenhuis Hematology –
Oncology Department, Roeselare, Belgium
650: Boasson M, Service des Maladies du Sang CHRU,
Angers, France
656: Vitek A, Institute of Hematology and Blood Transfusion,
Prague, Czech Repub
658: Barbui T, Divisione di Ematologia Ospedale Bergamo,
Bergamo, Italy
660: Gugliotta L, Unita Operativa Ematologia Arcispedale S.
Maria Nuova Reggio, Emilia, Italy
663: Sanz MA, Hospital Universitario La Fe Servicio de
Hematologia, Valencia, Spain
666: Bourhis JH, BMT Unit, Hematology Division Institut
Gustave, Roussy Villejuif Cedex, France
671: Michallet M, BMT Unit Pavillon E Hopital E. Herriot,
Lyon, France
672: Lioure B, Onco-He
´
matologie Hopital de Hautepierre,
Strasbourg, France
Comparative outcome of RIC and MA regimen
M Aoudjhane et al
2311
Leukemia
676: Bordigoni P, Me
´
decine Infantile II Hopitaux de Barbois
Enfants Vandoeuvre les, Nancy, France
680: Kienast J, Department of Hematol./Oncol. University of
Mu
¨
nster, Mu
¨
nster, Germany
691: Dincer S, Ankara Numune Education and Research
Hospital, Ankara, Turkey
692: Musso M, Ospedale La Maddalena – Dapartment
Oncologico Unita
`
Operativa di Oncoematologiae, Palermo,
Italy
704: Orchard K, Haematology, Oncology, & Paediatrics
Department of Haematology, Southampton, United Kingdom
710: Herrmann RP, Hematology Dept., BMT Unit Royal Perth
Hospital, Wellington, St. Perth, Australia
713: Hunter AE, Department of Haematology, Leicester Royal
Infirmary, Leicester, United Kingdom
717: Russell NH, Nottingham City Hospital, Hucknall Road,
Nottingham, United Kingdom
718: Koza V, Department of Hematology/Oncology, Charles
University Hospital, Pilsen, Czech Repub
722: Besalduch J, Hematology Service Hospital Universitari
Son Dureta, Palma de Mallorca, Spain
725: Afanassiev BV, Department of BMT, Centre of
Hematology SPb State I. Pavlov Medical University,
St Petersburg, Russia
727: Caballero D, Servicio de Hematologı´a Hospital Clı´nico
Salamanca, Spain
728: Ferna
´
ndez MN, Clinica Puerta de Hierro Servicio de
Hematologia y Hemoterapia, Madrid, Spain
729: Jebavy L, Charles University Hospital, Department of
Clinical Hematology, Hradec Kra
´
love
´
, Czech Repub
730: Komarnicki M, Department of Hematology K Marcin-
kowski University, Poznan, Poland
731: Wahlin A, Department of Internal Medicine, Umea
University Hospital, Umea, Sweden
734: Martı´nez-Rubio AM, Hospital Infantil La Paz Hemato-
Oncologia Madrid Spain
735: Moraleda Jimenez JM, Hospital Morales Meseguer
Unidad de Trasplante de Me
´
dula Osea, Murcia, Spain
740: Juliusson G, Department of Hematology, University
Hospital, Linko
¨
ping, SWEDEN
744: Noens LA, Haematology and Bloodbank University
Hospital Gent, Gent, Belgium
751: Efremidis A, Hellenic Cancer Institute, St Savvas
Oncology Hospital, Athens, Greece
754: Nagler A, Department of Bone Marrow Transplantation,
Tel-Aviv University, Tel-Hashomer, Israel
759: Gran
˜
ena A, Department of Hematology, Institut Catala
d’Oncologia, Barcelona, Spain
763: Mufti GJ, Department of Haematological Medicine, GKT
School of Medicine, London, United Kingdom
766: Rotoli B, Division of Hematology, ‘Federico II’ Medical
School, Napoli, Italy
778: Vora A, Haematology Department, Sheffield Children’s
Hospital, Sheffield, United Kingdom
780: Chopra R, Department of Haematology, Christie NHS
Trust Hospital, Manchester, United Kingdom
785: Joerg S, Department of Internal Med., BMT Unit
University of Saarland, Hamburg, Germany
786: Kolbe K, III. Medizinische Klinik und Poliklinik,
Johannes-Gutenberg-University, Mainz, Germany
787: Andreesen R, Department of Hematology and Oncology
University, Regensburg, Regensburg, Germany
788: Leoni P, Clinica di Ematologia Ospedale di Torrette,
Ancona-Torrette, Italy
792: Milone G, Ospedale Ferrarotto Divisione Clinicizzata di
Ematologia, Catania, Italy
797: Rodeghiero F, Department of Hematology S Bortolo
Hospital, Vicenza, Italy
799: Hellmann A, BMT Unit, Department of Haematology,
Medical University of Gdansk, Gdansk, Poland
807: Arnold R, Charit Campus, Virchow-Klinkum, Berlin,
Germany
808: Ehninger G, Universitaetsklinikum Dresden Medizi-
nische Klinik und Poliklinik I, Dresden, Germany
809: Gramatzki M, Division of Hematology/Oncology,
Department of Medicine III, University Erlangen, Erlangen,
Germany
810: Finke J, Department of Medicine – Hematology,
Oncology University of Freiburg, Freiburg, Germany
813: Bregni M, Hematology and BMT Istituto Scientifico HS
Raffaele, ilano, Italy
816: Rzepecki P, Bone Marrow Transplantation Unit, Military
Medical Academy, Warsaw, Poland
819: Diez-Martin JL, Seccio
´
n de Trasplante de Medula Osea
Hospital GU Gregorio Maranon, Madrid, Spain
823: Hamon MD, Plymouth Hospitals, NHS Trust, Derriford
Hospital, Plymouth, United Kingdom
825: Levis A, SS Antonio e Biagio e C Arrigo Haematology
Department, Alessandria, Italy
941: Tilly H, Centre Henri Becquerel, Rouen, France
954: Wiktor-Jedrzejczak W, Department of Hematology &
Oncology, The Medical University of Warsaw, Warsaw, Poland
Comparative outcome of RIC and MA regimen
M Aoudjhane et al
2312
Leukemia
