Copyright 2017 American Medical Association. All rights reserved.
Long-term Outcomes After Autologous Hematopoietic Stem
Cell Transplantation for Multiple Sclerosis
Paolo A. Muraro, MD; Marcelo Pasquini, MD; Harold L. Atkins, MD; James D. Bowen, MD; Dominique Farge, MD; Athanasios Fassas, MD;
Mark S. Freedman, MD; George E. Georges, MD; Francesca Gualandi, MD; Nelson Hamerschlak, MD; Eva Havrdova, MD; Vassilios K. Kimiskidis, MD;
Tomas Kozak, MD; Giovanni L. Mancardi, MD; Luca Massacesi, MD; Daniela A. Moraes, MD; Richard A. Nash, MD; Steven Pavletic, MD; Jian Ouyang, MD;
Montserrat Rovira, MD; Albert Saiz, MD; Belinda Simoes, MD; Marek Trněný, MD; Lin Zhu, MD; Manuela Badoglio, MSc; Xiaobo Zhong, MS;
Maria Pia Sormani, PhD; Riccardo Saccardi, MD; for the Multiple Sclerosis–Autologous Hematopoietic Stem Cell Transplantation (MS-AHSCT)
Long-term Outcomes Study Group
IMPORTANCE
Autologous hematopoietic stem cell transplantation (AHSCT) may be effective
in aggressive forms of multiple sclerosis (MS) that fail to respond to standard therapies.
OBJECTIVE To evaluate the long-term outcomes in patients who underwent AHSCT for the
treatment of MS in a large multicenter cohort.
DESIGN, SETTING, AND PARTICIPANTS Data were obtained in a multicenter, observational,
retrospective cohort study. Eligibility criteria were receipt of AHSCT for the treatment of MS
between January 1995 and December 2006 and the availability of a prespecified minimum
data set comprising the disease subtype at baseline; the Expanded Disability Status Scale
(EDSS) score at baseline; information on the administered conditioning regimen and graft
manipulation; and at least 1 follow-up visit or report after transplant. The last patient visit was
on July 1, 2012. To avoid bias, all eligible patients were included in the analysis regardless of their
duration of follow-up. Data analysis was conducted from September 1, 2014 to April 27, 2015.
EXPOSURES Demographic, disease-related, and treatment-related exposures were
considered variables of interest, including age, disease subtype, baseline EDSS score, number
of previous disease-modifying treatments, and intensity of the conditioning regimen.
MAIN OUTCOMES AND MEASURES The primary outcomes were MS progression-free survival
and overall survival. The probabilities of progression-free survival and overall survival were
calculated using Kaplan-Meier survival curves and multivariable Cox proportional hazards
regression analysis models.
RESULTS Valid data were obtained from 25 centers in 13 countries for 281 evaluable patients,
with median follow-up of 6.6 years (range, 0.2-16 years). Seventy-eight percent (218 of 281) of
patients had progressive forms of MS. The median EDSS score before mobilization of peripheral
blood stem cells was 6.5 (range, 1.5-9). Eight deaths (2.8%; 95% CI, 1.0%-4.9%) were reported
within 100 days of transplant and were considered transplant-related mortality. The 5-year
probability of progression-free survival as assessed by the EDSS score was 46% (95% CI,
42%-54%), and overall survival was 93% (95% CI, 89%-96%) at 5 years. Factors associated
with neurological progression after transplant were older age (hazard ratio [HR], 1.03; 95% CI,
1.00-1.05), progressive vs relapsing form of MS (HR, 2.33; 95% CI, 1.27-4.28), and more than
2 previous disease-modifying therapies (HR, 1.65; 95% CI, 1.10-2.47). Higher baseline EDSS
score was associated with worse overall survival (HR, 2.03; 95% CI, 1.40-2.95).
CONCLUSIONS AND RELEVANCE In this observational study of patients with MS treated with
AHSCT, almost half of them remained free from neurological progression for 5 years after
transplant. Younger age, relapsing form of MS, fewer prior immunotherapies, and lower
baseline EDSS score were factors associated with better outcomes. The results support the
rationale for further randomized clinical trials of AHSCT for the treatment of MS.
JAMA Neurol. 2017;74(4):459-469. doi:10.1001/jamaneurol.2016.5867
Published online February 20, 2017.
Editorial page 392
Author Audio Interview
Supplemental content
Author Affiliations: Author
affiliations are listed at the end of this
article.
Group Information: The Multiple
Sclerosis–Autologous Hematopoietic
Stem Cell Transplantation
(MS-AHSCT) Long-term Outcomes
Study Group members are listed at
the end of this article.
Corresponding Author: Paolo A.
Muraro, MD, Division of Brain
Sciences, Imperial College London,
160 Du Cane Rd, Burlington Danes
Building, Fourth Floor, London W12
0NN, England (p.muraro@imperial
.ac.uk).
Research
JAMA Neurology | Original Investigation
(Reprinted) 459
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M
ore than 2.3 million people in the world are affected
by multiple sclerosis (MS).
1
The disease typically
manifests in young adulthood and can cause severe
neurological disability, a major socioeconomic burden.
2
Pa-
tients with an aggressive course of MS often fail to respond to
several lines of disease-modifying treatment, and their con-
dition deteriorates within a few years.
Autologous hematopoietic stem cell transplantation
(AHSCT) is being investigated as a treatment for aggressive MS.
3
The rationale of this approach is the use of high-dose immu-
nosuppressive therapy to suppress the autoimmune inflam-
matory process. Infusion of autologous hematopoietic stem
cells boosts bone marrow recovery and promotes immune re-
constitution. The procedure has been shown to induce a de-
gree of immune “resetting.”
4,5
The treatment goals are to ar-
rest the worsening of neurological disability, induce a prolonged
medication-free interval, and potentially effect an improve-
ment in neurological function. Early clinical trials estab-
lished the proof of principle that AHSCT could invoke disease
remission in patients with severe MS.
6
Studies have shown that
AHSCT is effective in suppressing disease reactivation as as-
sessed clinically and on magnetic resonance imaging (MRI),
7-9
can result in neurological improvement in patients with re-
lapsing-remitting MS,
7,8,10-12
and can halt all detectable cen-
tral nervous system inflammatory activity for a prolonged
period.
13
However, outcome assessments in most studies were
limited to a short follow-up, and longer-term outcomes have
been reported only from small case series.
14-16
Therefore, it is
important to examine the course of MS after AHSCT in a large
patient population and their rates of risks and complications
over the longer term.
The primary objective of this study was to evaluate the
long-term outcomes in patients who underwent AHSCT for the
treatment of MS in a large multicenter cohort by analyzing pro-
gression-free survival, evolution of neurological disability,
overall survival, transplant-related mortality, and late ef-
fects, including new autoimmune and malignant disorders. A
secondary aim was to examine the association of demo-
graphic and MS disease-related and treatment-related vari-
ables with long-term outcomes.
Methods
Study Design, Setting, and Data Sources
This study was a multicenter, observational, retrospective co-
hort study on AHSCT for the treatment of MS and was per-
formed through collaboration between the Center for Inter-
national Blood and Marrow Transplant Research (CIBMTR)
Autoimmune Disease Working Committee and the European
Blood and Marrow Transplant (EBMT) Group Autoimmune Dis-
ease Working Party. The CIBMTR is a voluntary working group
of more than 450 transplant centers worldwide that contrib-
ute detailed data on consecutive marrow transplants to a
statistical center located at the Medical College of Wisconsin,
Milwaukee, and to the National Marrow Donor Program Co-
ordinating Center, Minneapolis, Minnesota.
17
The EBMT is a
nonprofit organization comprising 640 transplant centers,
mainly in Europe. All transplant centers are required to ob-
tain written informed consent from all patients to report their
data to the CIBMTR and the EBMT, in accord with the 1975 Dec-
laration of Helsinki. Institutional review board approval for data
collection and the use of data for research purposes was ob-
tained locally by each center. Only fully anonymized data were
transferred to the study database. After review by the study
steering committee (P.A.M., M.P., H.L.A., J.D.B., D.F., A.F.,
M.S.F., E.H., T.K., G.L.M., R.A.N., S.P., A.S., M.P.S., and R.S.),
the trial protocol (eAppendix in the Supplement) was ap-
proved by the CIBMTR Joint Affiliation Board and the EBMT
Board of Association, in agreement with the rules for retro-
spective studies of both organizations. Multiple sclerosis data
before transplant and during follow-up were prospectively ob-
tained from participating transplant centers on disease-
specific forms, which were harmonized between the 2
registries.
18
For the purposes of this study, all bone marrow
transplant centers that reported at least 1 AHSCT for MS to the
CIBMTR or EBMT between January 1995 and December 2006
were sent an invitation to participate in the study together with
a protocol summary. The centers that agreed to participate were
asked to identify a transplant physician and a neurologist to
oversee all patient data for the accuracy and completeness at
each site. To better describe the disease activity before and af-
ter transplant and to extend the follow-up for our study, ad-
ditional data collection was performed retrospectively. To this
end, study team members (M.P. and M.B.) developed a supple-
mental data collection form that was preprinted with the pre-
viously reported data to facilitate additional data collection and
concurrent verification of the accuracy of existing informa-
tion. The overall completeness of enrollment in our study, cal-
culated as the percentage of all procedures reported to the 2
registries during the study period, was 57.0% (281 of 493). A
Consolidated Standards of Reporting Trials diagram of enroll-
ment and screening of the cases potentially eligible for inclu-
sion in the study is shown in the eFigure in the Supplement.
Our study is reported according to the Strengthening the Re-
porting of Observational Studies in Epidemiology (STROBE)
guidelines (the checklist used is included in the eAppendix in
the Supplement).
Key Points
Question What are the long-term outcomes after autologous
hematopoietic stem cell transplantation for the treatment of
multiple sclerosis?
Findings In this multicenter cohort study of 281 patients with
predominantly progressive forms of multiple sclerosis who
underwent autologous hematopoietic stem cell transplant
between 1995 and 2006, transplant-related mortality was 2.8%
within 100 days of transplant, and neurological progression-free
survival was 46% at 5 years. Younger age, relapsing form of
multiple sclerosis, fewer prior immunotherapies, and lower
neurological disability score were significantly associated with
better outcomes.
Meaning The results support the rationale for further randomized
clinical trials of autologous hematopoietic stem cell
transplantation for the treatment of multiple sclerosis.
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Patients and Treatments
For each case included in the study, a minimum data set was
required that comprised the following: (1) the MS disease sub-
type at baseline (relapsing-remitting, progressive relapsing, pri-
mary progressive, or secondary progressive); (2) the Ex-
panded Disability Status Scale (EDSS) score at baseline, with
0 indicating no disability, 7 indicating wheelchair bound, and
10 indicating death from MS (details are listed in eTable 1 in
the Supplement); (3) information on the administered condi-
tioning regimen and graft manipulation; and (4) at least 1 fol-
low-up visit or report after transplant. The last patient visit was
on July 1, 2012. Mobilization of peripheral blood stem cells was
performed by the administration of a hematopoietic growth
factor with or without chemotherapy; the type of growth fac-
tor and type of chemotherapy were sought for data-recording
purposes. Graft manipulation to reduce the content of im-
mune cells was also recorded. Conditioning regimens that in-
cluded busulfan or total-body irradiation were classified as high
intensity, while regimens that included cyclophosphamide
alone or in combination with antithymocyte globulin or
fludarabine phosphate were classified as low intensity. All other
regimens were considered intermediate intensity.
Study End Points
Progression-free s ur vival was defined as survival in the ab-
sence of progression of MS. Progression of MS was defined clini-
cally as an increase of 1 point in the EDSS score confirmed at
12 months (0.5 points if the baseline EDSS score was ≥5.5)
compared with the pretreatment baseline. The pretreatment
baseline was defined as the last assessment before mobiliza-
tion of peripheral blood stem cells (for peripherally mobi-
lized autologous grafts) or before immunosuppressive condi-
tioning (for bone marrow autologous grafts). The EDSS score
increases that were detected at the last visit and thus could be
confirmed were considered events according to a more con-
servative approach. A sensitivity analysis was performed cen-
soring these last visit events. Death from any cause was con-
sidered MS progression in this analysis. Overall survival was
considered time to death by any cause. For all patients who
died after their AHSCT, the cause of death was examined. Early
deaths that occurred within 100 days of transplant, which are
considered treatment related, were described separately.
Surviving patients were censored at the time of last follow-
up. Information regarding the incidence of late effects was
obtained, including malignant cancers and secondary auto-
immune diseases.
Statistical Analysis
Data obtained from the CIBMTR and EBMT were summarized
in descriptive tables of demographic information for the en-
tire study population. Continuous variables were reported as
medians and ranges or as means (SDs), while categorical vari-
ables were reported as absolute numbers and percentages of
total patients. The probability of progression-free survival was
calculated using the life-table estimator, and overall survival
was calculated using the Kaplan-Meier estimator. A multivar-
iate analysis assessing the association of baseline character-
istics and transplantation methods with progression-free and
overall survival was performed using multivariate Cox pro-
portional hazards regression analysis models, adjusted for cen-
ter. Proportionality of hazard was checked by plotting log-log
transformation of the Kaplan-Meier survival curve as follows
for each level of covariates: log-log(S[t]) vs time t, where S in-
dicates the statistic. The assumption of proportional hazard
is tenable if the difference between the 2 log-log Kaplan-
Meier survival curves is constant over time.
Variables significantly associated with each outcome event
on univariate analysis were included as covariates in the mul-
tivariate model, which selected the independent set of vari-
ables using a stepwise approach. For each patient having an
EDSS assessment 1 year before and 1 year after transplant, the
yearly EDSS score change before and after transplant was cal-
culated. These changes were compared by a repeated-
measures analysis of variance with 2 time points (change be-
fore vs change after transplant), also including disease subtype
(relapsing vs progressive forms) and an interaction term (pe-
riod of transplant × disease subtype) to evaluate whether the
EDSS score change before and after transplant differed be-
tween patients with relapsing vs progressive disease.
A smoothing technique (locally weighted polynomial
regression
19
) was applied to describe the EDSS score trend over
time in patients with relapsing vs progressive disease for those
individuals having the EDSS date of assessment reported. This
technique is a nonparametric graphical tool to fit a smooth
curve to the points in a scatterplot based on local weighted re-
gression analyses.
19
A 2-sided significance level of 5% was used. Analyses were
performed using statistical software programs (R, version 3.2;
The R Project for Statistical Computing and SPSS, version 19;
SPSS Inc).
Results
Patient Demographics and Procedures
Valid data were obtained from 25 centers in 13 countries for
281 patients. Demographic and clinical data at the time of
AHSCT are summarized in Table 1. The median time from di-
agnosis of MS to AHSCT was 81 months (range, <1 to 413
months). At the time of AHSCT, 171 of 281 patients (60.9%) had
received 2 or more prior MS treatments. At the assessment pre-
ceding mobilization of peripheral blood stem cells, the most
represented disease subtype was secondary progressive MS,
contributing 186 of 281 patients (66.2%), and the median EDSS
score before mobilization of peripheral blood stem cells was
6.5 (range, 1.5-9), indicating moderately advanced disability
on average.
A few differences existed between the subsets of patients
reported to the CIBMTR and the EBMT, reflecting different pa-
tient selection practices in the 2 groups of countries. Com-
pared with the CIBMTR cohort, the EBMT cohort (1) was
younger (median age, 35 vs 40 years; P < .001), (2) more
often had more than 2 MS treatments before transplant (51.7%
[74 of 143] vs 32.1% [34 of 111], P = .002), (3) had fewer
patients with secondary progressive MS (60.6% [103 of
170] vs 74.8% [83 of 111], P = .001), (4) had shorter time from
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Table 1. Demographic and Clinical Characteristics of Patients
Variable
CIBMTR
(n = 111)
EBMT
(n = 170)
Total Cohort
(N = 281)
No. of centers 8 17 25
Age, median (range), y 40 (26 to 60) 35 (15 to 65) 37 (15 to 65)
Age group, No. (%), y
10-19 0 6 (3.5) 6 (2.1)
20-29 11 (9.9) 47 (27.6) 58 (20.6)
30-39 40 (36.0) 67 (39.4) 107 (38.1)
40-49 44 (39.6) 41 (24.1) 85 (30.2)
>50 16 (14.4) 9 (5.3) 25 (9.0)
Sex, No. (%)
Male 48 (43.2) 69 (40.6) 117 (41.6)
Female 63 (56.8) 101 (59.4) 164 (58.4)
EDSS score before mobilization of PBCs
No. (%) evaluated 111 (100) 170 (100) 281 (100)
Median (range) 6.5 (2.5 to 9) 6.5 (1.5 to 9) 6.5 (1.5 to 9)
EDSS score before conditioning regimen
Missing, No. (%) 62 (55.9) 39 (22.9) 101 (35.9)
No. (%) evaluated 49 (44.1) 131 (77.1) 180 (64.1)
Median (range) 6 (3.5 to 9) 6.5 (1.5 to 9.5) 6 (1.5 to 9.5)
No. of MS treatments before AHSCT
a
Missing 52732
No. evaluated 106 143 249
1 Treatment, No. (%) 42 (39.6) 36 (25.2) 78 (31.3)
2 Treatments, No. (%) 30 (28.3) 33 (23.1) 63 (25.3)
>2 Treatments, No. (%) 34 (32.1) 74 (51.7) 108 (43.4)
MS subtype at baseline, No. (%)
Relapsing-remitting 12 (10.8) 34 (20.0)
b
46 (16.4)
Progressive relapsing 0 17 (10.0) 17 (6.0)
Primary progressive 16 (14.4) 16 (9.4) 32 (11.4)
Secondary progressive 83 (74.8) 103 (60.6) 186 (66.2)
Time from diagnosis of MS to AHSCT
No. (%) evaluated 110 (99.1) 170 (100) 280 (99.6)
Median (range), mo 91 (<1 to 413) 77 (2 to 340) 81 (<1 to 413)
Time from mobilization of PBCs to AHSCT
No. (%) evaluated 79 (71.2) 169 (99.4) 248 (88.3)
Median (range), mo 1 (<1 to 7) 2 (<1 to 9) 2 (<1 to 9)
Time of AHSCT, No. (%)
1995-2000 24 (21.6) 71 (41.8) 95 (33.8)
2001-2006 87 (78.4) 99 (58.2) 186 (66.2)
Chemomobilization of PBCs, No. (%)
c
101 (91.0) 162 (95.3) 263 (93.6)
Graft manipulation, No. (%)
d
Yes 53 (47.7) 70 (41.2) 123 (43.8)
No 58 (52.3) 100 (58.8) 158 (56.2)
Conditioning Regimen, No. (%)
High intensity 43 (38.7) 10 (5.9) 53 (18.9)
Cyclophosphamide plus TBI plus antithymocyte globulin 28 (25.2) 0 28 (10.0)
Busulfan plus cyclophosphamide plus antithymocyte globulin 15 (13.5) 0 15 (5.3)
Busulfan plus antithymocyte globulin 0 10 (5.9) 10 (3.6)
(continued)
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diagnosis of MS to transplant (median, 77 vs 91 months;
P = .04), and (5) had a greater proportion of patients who
underwent transplant during the first half (1995-2000) of
the 12-year period qualifying for inclusion in our study (41.8%
[71 of 170] vs 21.6% [24 of 111], P < .01).
In total, 66.2% (186 of 281) of the patients underwent
AHSCT during the second half (2001-2006) of the study. De-
tails of mobilization of peripheral blood stem cells, graft ma-
nipulation, and conditioning regimens are also listed in Table 1.
The proportions of patients who received high-intensity, in-
termediate-intensity, and low-intensity conditioning regi-
mens were similar (approximately one-third each) in the
CIBMTR cohort, whereas 88.8% (151 of 170) of patients in the
EBMT cohort received an intermediate-intensity regimen, most
commonly BEAM (carmustine, etoposide, cytarabine, and mel-
phalan) plus antithymocyte globulin. The percentage of pa-
tients treated with high-intensity regimens was higher among
patients with progressive MS (21.6% [47 of 218]) than among
patients with relapsing MS (9.5% [6 of 63]) (P = .05). The me-
dian duration of follow-up after AHSCT was 6.6 years (range,
0.2-16 years).
Progression-Free Survival
Progression-free survival as assessed by the EDSS score was
considered the primary neurological end point. In total, 239
of 281 patients (85.1%) with yearly EDSS assessments after
transplant were eligible for this analysis. Multiple sclerosis pro-
gression-free survival in all evaluable patients was 46% (95%
CI, 42%-54%) at 5 years after AHSCT (Figure 1A). Progression-
free survival in the subgroup with relapsing MS was 82% (95%
CI, 71%-93%) at 3 years, 78% (95% CI, 66%-91%) at 4 years, and
73% (95% CI, 57%-88%) at 5 years after AHSCT. Among pa-
tients with secondary progressive MS, the largest subgroup in
our study, 33% (95% CI, 24%-42%) remained free from EDSS
score deterioration at 5 years after AHSCT. When applying a
multivariable Cox proportional hazards regression analysis, the
assumption of proportional hazard was tenable. Factors asso-
ciated with the risk of EDSS score deterioration as identified
by univariate Cox proportional hazards regression analysis were
age, progressive vs relapsing form of MS, and number of prior
treatments (Table 2). The significance of these factors was con-
firmed on multivariate analysis (Table 2 and Figure 1B, C, and
D). Younger age and relapsing forms of MS were indepen-
dently associated with better progression-free survival rates
(Figure 1B and C). There was no statistical difference in the risk
of disease progression between patients with primary pro-
gressive MS and patients with secondary progressive MS
(hazard ratio [HR], 1.09; P = .63) (Figure 1C). Patients who re-
ceived 3 or more immunosuppressive or modulatory treat-
ments before AHSCT had a higher probability of disease pro-
gression than those who received 1 to 2 treatments before
AHSCT (Figure 1D). The results were unchanged when uncon-
firmed disease progressions at the last visits were considered
censored observations.
EDSS Score Change in the Periods
Before and After AHSCT
It was important to consider the evolution of neurological dis-
ability in patients before they underwent AHSCT. This infor-
mation was available in a subset of patients in the study. There
were 111 patients who met the minimum requirement for this
evaluation, which was the availability of at least 1 EDSS score
during the 3 years before and after AHSCT, including the re-
spective dates of assessment. In the evaluable subgroup, the
mean EDSS score increased by 0.94 points (95% CI, 0.77-1.11
points) during the 12 months before transplant compared with
a mean decrease of −0.32 points (95% CI, −0.15 to −0.49 points)
during the 12 months after transplant (P < .001). A test for in-
teraction demonstrated that the EDSS score change before and
after transplant was significantly different between patients
with relapsing vs progressive MS (P < .001): for relapsing MS,
the EDSS score change 1 year before transplant was +1.42 (95%
Table 1. Demographic and Clinical Characteristics of Patients (continued)
Variable
CIBMTR
(n = 111)
EBMT
(n = 170)
Total Cohort
(N = 281)
Intermediate intensity 28 (25.2) 151 (88.8) 179 (63.7)
BEAM plus antithymocyte globulin 23 (20.7) 86 (50.6) 109 (38.8)
BEAM 0 40 (23.5) 40 (14.2)
Cyclophosphamide plus thiotepa 0 7 (4.1) 7 (2.5)
TLI plus melphalan 5 (4.5) 0 5 (1.8)
Carmustine plus cyclophosphamide plus antithymocyte globulin 0 18 (10.6) 18 (6.4)
Low intensity 40 (36.0) 9 (5.3) 49 (17.4)
Cyclophosphamide plus antithymocyte globulin 37 (33.3) 9 (5.3) 46 (16.4)
Cyclophosphamide plus fludarabine phosphate 3 (2.7) 0 3 (1.1)
Antithymocyte globulin 104 (93.7) 128 (75.3) 232 (82.6)
Abbreviations: AHSCT, autologous hematopoietic stem cell transplantation;
BEAM, carmustine, etoposide, cytarabine, and melphalan; CIBMTR, Center for
International Blood and Marrow Transplant Research; EBMT, European Blood
and Marrow Transplant Group; EDSS, Expanded Disability Status Scale;
MS, multiple sclerosis; PBCs, peripheral blood cells; TBI, total-body irradiation;
TLI, total lymphoid irradiation.
a
Indicates the number of disease-modifying therapies received for the
treatment of MS before AHSCT.
b
Includes 1 case reported as Marburg-type MS.
c
Indicates whether a chemotherapy was combined with growth factor to
mobilize hematopoietic stem cells.
d
Indicates whether graft manipulation was performed with CD34 selection or
T-cell depletion.
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