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Does size matter? Center-specific characteristics and
survival after allogeneic hematopoietic cell
transplantation for acute myeloid leukemia: an analysis
of the German Registry for Stem Cell Transplantation
and Cell Therapy
by Wolfgang Bethge, Sarah Flossdorf, Franziska Hanke, Christoph Schmid, Mark Ringhoer,
Stefan Klein, Bernd Hertenstein, Johannes Schetelig, Matthias Stelljes, omas Schroeder,
Igor Wolfgang Blau, Francis Ayuk, Matthias Eder, Robert Zeiser, Katharina Fleischhauer,
Nicolaus Kröger, and Peter Dreger.
Collaborative Groups: German Working Group for Hematopoietic Stem Cell Transplantation and
Cellular erapy (DAG-HSZT), German Registry for Hematopoietic Stem Cell Transplantation
and Cell erapy (DRST).
Received: August 5, 2024.
Accepted: November 28, 2024.
Citation: Wolfgang Bethge, Sarah Flossdorf, Franziska Hanke, Christoph Schmid, Mark Ringhoer,
Stefan Klein, Bernd Hertenstein, Johannes Schetelig, Matthias Stelljes, omas Schroeder,
Igor Wolfgang Blau, Francis Ayuk, Matthias Eder, Robert Zeiser, Katharina Fleischhauer,
Nicolaus Kröger, and Peter Dreger.
Collaborative Groups: German Working Group for Hematopoietic Stem Cell Transplantation and
Cellular erapy (DAG-HSZT), German Registry for Hematopoietic Stem Cell Transplantation
and Cell erapy (DRST). Does size matter? Center-specic characteristics and survival aer allogeneic
hematopoietic cell transplantation for acute myeloid leukemia: an analysis of the German Registry
for Stem Cell Transplantation and Cell erapy.
Haematologica. 2024 Dec 5. doi: 10.3324/haematol.2024.286385 [Epub ahead of print]
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1
Does size matter? Center-specific characteristics and survival after allogeneic
hematopoietic cell transplantation for acute myeloid leukemia: an analysis of
the German Registry for Stem Cell Transplantation and Cell Therapy
Wolfgang Bethge1,2, Sarah Flossdorf3,4, Franziska Hanke4, Christoph Schmid5, Mark
Ringhoffer6, Stefan Klein7, Bernd Hertenstein8, Johannes Schetelig2,9, Matthias Stelljes2,10,
Thomas Schroeder11, Igor Wolfgang Blau12, Francis Ayuk2,13, Matthias Eder14, Robert Zeiser15,
Katharina Fleischhauer4,11, Nicolaus Kröger4,13, Peter Dreger2,16
And on behalf of the German Working Group for Hematopoietic Stem Cell Transplantation
and Cellular Therapy e.V. (DAG-HSZT) and the German Registry for Hematopoietic Stem Cell
Transplantation and Cell Therapy (DRST)
Collaborative Groups: German Working Group for Hematopoietic Stem Cell
Transplantation and Cellular Therapy (DAG-HSZT)), German Registry for Hematopoietic
Stem Cell Transplantation and Cell Therapy (DRST))
1University Hospital Tuebingen, Tuebingen, Germany, 2German Working Group for Hematopoietic Stem Cell
Transplantation and Cellular Therapy, 3Institute for Medical Informatics, Biometry, and Epidemiology,
University Hospital Essen, University of Duisburg-Essen, Essen, Germany, 4German Registry for Hematopoietic
Stem Cell Transplantation and Cell Therapy, Ulm, Germany, 5University Hospital Augsburg, Augsburg, Germany,
6Hospital Karlsruhe, Karlsruhe, Germany, 7University Hospital Mannheim, Mannheim, Germany, 8Central
Hospital Bremen, Bremen, Germany, 9University Hospital Dresden, Dresden, Germany, 10University Hospital
Muenster, Muenster, Germany, 11University Hospital Essen, Essen, Germany, 12University Hospital Charité
Berlin, Berlin, Germany, 13University Medical Center Hamburg, Hamburg, Germany, 14University Hospital
Hannover, Hannover, Germany, 15University Hospital Freiburg, Freiburg, Germany, 16University Hospital
Heidelberg, Heidelberg, Germany
2
Correspondence:
Prof. Dr. med. Wolfgang Bethge
University Hospital Tuebingen
Hematology & Oncology
Otfried-Mueller Str. 10
D-72076 Tuebingen
Germany
Tel: +49-7071-2983176
Fax: +49-7071-294514
Email: wolfgang.bethge@med.uni-tuebingen.de
Authorship:
WB designed the research, collected and analyzed data, wrote manuscript, S F
designed the research, analyzed data and wrote and reviewed manus cript, F H
performed data management and reviewed m anuscript, C S designed the research ,
collected patient data and reviewed manuscript, MR
designed the research, collected
patient data and reviewed manuscript, S K designed the research, collected patient
data and reviewed manuscript, BH collected patient data and re viewed manuscript,
J S designed the research, collected patient data and reviewed manuscript, MS
collected patient data and reviewed manuscript, TS
3
collected patient data and reviewed manuscript; IB collected patient data and reviewed
manuscript, FA collected patient data and reviewed manuscript, ME collected patient data
and reviewed manuscript, RZ collected patient data and reviewed manuscript, KF and NK
supervised data protection and reviewed manuscript, PD designed the research, collected
and analyzed data, wrote manuscript.
Conflict of Interest Statement:
The authors do not declare any conflicts of interest in relation to the manuscript above.
Data sharing statement:
Original analysis data and protocols of this paper may be available to other investigators by
request to the DRST (support@drst.de).
4
Abstract:
We investigated the effect of center-specific variables on overall survival (OS) after
allogeneic hematopoietic cell transplantation (alloHCT) in acute myeloid leukemia (AML).
Eligible were adult patients reported to DRST registry receiving first alloHCT for AML from a
related or matched (>= 9/10 HLA-match) unrelated donor 2015-2021. Primary endpoint was
OS at 12 months from alloHCT. Univariable and multivariable analyses after best subset
selection was performed. Of 5328 patients, 83% received alloHCT in a high-volume center
(≥40 alloHCT/year); 90% in a university hospital; 90% in a center performing alloHCT for ≥10
years; and 73% in a Joint Accreditation Committee IHCT-Europe & EBMT (JACIE) accredited
center. 52% of the patients were in CR1, and ELN risk was adverse in 37% and intermediate
in 42%. On multivariable analysis, center-specific factors predicting adverse 12-month OS
were program duration <5-10 years (hazard ratio (HR) 1.23, 95% CI [1.02; 1.49]); center
volume <40 alloHCT/year (HR 1.21, [1.02; 1.45]); and non-university hospital (HR 1.21, [0.98;
1.49]), whereas not JACIE accreditation. Spline modeling suggested a negative effect of a
center volume up to 45 alloHCTs per year. Center volume, center experience, university
hospital, but not JACIE accreditation have an impact on alloHCT outcomes in adult patients
with AML in Germany.
5
Introduction
While patient-, disease- and procedure-related outcome predictors in allogeneic
hematopoietic cell transplantation (alloHCT) for acute myeloid leukemia (AML) are well
characterized, the impact of center-specific variables on outcomes are still a matter of
debate. Standards of patient selection, conditioning regimen selection, GVHD prophylaxis
and supportive care practice as well as outpatient follow-up programs and infrastructure
may vary considerably between centers and health care systems(1-4). Furthermore, center
size, experience, and staff expertise in addition to the frequency of alloHCT performed may
influence the quality of patient care and alloHCT outcome(5-7).
Recently, German health authorities redefined the volume of alloHCT per center in Germany
required to qualify for reimbursement at ≥40 alloHCT per year. This decision was largely
based on a recent CIBMTR analysis by Majhail et al. reporting this threshold as outcome-
relevant for alloHCT in the US(8). As health systems, infrastructure, and treatment practices
may strongly differ between countries, the purpose of the present study was for the first
time to investigate the effects of center-related factors, such as numbers of alloHCT
procedures per year, program duration, university hospital, and Joint Accreditation
Committee IHCT-Europe & EBMT (JACIE) accreditation, adjusted for common disease- and
transplant-specific confounders on survival after alloHCT in Germany, using AML as a
standard indication. To address these questions, we took advantage of the German Registry
for Hematopoietic Stem Cell Transplantation and Cell Therapy (DRST), the German national
partner of the EBMT.
6
Methods
Data source
The DRST is a registered association that maintains the German Registry for Hematopoietic
Stem Cell Transplantation and Cell Therapy. The DRST performs data collection of
hematopoietic cell transplantations (HCT) and cellular therapies in Germany in cooperation
with the European Society for Blood and Marrow Transplantation (EBMT) using the EBMT
database. Accreditation as a DRST center requires a signed tripartite Joint Controllership
Agreement with EBMT and DRST and the submission of core data from all consecutive HCT
and cellular therapy recipients to the EBMT Registry in which patients can be identified by
the diagnosis of underlying disease and type of HCT resp. cellular therapy. EBMT/DRST
registry data is routinely audited to determine accuracy of data collected as part of the JACIE
certification. Data collection requires written informed consent using a consent form based
on a standard DRST/EBMT template following the European data protection regulations and
the Declaration of Helsinki.
Study design
This study was performed by request of the DAG-HSZT (German Working Group for
Hematopoietic Stem Cell Transplantation and Cellular Therapy) and approved by the data
access commission of DRST.
The study was performed in accordance with the Declaration of Helsinki and approved by
the Ethical Committee of the University of Tuebingen (Ref. Nr. 277/2020BO2).
7
Eligible were adult (≥18 years) patients with AML at any disease status treated with a first
allogeneic HCT using a peripheral blood or bone marrow graft from a matched or
mismatched related (including haploidentical) or (9/10-10/10 HLA-compatible) unrelated
donor between 2015 and 2021 and registered with the DRST.
The objective of the study was to assess the impact of center-specific factors such as number
of transplant procedures/year, university hospital yes/no, JACIE accreditation yes/no, years
of center experience in alloHCT in the respective year of HCT on outcome of allogeneic HCT
within the German health care system.
Statistical analyses
Descriptive statistics were presented for patient-, transplant- and center-related variables
separately for patients transplanted in a center with less than 40 transplants per year (low
volume centers) and more than or equal to 40 transplants per year (high volume centers).
Absolute and relative numbers were reported for categorical variables and mean and
standard deviation for continuous variables. Allocation of the respective patients to either
center with <40 and ≥40 allogeneic transplantation procedures per year was performed
according to center volume in the respective year of HCT. Administrative censoring after 1
year follow-up post HCT was used for survival analysis in order to keep the dataset
homogeneous. In addition, identical analyses were done without administrative censoring.
OS, EFS (event defined as relapse, progression or death) and the competing risks of
relapse/progression and non-relapse/progression mortality (NRM) were assessed in both
univariable and multivariable analyses. In addition to center size (<40 vs. >=40), age, gender,
disease status at alloHCT, graft source, donor type, conditioning, Karnofsky index, HCT-
8
specific Comorbidity Index (HCT-CI), European Leukemia Network AML Risk (ELN), university
status, center experience and Joined Accreditation Committee of the IHCT and the EBMT
(JACIE) accreditation were considered. Cox proportional hazards models (likelihood ratio
test) were calculated for OS and EFS and Fine & Gray models for competing risks (univariable
and multivariable respectively). The Kaplan-Meier method and the logrank-test was used for
univariable OS and EFS analysis of the impact of center size and the Aalen-Johansen
estimator and the Gray-test for competing risk analysis. For multivariable analysis, best
subset selection
with Akaike information criterion (AIC) was calculated to determine the
optimal set of variables. For sensitivity analysis, center size cut-points were set at each
possible value, and both univariable and multivariable analyses were calculated for all
endpoints using these cut-points. Hazard ratios were observed. An additional sensitivity
analysis considered center size as a continuous variable. As the relationship between center
size and the observed outcomes is non-linear, it is not possible to include center size as a
standard continuous variable in the multivariable model due to the assumption of linearity.
Spline modelling via p-splines was used to account for this non-linear modelling (9).
Results
Patient characteristics
A total of 5328 consecutive patients treated in 52 German centers performing alloHCT and
reporting to the DRST during the index period were included (Table 1). Median age was 58
years (range 18-83). 56% of patients were male. 52% of patients were documented in first
CR, and 45% had a more advanced disease status at HCT. In 95% of the patients, peripheral
blood stem cells were used as graft source, and bone marrow in the remainder. 1549 (20%)
9
patients were transplanted from an HLA-matched related (MRD), and 2595 (49%) from a
matched (10/10 HLA match) unrelated donor (MUD). Each 592 (11%) patients were
transplanted from a mismatched related donor (MMRD) i.e. haploidentical, and a
mismatched (9/10 HLA-match) unrelated donor (MMUD), respectively. Donor source was
balanced between high volume (>=40 HCT/year) and low volume (<40 HCT/year) centers
apart from a slightly higher number of MRD among the low volume centers. Low volume
centers had more patients with favorable performance status and HCT-CI (with HCT-CI score
often missing), respectively, and used myeloablative conditioning (MAC) more frequently.
High volume centers more often had >10 years center experience, were university hospitals,
and were JACIE accredited.
Outcome
Kaplan-Meier-estimated OS and EFS rates at 12 months were 65.8% (95% confidence interval
(95%CI)
[
62.7%; 69.1%]) for patients transplanted in a center with <40 HCT/year and 71.1%
[69.7%; 72.5%] in a center with ≥ 40 HCT/year (p (logrank) = 0.0004) and 57.5% [54.1%;
61.0%] and 61.5% [60.0%; 63.1%] (p=0.0112), respectively (Figure 1). Cumulative incidence
of the competing risks of relapse/progression and NRM estimated at 12 months were 24.2%
[21.3%; 27.2%] in centers with <40 HCT/year and 22.9% [21.6%; 24.3%] in centers with ≥40
HCT/year (p (Gray-test) =0.569) and 18.4% [15.8%; 21.1%] and 15.5% [14.4%; 16.7%] (p =
0.047), respectively (Figure 2).
On univariable analysis, center-specific predictors of an adverse OS (Table 2) were center
size measured in number of HCT in the year of HCT <40 vs. ≥40 (HR, 95% CI: 1.26 [1.11; 1.43],
p=<0.001), University Hospital no vs. yes (1.30 [1.11; 1.53], p=0.001), center experience 5-10
10
years and <5 years vs. ≥10 years (1.26 [1.06; 1.50], p=0.010 and 1.22 [0.87; 1.72]), whereas
JACIE accreditation had no significant effect (1.02 [0.91; 1.15], p=0.744). Patient- and
disease-specific factors were also analyzed in the univariable analysis and most of them
(except gender and conditioning) were statistically significant with effect sizes similar to
what have reported before (Tables 2-5). Likewise, on univariable analysis of predictors for
improved EFS (Table 3), the effects for center size HCT <40 vs. ≥40 (1.16 [1.04; 1.31],
p=0.011), University Hospital no vs. yes (1.20 [1.04; 1.38],
p=0.013), center experience 5-10
years and <5 years vs. ≥ 10 years (1.13 [0.96; 1.33], p=0.138 and 1.24 [0.93; 1.67], p=0.150),
and JACIE accreditation no vs. yes (1.02 [0.92; 1.13], p=0.714) were largely similar to OS
(Table 2). The same accounts for NRM, whereas significant effects of the 4 structural
parameters could not be proven for the endpoint relapse/progression (
Tables 4 and 5
).
On multivariable analysis, relevant center-specific predictors for improved OS were number
of HCT/year in year of HCT <40 vs. ≥40 (1.21 [1.02; 1.45], p=0.032), University Hospital no vs.
yes (1.21 [0.98; 1.49], p=0.071), and center experience 5-10 years and <5 years vs. ≥10 years
(1.234 [1.020; 1.494], p=0.031 and 1.063 [0.737; 1.532], 0.743), but not JACIE accreditation,
which did not remain in the model after best subset selection. Patient- and disease-specific
factors all remained in the model as relevant covariates, with effects similar to those in the
univariable analysis. Identical analyses without administrative censoring after 1 year follow-
up post HCT for survival analysis yielded essentially similar results (supplemental tables 1-4).
When the model determined for OS was calculated for the endpoints EFS and the competing
events relapse/progression and NRM, the effects of center-specific factors were less strong
compared to OS: center size HCT <40 vs. ≥40 (EFS: 1.12 [0.96; 1.31], p=0.164 /
11
Relapse/Progression: 1.05 [0.85; 1.28], p=0.668 / NRM: 1.23 [0.98; 1.56], p=0.080);
University Hospital no vs. yes (1.13 [0.93; 1.36], p=0.218 / 0.96 [0.76; 1.23], p=0.764 / 1.26
[0.95; 1.66], p=0.109) and center experience 5-10 years and <5 vs. ≥10 years (1.12 [0.94;
1.34], p=0.188 and 1.10 [0.80; 1.51], p=0.564 / 1.23 [1.00; 1.53], p=0.054 and 0.92 [0.60;
1.41], p=0.701 / 0.92 [0.70; 1.21], p=0.548 and 1.23 [0.80; 1.90], p=0.338 ).The impact of
patient- and disease-specific factors is shown in the Appendix (Tables S2-S4).
Modeling of center size effect
In order to assess whether the predefined cut-off level of 40 HCT/center/year was not just
by chance significant, we performed serial analyses of multivariable Cox regression and
calculated adjusted hazard ratios and 95%CIs for all cut-off points and plotted them. With
this method, HRs including CIs were below 1 for all cut-off points between 30 and 70
HCTs/year, whereas all other cut-offpoints had no significant discriminative impact (Figure
3A).
To further define the ideal cut-off point of center size (which is a non-linear variable), spline
modelling was performed (Figure 3B). HR and 95% CI for corresponding number of HCT/year
in comparison to all other HCT numbers in multivariable analysis were plotted. For OS, 45
HCT procedures/year and for EFS, 48 HCT procedures/year were identified as the minimum
center size without significantly higher hazards compared to other center sizes.
Discussion
Patient-, disease-, and procedure-specific factors influencing outcomes of allogeneic HCT
have been extensively studied and reported. Factors such as age, comorbidities, disease risk,
12
donor and conditioning have been shown to significantly influence outcome, similar to what
was observed in our cohort(9-12). In contrast, there is a paucity of studies examining the
impact of transplant center characteristics, such as center experience, volume of allogeneic
HCT performed, university hospital, and the existence of a certified quality management
system on HCT outcome. The few analyses available are restricted to individual health care
systems and are often based on relatively old data sets(7, 13-15). Most frequently, hospital
procedure specific volumes and service provider level have been proposed to have an
important impact(6, 14, 16). However, volume may also be just a surrogate marker for
experience, structural factors, and quality measures. Recent analyses in the US and Japan
have shown a significant impact of center volume and experience on HCT outcome(8, 17).
The data presented here analyze for the first time the influence of center volume in the
context of other center-specific factors on the outcome of allogeneic HCT in adult patients
within the German health care system using a large recent (2015-2021) data set. To allow a
homogeneous analysis while minimizing other confounding factors we decided to focus on
AML as the major indication for adult allogeneic HCT. Apart from excluding pediatric patients
and those receiving cord blood or <9/10 mismatched unrelated donor transplants, eligibility
was unrestricted in terms of age, performance status, comorbidity, ELN risk, disease status,
donor type, graft source, and transplant strategy in order to reflect the whole risk spectrum
associated with AML allotransplants in adults. Our study discloses differences in patient
selection according to the center size. Patients transplanted at high volume centers had
more often a reduced Karnofsky index and were more often transplanted from an unrelated
donor.
13
Similar to previous studies, our analysis confirmed a positive impact of center volume on
survival(9, 17-19). Giebel et al found in an EBMT study on 1413 patients with AML treated
with RIC alloHCT an adverse effect of an annual RIC transplant rate of 15 or less on PFS,
which was largely NRM-driven. Beyond 15 transplants per year they didn’t observe
significant outcome effects of increasing numbers, but there were only few patients who
had been transplanted in centers performing more than 50 patients per year(18). Similarly, a
recent large Japanese study reported reduced survival (HR 1.31 [1.2; 1.44] associated with
an annual transplant rate of 9.3 or less after alloHCT for AML, and also a second cut-off point
at of 32/year disclosed a significant OS disadvantage (HR 1.11 [1.03; 1.2] for the
intermediate volume group (9.1-32 allotransplants per year) compared to the centers with
higher annual volumes (17). In contrast to the present study, but also to the Giebel study,
the center effect was largely driven by relapse rather than NRM in the Japanese series.
Of note, with an HR of 1.12 [0.96; 1.31] on multivariable analysis the center effect was
smaller for EFS than for OS in our sample, suggesting that the observed survival benefit
associated with high volume centers was partly due to superior outcome
after
post-
transplant failure.
A unique added value of our study is that we were able to identify for the first time a
minimum ideal cut-off point for the center effect. Although on multivariable Cox modeling
each individual cut-off point between 30 and 70 alloHCT per year showed a survival
advantage in the centers above the cut-off point compared to those below, spline modeling
suggested a significant negative effect of each center volume below 45 allotransplants per
year compared to all other center sizes. Center volumes of 45 or higher do not compare
14
significantly worse to all other center sizes, implying that a significant OS benefit of further
increasing the cut-off point does not become apparent beyond 45 allotransplants per year.
These findings are in keeping with a recent CIBMTR analysis by Majhail et al. where center
transplantation volumes >40 alloHCT/year and presence of a survivorship program dedicated
to HCT recipients were associated with superior OS(8). However, as already discussed by
Majhail et al. one has to caution against using our threshold as singular benchmark for
qualifying individual centers for allogeneic HCT. The survival difference between the two
center volume categories was relatively small, and center volume is only one factor among
multiple structural parameters driving alloHCT outcome. Other center-specific factors
predicting favorable survival in our analysis were university hospital status and program
duration >5-10 years, the latter being in line with a previous analysis of the EBMT(5). The
same EBMT analysis reported an NRM-driven, modest effect of running an accredited QM
system on OS(5), a finding which could not be reproduced in the present analysis and also
not in the Majhail study
8
. However nearly 80% of the high-volume centers in our study were
also JACIE-accredited.
Using center volume as sole benchmark for quality of patient care also potentially ignores
the important aspect of center accessibility and proximity to allow close follow up for the
patient. The study of Majhail already highlighted the importance of a survivorship and
structured long-term follow up program. At least half of the treatment related mortality of
allogeneic HCT occurs beyond day 100 after HCT(19). A number of guidelines and
recommendations exist for a specific long-term follow up program after allogeneic HCT(20).
15
Unfortunately, we had no information on long-term follow-up program and structure within
our data set.
Being a retrospective registry report, our study has several limitations. There is certainly
heterogeneity in patient selection across various centers. Data quality and granularity suffers
from the retrospective nature of data collection. On the other hand, particular strengths of
this analysis consist in the large sample size, enabling informative risk factor analyses, and in
the comprehensive coverage of the German SOC HCT activity, with almost all qualified
centers contributing data. However, before being generalized, our data need to be validated
in other health systems and in other alloHCT indications. In this context it will be important
to explore if alloHCT experience has a disease-specific component which overrides the
general allotransplant expertise, as it has been reported for less common indications(21).
Taken together, this analysis suggests that in adult patients with AML, in the German health
care system the structural parameters center volume, center experience, and university
hospital status have a modest effect of almost similar size on survival after alloHCT. The
benefit of higher center volumes can be shown for each individual cut-off below 45
allotransplants per year. Validation of these findings in other allotransplant settings and
health systems is warranted. These findings support efforts to centralize highly specialized
therapeutic interventions such as alloHCT in experienced large volume, high-end care
centers. However, health care planning has to simultaneously ensure easy patient access to
alloHCT services also in less populated regions. This may be able by establishing
decentralized network structures including regional long-term follow-up hubs and modern
telemedicine approaches.
16
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19. Brown RA, Adkins D, Khoury H, et al. Long-term follow-up of high-risk allogeneic
peripheral-blood stem-cell transplant recipients: graft-versus-host disease and transplant-
related mortality. J Clin Oncol. 1999;17(3):806-812.
20. Bhatia S. Caring for the long-term survivor after allogeneic stem cell transplantation.
Hematology Am Soc Hematol Educ Program. 2014;2014(1):495-503.
21. Schetelig J, de Wreede LC, Andersen NS, et al. Centre characteristics and procedure-
related factors have an impact on outcomes of allogeneic transplantation for patients with
CLL: a retrospective analysis from the European Society for Blood and Marrow
Transplantation (EBMT). Br J Haematol. 2017;178(4):521-533.
18
Table 1: Patient characteristics
Variable Group
<40
HCT/year
N = 893
(16.8%)
≥40
HCT/year
N = 4435
(83.2%)
Variable Group
<40
HCT/year
N = 893
(16.8%)
≥40
HCT/year
N = 4435
(83.2%)
Variable Group
<40
HCT/year
N = 893
(16.8%)
≥40
HCT/year
N = 4435
(83.2%)
Age (mean
(sd)) 54.9
(13.07) 55.57
(13.02) Donor (N (%)) MRD 312
(34.9%) 1237
(27.9%) HCT-CI (N
(%)) 0-2 570
(63.8%) 2479
(55.9%)
Gender (N
(%)) male 507
(56.8%) 2460
(55.5%) MMRD
99
(11.1%) 493
(11.1%) 3-10
233
(26.1%) 1154
(26%)
female 386
(43.2%) 1969
(44.4%) MMUD
95
(10.6%) 497
(11.2%) missing
90
(10.1%) 802
(18.1%)
unknown - 6
(0.1%) MUD
387
(43.3%) 2208
(49.8%) ELN (N (%)) adverse 27
4
(30.7%) 1281
(28.9%)
Disease
status at Tx
(N (%)) CR 472
(52.9%) 2317
(52.2%)
Conditioning
(N (%)) MAC 645
(72.2%) 1980
(44.6%)
BPDCN
8
(0.9%) 22
(0.5%)
not 1. CR 400
(44.8%) 2020
(45.5%) non-
MAC 236
(26.4%) 2232
(50.3%) favorable
129
(14.4%) 690
(15.6%)
unknown 21
(2.4%) 98
(2.2%) unknown
12
(1.3%) 223
(5.0%) intermediate
269
(30.1%) 1489
(33.6%)
Graft (N (%)) PB 847
(94.8%) 4206
(94.8%)
Karnofsky
Index
(N (%)) 90/100 630
(70.5%) 2542
(57.3%)
unknown
213
(23.9%) 953
(21.5%)
BM 41
(4.6%) 215
(4.8%)
70/80 186
(20.8%) 1444
(32.6%)
Center
Experience
(N (%)) ≥ 10 years 592
(66.3%) 4206
(94.8%)
CB 1
(0.1%) 2
(0.0%) 10-60 24
(2.7%) 140
(3.2%) 5-10 years
228
(25.5%) 193
(4.4%)
unknown 4
(0.4%) 12
(0.3%) unknown
53
(5.9%) 309
(7.0%) < 5 years 73
(8.2%) 36
(0.8%)
University
Hospital (N
(%)) yes 458
(51.3%) 4338
(97.8%)
JACIE (N (%))
yes 369
(41.3%) 3517
(79.3%)
no
435
(48.7%) 97
(2.2%) no 52
4
(58.7%) 918
(20.7%)
Legend:
HCT-CI: Hematopoietic Cell Transplantation-Comorbidity Index, ELN: European
Leukemia Network Classification, CR: Complete Remission; PB: Peripheral Blood; BM: Bone
Marrow; CB: Cord Blood; MRD: Matched Related Donor; MMRD: Mismatched Related
Donor; MUD: Matched Unrelated Donor; MMUD: Mismatched Unrelated Donor; MAC:
Myeloablative Conditioning; HCT/Tx: Hematopoietic Cell Transplantation; JACIE: Joint
Accreditation Committee IHCT-Europe & EBMT
19
Table 2: Risk factor analysis overall survival
Variable Reference Exposure univariable analysis
(HR [95%-CI], p-value) multivariable analysis
(HR [95%-CI], p-v alu e)
Center Size (HCT/year) ≥ 40 < 40 1.260 [1.108 ; 1.434], <0.001 1.212 [1.016; 1.445], 0.032
University Hospital yes no 1.303 [1.112; 1.527], 0.001 1.210 [0.984; 1.488], 0.071
Center Experience ≥ 10 years 5-10 years 1.260 [1.057; 1.503], 0.010 1.234 [1.020; 1.494], 0.031
< 5 years 1.223 [0.870; 1.719], 0.247 1.063 [0.737; 1.532], 0.743
JACIE yes no 1.020 [0.907; 1.146], 0.744
Age continuous - 1.028 [1.023; 1.033], <0.001 1.024 [1.019; 1.029], <0.001
Gender m f 0.929 [0.837; 1.031], 0.164 1.024 [0.919; 1.141], 0.667
Karnofsky Index 90/100 70/80 1.569 [1.402; 1.754], <0.001 1.368 [1.214; 1.541], <0.001
10-60 2.388 [1.880; 3.034], <0.001 1.827 [1.428; 2.337], <0.001
unknown 1.729 [1.435; 2.084], <0.001 1.516 [1.222; 1.881], <0.001
HCT-CI 0-2 3-10 1.407 [1.250; 1.584], <0.001 1.201 [1.061; 1.359], 0.004
unknown 1.484 [1.295; 1.700], <0.001 1.380 [1.186; 1.606], <0.001
ELN adverse BPDCN 0.916 [0.474; 1.770], 0.794 1.025 [0.527; 1.992], 0.942
favorable 0.538 [0.451; 0.642], <0.001 0.549 [0.457; 0.659], <0.001
intermediate 0.715 [0.630; 0.811], <0.001 0.786 [0.689; 0.895], <0.001
unknown 0.768 [0.667; 0.883], <0.001 0.710 [0.611; 0.826], <0.001
Conditioning MAC non-MAC 1.085 [0.977; 1.205], 0.128 0.930 [0.829; 1.043], 0.212
Disease status at Tx 1. CR not 1. CR 2.149 [1.930; 2.392], <0.001 1.985 [1.775; 2.219], <0.001
Graft PB BM 1.368 [1.106; 1.694], 0.004 1.203 [0.943; 1.533], 0.136
Donor MRD MMRD 1.501 [1.26 5; 1.782], <0.001 1.305 [ 1.08 0; 1.577], 0.006
MMUD 1.567 [1.325; 1.854], <0.001 1.405 [1.178; 1.675], <0.001
MUD 1.053 [0.927; 1.196], 0.424 0.974 [0.852; 1.114], 0.705
Legend:
HCT-CI: Hematopoietic Cell Transplantation-Comorbidity Index, ELN: European
Leukemia Network Classification, CR: Complete Remission; PB: Peripheral Blood; BM: Bone
Marrow; CB: Cord Blood; MRD: Matched Related Donor; MMRD: Mismatched Related
Donor; MUD: Matched Unrelated Donor; MMUD: Mismatched Unrelated Donor; MAC:
Myeloablative Conditioning; HCT/Tx: Hematopoietic Cell Transplantation; JACIE: Joint
Accreditation Committee IHCT-Europe & EBMT; BPDCN: blastic plasmacytoid dendritic cell
neoplasm
20
Table 3: Risk factor analysis event free survival
Variable Reference Exposure univariable analysis
(HR [95%-CI], p-value) multivariable analysis
(HR [95%-CI], p-v alu e)
Center Size (HCT/year) ≥ 40 < 40 1.162 [ 1.0 35; 1.306], 0.011
1.119 [0.955; 1.310], 0.164
University Hospital yes no 1.200 [1.040; 1.384], 0.013
1.125 [0.933; 1.356], 0.218
Center Experience ≥ 10 years 5-10 years 1.130 [0.962; 1.329], 0.138
1.124 [0.944; 1.339], 0.188
< 5 years 1.243 [0.925; 1.671], 0.150
1.097 [0.800; 1.506], 0.564
JACIE yes no 1.019 [0.920; 1.129], 0.714
Age continuous - 1.012 [1.008; 1.016], <0.001
1.009 [1.005; 1.013], <0.001
Gender m f 0.936 [0.855; 1.026], 0.158
0.978 [0.890; 1.076], 0.650
Karnofsky Index 90/100 70/80 1.304 [1.181; 1.440], <0.001
1.205 [1.085; 1.338], 0.001
10-60 1.840 [1.469; 2.304], <0.001
1.499 [1.189; 1.890], 0.001
unknown 1.519 [1.282; 1.801], <0.001
1.435 [1.185; 1.738], <0.001
HCT-CI 0-2 3-10 1.168 [1.051; 1.299], 0.004
1.049 [0.939; 1.172], 0.394
unknown 1.313 [1.163; 1.481], <0.001
1.274 [1.115; 1.455], <0.001
ELN adverse BPDCN 0.760 [0.407; 1.420], 0.39 0
0.858 [0.458; 1.609], 0.634
favorable 0.575 [0.494; 0.670], <0.001
0.564 [0.481; 0.660], <0.001
intermediate 0.777 [0.696; 0.86 7], <0.001
0.826 [0.737; 0.926], 0.001
unknown 0.757 [0.667; 0.858], <0.001
0.700 [0.612; 0.800], <0.001
Conditioning MAC non-MAC 1.040 [0.948; 1.140], 0.40 7
0.972 [0.879; 1.075], 0.580
Disease status at Tx 1. CR not 1. CR 1.879 [1.714; 2.061], <0.001
1.830 [1.662; 2.015], <0.001
Graft PB BM 1.483 [1.232; 1.785], <0.001
1.378 [1.119; 1.696], 0.003
Donor MRD MMRD 1.214 [1.040; 1.419], 0.01 4
1.056 [0.890; 1.251], 0.533
MMUD 1.360 [1.172; 1.579], <0.001
1.260 [1.078; 1.473], 0.004
MUD 0.989 [0.887; 1.103], 0.84 9
0.972 [0.867; 1.090], 0.628
Legend:
HCT-CI: Hematopoietic Cell Transplantation-Comorbidity Index, ELN: European
Leukemia Network Classification, CR: Complete Remission; PB: Peripheral Blood; BM: Bone
Marrow; CB: Cord Blood; MRD: Matched Related Donor; MMRD: Mismatched Related
Donor; MUD: Matched Unrelated Donor; MMUD: Mismatched Unrelated Donor; MAC:
Myeloablative Conditioning; HCT/Tx: Hematopoietic Cell Transplantation; JACIE: Joint
Accreditation Committee IHCT-Europe & EBMT; BPDCN: blastic plasmacytoid dendritic cell
neoplasm
21
Table 4: Risk factor analysis non-relapse mortality
Variable Reference Exposure univariable analysis
(HR [95%-CI], p-value) multivariable analysis
(HR [95%-CI], p-v alu e)
Center Size (HCT/year) ≥ 40 < 40 1.218 [ 1.0 22; 1.451], 0.028
1.232 [0.975; 1.556], 0.080
University Hospital yes no 1.311 [1.061; 1.620], 0.012
1.255 [0.951; 1.656], 0.109
Center Experience ≥ 10 years 5-10 years 0.992 [0.765; 1.287], 0.953
0.918 [0.695; 1.213], 0.548
< 5 years 1.392 [0.905; 2.140], 0.132
1.234 [0.803; 1.896], 0.338
JACIE yes no 1.045 [0.894; 1.222], 0.581
Age continuous - 1.038 [1.031; 1.046], <0.001
1.033 [1.025; 1.041], <0.001
Gender m f 0.998 [0.868; 1.148], 0.977
1.074 [0.930; 1.240], 0.328
Karnofsky Index 90/100 70/80 1.622 [1.396; 1.885], <0.001
1.375 [1.174; 1.611], <0.001
10-60 2.661 [1.974; 3.586], <0.001
2.083 [1.536; 2.825], <0.001
unknown 1.493 [1.136; 1.960], 0.004
1.440 [1.067; 1.943], 0.017
HCT-CI 0-2 3-10 1.607 [1.374; 1.880], <0.001
1.346 [1.143; 1.584], <0.001
unknown 1.432 [1.187; 1.727], <0.001
1.377 [1.122; 1.690], 0.002
ELN adverse BPDCN 1.000 [0.426; 2.348], 1.00 0
1.162 [0.509; 2.653], 0.722
favorable 0.650 [0.513; 0.824], <0.001
0.676 [0.530; 0.863], 0.002
intermediate 0.874 [0.738; 1.037], 0.122
0.987 [0.830; 1.174], 0.886
unknown 0.875 [0.722; 1.061], 0.174
0.870 [0.707; 1.070], 0.186
Conditioning MAC non-MAC 1.206 [1.047; 1.388], 0.00 9
0.981 [0.840; 1.146], 0.808
Disease status at Tx 1. CR not 1. CR 1.935 [1.676; 2.234], <0.001
1.719 [1.482; 1.994], <0.001
Graft PB BM 1.124 [0.827; 1.527], 0.455
0.978 [0.700; 1.365], 0.894
Donor MRD MMRD 1.559 [1.23 7 ; 1.964], <0.001
1.461 [1.136; 1.880], 0.003
MMUD 1.678 [1.341; 2.098], <0.001
1.481 [1.174; 1.868], 0.001
MUD 1.108 [0.930; 1.319], 0.25 1
0.978 [0.814; 1.174], 0.810
Legend:
HCT-CI: Hematopoietic Cell Transplantation-Comorbidity Index, ELN: European
Leukemia Network Classification, CR: Complete Remission; PB: Peripheral Blood; BM: Bone
Marrow; CB: Cord Blood; MRD: Matched Related Donor; MMRD: Mismatched Related
Donor; MUD: Matched Unrelated Donor; MMUD: Mismatched Unrelated Donor; MAC:
Myeloablative Conditioning; HCT/Tx: Hematopoietic Cell Transplantation; JACIE: Joint
Accreditation Committee IHCT-Europe & EBMT; BPDCN: blastic plasmacytoid dendritic cell
neoplasm
22
Table 5: Statistical Analysis Relapse/Progression
Variable Reference Exposure univariable analysis
(HR [95%-CI], p-value) multivariable analysis
(HR [95%-CI], p-v alu e)
Center Size (HCT/year) ≥ 40 < 40 1.078 [ 0.9 27; 1.255], 0.328
1.045 [0.854; 1.280], 0.668
University Hospital yes no 1.055 [0.873; 1.275], 0.580
0.963 [0.755; 1.229], 0.764
Center Experience ≥ 10 years 5-10 years 1.207 [0.988; 1.474], 0.066
1.234 [0.997; 1.529], 0.054
< 5 years 1.075 [0.732; 1.578], 0.713
0.920 [0.600; 1.410], 0.701
JACIE yes no 0.991 [0.869; 1.131], 0.899
Age continuous - 0.994 [0.990; 0.998], 0.007
0.993 [0.988; 0.998], 0.003
Gender m f 0.904 [0.804; 1.016], 0.090
0.920 [0.814; 1.040], 0.182
Karnofsky Index 90/100 70/80 1.030 [0.904; 1.173], 0.660
1.012 [0.882; 1.162], 0.862
10-60 1.099 [0.796; 1.516], 0.567
0.960 [0.690; 1.334], 0.807
unknown 1.385 [1.122; 1.710], 0.002
1.237 [0.972; 1.573], 0.084
HCT-CI 0-2 3-10 0.867 [0.751; 0.999], 0.049
0.845 [0.728; 0.982], 0.028
unknown 1.167 [1.001; 1.360], 0.049
1.151 [0.973; 1.363], 0.101
ELN adverse BPDCN 0.645 [0.260; 1.603], 0.346
0.700 [0.284; 1.729], 0.440
favorable 0.588 [0.485; 0.715], <0.001
0.557 [0.455; 0.682], <0.001
intermediate 0.754 [0.655; 0.86 7], <0.001
0.766 [0.662; 0.886], <0.001
unknown 0.723 [0.616; 0.849], <0.001
0.662 [0.557; 0.786], <0.001
Conditioning MAC non-MAC 0.925 [0.822; 1.042], 0.19 9
0.985 [0.868; 1.117], 0.809
Disease status at Tx 1. CR not 1. CR 1.576 [1.402; 1.772], <0.001
1.634 [1.446; 1.847], <0.001
Graft PB BM 1.640 [1.312; 2.051], <0.001
1.630 [1.264; 2.100], <0.001
Donor MRD MMRD 0.958 [0.780; 1.177], 0.68 1
0.804 [0.641; 1.009], 0.060
MMUD 1.082 [0.890; 1.315], 0.430
1.065 [0.866; 1.308], 0.551
MUD 0.921 [0.803; 1.055], 0.23 5
0.979 [0.848; 1.131], 0.776
Legend:
HCT-CI: Hematopoietic Cell Transplantation-Comorbidity Index, ELN: European
Leukemia Network Classification, CR: Complete Remission; PB: Peripheral Blood; BM: Bone
Marrow; CB: Cord Blood; MRD: Matched Related Donor; MMRD: Mismatched Related
Donor; MUD: Matched Unrelated Donor; MMUD: Mismatched Unrelated Donor; MAC:
Myeloablative Conditioning; HCT/Tx: Hematopoietic Cell Transplantation; JACIE: Joint
Accreditation Committee IHCT-Europe & EBMT; BPDCN: blastic plasmacytoid dendritic cell
neoplasm
23
Figure Legends:
Figure 1: Kaplan-Meier Plots of Survival
A: Overall Survival
B: Event Free Survival
Figure 2: Cumulative Incidence Non-Relapse Mortality and Relapse
Figure 3: Multivariable analysis of HR + 95%-CI for all cutpoints.
(A) Center size as non-linear variable
(B) Evaluation by Spline Modelling. HR (95% CI) for corresponding number of HCT/year in
comparison to all other HCT-numbers in multivariate analysis
Page 1 of 4
Supplemental Tables
Does size matter? Center-specific characteristics and survival after allogeneic
hematopoietic cell transplantation for acute myeloid leukemia: An analysis of
the German Registry for Stem Cell Transplantation and Cell Therapy
Variable
Reference
Exposure
univariable analysis
(HR [95%-CI], p-value)
multivariable analysis
(HR [95%-CI], p-value)
Center Size (HCT/year)
≥ 40
< 40
1.178 [1.057; 1.312], 0.003
1.193 [1.026; 1.389], 0.022
University Hospital
yes
no
1.171 [1.023; 1.340], 0.022
1.113 [0.930; 1.331], 0.244
Center Experience
≥ 10 years
5-10 years
1.144 [0.987; 1.325], 0.075
1.087 [0.925; 1.277], 0.310
< 5 years
1.121 [0.842; 1.493], 0.434
1.042 [0.767; 1.416], 0.793
JACIE
yes
no
1.013 [0.919; 1.117], 0.797
Age
continuous
-
1.020 [1.016; 1.023], <0.001
1.015 [1.012; 1.019], <0.001
Gender
m
f
0.872 [0.801; 0.950], 0.002
0.939 [0.859; 1.027], 0.171
Karnofsky Index
90/100
70/80
1.461 [1.332; 1.602], <0.001
1.335 [1.210; 1.473], <0.001
10-60
2.166 [1.757; 2.671], <0.001
1.795 [1.446; 2.227], <0.001
unknown
1.551 [1.328; 1.812], <0.001
1.421 [1.189; 1.698], <0.001
HCT-CI
0-2
3-10
1.344 [1.218; 1.483], <0.001
1.182 [1.066; 1.310], 0.001
unknown
1.454 [1.302; 1.624], <0.001
1.390 [1.230; 1.572], <0.001
ELN
adverse
BPDCN
0.874 [0.505; 1.513], 0.632
0.929 [0.523; 1.650], 0.801
favorable
0.530 [0.459; 0.612], <0.001
0.535 [0.461; 0.621], <0.001
intermediate
0.692 [0.623; 0.769], <0.001
0.757 [0.679; 0.844], <0.001
unknown
0.766 [0.684; 0.858], <0.001
0.716 [0.634; 0.809], <0.001
Conditioning
MAC
non-MAC
1.139 [1.045; 1.241], 0.003
1.005 [0.913; 1.105], 0.926
Disease status at Tx
1. CR
not 1. CR
1.822 [1.671; 1.986], <0.001
1.702 [1.556; 1.863], <0.001
Graft
PB
BM
1.285 [1.072; 1.541], 0.007
1.167 [0.950; 1.433], 0.141
Donor
MRD
MMRD
1.257 [1.087; 1.454], 0.002
1.130 [0.962; 1.327], 0.137
MMUD
1.374 [1.196; 1.580], <0.001
1.287 [1.113; 1.489], 0.001
MUD
0.991 [0.895; 1.097], 0.855
0.945 [0.848; 1.052], 0.300
Legend: HCT-CI: Hematopoietic Cell Transplantation-Comorbidity Index, ELN: European Leukemia
Network Classification, CR: Complete Remission; PB: Peripheral Blood; BM: Bone Marrow; CB: Cord
Blood; MRD: Matched Related Donor; MMRD: Mismatched Related Donor; MUD: Matched Unrelated
Donor; MMUD: Mismatched Unrelated Donor; MAC: Myeloablative Conditioning; HCT/Tx:
Hematopoietic Cell Transplantation; JACIE: Joint Accreditation Committee IHCT-Europe & EBMT;
BPDCN: blastic plasmacytoid dendritic cell neoplasm
Supplemental Table 1: Overall survival without 1 year cut off follow-up
Page 2 of 4
Variable
Reference
Exposure
univariable analysis
(HR [95%-CI], p-value)
multivariable analysis
(HR [95%-CI], p-value)
Center Size (HCT/year)
≥ 40
< 40
1.116 [1.006; 1.238], 0.038
1.089 [0.943; 1.258], 0.242
University Hospital
yes
no
1.142 [1.005; 1.298], 0.042
1.121 [0.946; 1.328], 0.188
Center Experience
≥ 10 years
5-10 years
1.104 [0.959; 1.271], 0.170
1.076 [0.923; 1.255], 0.350
< 5 years
1.018 [0.767; 1.351], 0.901
0.937 [0.695; 1.264], 0.670
JACIE
yes
no
1.000 [0.913; 1.096], 0.999
Age
continuous
-
1.011 [1.008; 1.015], <0.001
1.009 [1.005; 1.012], <0.001
Gender
m
f
0.908 [0.838; 0.984], 0.018
0.946 [0.870; 1.028], 0.190
Karnofsky Index
90/100
70/80
1.273 [1.166; 1.390], <0.001
1.197 [1.091; 1.313], <0.001
10-60
1.753 [1.427; 2.155], <0.001
1.486 [1.203; 1.837], <0.001
unknown
1.425 [1.225; 1.657], <0.001
1.385 [1.169; 1.641], <0.001
HCT-CI
0-2
3-10
1.158 [1.054; 1.271], 0.002
1.048 [0.950; 1.155], 0.350
unknown
1.307 [1.176; 1.453], <0.001
1.298 [1.156; 1.458], <0.001
ELN
adverse
BPDCN
0.795 [0.469; 1.349], 0.395
0.825 [0.475; 1.432], 0.493
favorable
0.580 [0.508; 0.662], <0.001
0.573 [0.499; 0.657], <0.001
intermediate
0.744 [0.674; 0.821], <0.001
0.789 [0.712; 0.874], <0.001
unknown
0.769 [0.690; 0.858], <0.001
0.721 [0.641; 0.809], <0.001
Conditioning
MAC
non-MAC
1.071 [0.988; 1.162], 0.095
0.991 [0.906; 1.083], 0.836
Disease status at Tx
1. CR
not 1. CR
1.692 [1.562; 1.834], <0.001
1.643 [1.511; 1.787], <0.001
Graft
PB
BM
1.307 [1.099; 1.554], 0.002
1.222 [1.008; 1.483], 0.042
Donor
MRD
MMRD
1.131 [0.984; 1.300], 0.084
1.021 [0.877; 1.189], 0.789
MMUD
1.242 [1.087; 1.420], 0.001
1.167 [1.014; 1.342], 0.031
MUD
0.983 [0.894; 1.080], 0.720
0.966 [0.875; 1.068], 0.500
Legend: HCT-CI: Hematopoietic Cell Transplantation-Comorbidity Index, ELN: European Leukemia
Network Classification, CR: Complete Remission; PB: Peripheral Blood; BM: Bone Marrow; CB: Cord
Blood; MRD: Matched Related Donor; MMRD: Mismatched Related Donor; MUD: Matched Unrelated
Donor; MMUD: Mismatched Unrelated Donor; MAC: Myeloablative Conditioning; HCT/Tx:
Hematopoietic Cell Transplantation; JACIE: Joint Accreditation Committee IHCT-Europe & EBMT;
BPDCN: blastic plasmacytoid dendritic cell neoplasm
Supplemental Table 2: Event free survival without 1 year cut off follow-up
Page 3 of 4
Variable
Reference
Exposure
univariable analysis
(HR [95%-CI], p-value)
multivariable analysis
(HR [95%-CI], p-value)
Center Size (HCT/year)
≥ 40
< 40
1.034[0.907; 1.178], 0.615
0.994 [0.830; 1.190], 0.947
University Hospital
yes
no
1.036 [0.881; 1.217], 0.671
1.000 [0.808; 1.238], 0.998
Center Experience
≥ 10 years
5-10 years
1.189 [1.004; 1.407], 0.045
1.186 [0.987; 1.425], 0.068
< 5 years
0.921 [0.641; 1.324], 0.658
0.796 [0.538; 1.180], 0.256
JACIE
yes
no
0.978 [0.873; 1.095], 0.697
Age
continuous
-
0.994 [0.990; 0.997], 0.001
0.993 [0.989; 0.997], 0.001
Gender
m
f
0.914 [0.827; 1.009], 0.074
0.926 [0.835; 1.027], 0.144
Karnofsky Index
90/100
70/80
0.988 [0.884; 1.104], 0.833
0.993 [0.883; 1.116], 0.904
10-60
0.967 [0.723; 1.294], 0.823
0.891 [0.661; 1.200], 0.446
unknown
1.338 [1.119; 1.599], 0.001
1.248 [1.024; 1.522], 0.028
HCT-CI
0-2
3-10
0.831 [0.735; 0.939], 0.003
0.820 [0.721; 0.933], 0.003
unknown
1.178 [1.037; 1.338], 0.012
1.174 [1.022; 1.350], 0.024
ELN
adverse
BPDCN
0.656 [0.312; 1.382], 0.268
0.614 [0.271; 1.393], 0.243
favorable
0.610 [0.518; 0.719], <0.001
0.586 [0.494; 0.696], <0.001
intermediate
0.739 [0.654; 0.834], <0.001
0.745 [0.657; 0.846], <0.001
unknown
0.776 [0.680; 0.886], <0.001
0.718 [0.624; 0.827], <0.001
Conditioning
MAC
non-MAC
0.945 [0.855; 1.045], 0.269
0.997 [0.895; 1.111], 0.959
Disease status at Tx
1. CR
not 1. CR
1.402 [1.270; 1.548], <0.001
1.448 [1.306; 1.606], <0.001
Graft
PB
BM
1.444 [1.176; 1.773], <0.001
1.449 [1.148; 1.829], 0.002
Donor
MRD
MMRD
0.910 [0.763; 1.087], 0.299
0.800 [0.659; 0.972], 0.025
MMUD
0.944 [0.793; 1.123], 0.515
0.924 [0.768; 1.112], 0.403
MUD
0.931 [0.831; 1.044], 0.222
0.987 [0.875; 1.113], 0.830
Legend: HCT-CI: Hematopoietic Cell Transplantation-Comorbidity Index, ELN: European Leukemia
Network Classification, CR: Complete Remission; PB: Peripheral Blood; BM: Bone Marrow; CB: Cord
Blood; MRD: Matched Related Donor; MMRD: Mismatched Related Donor; MUD: Matched Unrelated
Donor; MMUD: Mismatched Unrelated Donor; MAC: Myeloablative Conditioning; HCT/Tx:
Hematopoietic Cell Transplantation; JACIE: Joint Accreditation Committee IHCT-Europe & EBMT;
BPDCN: blastic plasmacytoid dendritic cell neoplasm
Supplemental Table 3: Relapse/Progression without 1 year cut off follow-up
Page 4 of 4
Variable
Reference
Exposure
univariable analysis
(HR [95%-CI], p-value)
multivariable analysis
(HR [95%-CI], p-value)
Center Size (HCT/year)
≥ 40
< 40
1.172[1.001; 1.374],0.049
1.229 [0.995; 1.517], 0.056
University Hospital
yes
no
1.202 [0.989; 1.462], 0.065
1.179 [0.914; 1.521], 0.204
Center Experience
≥ 10 years
5-10 years
0.973 [0.773; 1.225], 0.815
0.896 [0.699; 1.148], 0.386
< 5 years
1.109 [0.717; 1.715], 0.643
1.066 [0.692; 1.640], 0.772
JACIE
yes
no
0.992 [0.861; 1.143], 0.912
Age
continuous
-
1.037 [1.031; 1.044], <0.001
1.031 [1.025; 1.038], <0.001
Gender
m
f
0.927 [0.818; 1.051], 0.237
0.997 [0.877; 1.134], 0.963
Karnofsky Index
90/100
70/80
1.571 [1.375; 1.795], <0.001
1.358 [1.181; 1.562], <0.001
10-60
2.537 [1.940; 3.316], <0.001
2.056 [1.556; 2.717], <0.001
unknown
1.306 [1.015; 1.680], 0.038
1.282 [0.971; 1.692], 0.080
HCT-CI
0-2
3-10
1.658 [1.444; 1.904], <0.001
1.399 [1.211; 1.616], <0.001
unknown
1.392 [1.176; 1.647], <0.001
1.349 [1.124; 1.619], 0.001
ELN
adverse
BPDCN
1.152 [0.568; 2.336], 0.695
1.294 [0.649; 2.583], 0.464
favorable
0.692 [0.563; 0.852], 0.001
0.715 [0.577; 0.885], 0.002
intermediate
0.863 [0.740; 1.007], 0.061
0.966 [0.826; 1.130], 0.666
unknown
0.913 [0.771; 1.080], 0.289
0.919 [0.769; 1.099], 0.357
Conditioning
MAC
non-MAC
1.262 [1.113; 1.431], <0.001
1.026 [0.893; 1.178], 0.718
Disease status at Tx
1. CR
not 1. CR
1.679 [1.480; 1.904], <0.001
1.487 [1.306; 1.694], <0.001
Graft
PB
BM
0.961 [0.715; 1.291], 0.790
0.845 [0.610; 1.169], 0.309
Donor
MRD
MMRD
1.395 [1.129; 1.723], 0.002
1.371 [1.090; 1.725], 0.007
MMUD
1.595 [1.308; 1.945], <0.001
1.447 [1.179; 1.777], <0.001
MUD
1.080 [0.926; 1.258], 0.326
0.954 [0.813; 1.120], 0.563
Legend: HCT-CI: Hematopoietic Cell Transplantation-Comorbidity Index, ELN: European Leukemia
Network Classification, CR: Complete Remission; PB: Peripheral Blood; BM: Bone Marrow; CB: Cord
Blood; MRD: Matched Related Donor; MMRD: Mismatched Related Donor; MUD: Matched Unrelated
Donor; MMUD: Mismatched Unrelated Donor; MAC: Myeloablative Conditioning; HCT/Tx:
Hematopoietic Cell Transplantation; JACIE: Joint Accreditation Committee IHCT-Europe & EBMT;
BPDCN: blastic plasmacytoid dendritic cell neoplasm
Supplemental Table 4: Non-relapse mortality without 1 year cut off follow-up