Definition of endpoints and statistical analysis: The primary outcomes investigated were
relapse, non-relapse mortality (NRM) and disease-free survival (DFS). Hematological or
extramedullary relapse was defined as reappearance of leukemic cells either in the bone
marrow/peripheral blood or in an extramedullary site after the allograft. NRM was defined
as death related to transplantation and not to relapse. DFS was defined as the time from
UCBT to either relapse or death. Secondary end-points were incidence of neutrophil
recovery (defined as first of 3 consecutive days with a neutrophil count of at least 0.5x10 9/L),
acute graft-versus-host disease (GVHD), and chronic GVHD. Diagnosis and grading for GVHD
were performed according to published criteria 11, 12. Primary endpoints were analyzed in the
whole cohort of patients and in two subgroups (patients transplanted in CR1 and in CR2).
Secondary outcomes, such as neutrophil engraftment, acute and chronic GVHD were
analyzed only in the whole cohort of patients. The probability of DFS was calculated using
the Kaplan-Meier method and the log-rank test for univariate comparisons
13.
Cumulative
incidence (CI) function with competing events was used to estimate neutrophil engraftment,
acute and chronic GVHD, relapse and NRM 14. Prognostic factors for relapse and NRM were
evaluated using the Fine and Gray model
15.
All probabilities of DFS, relapse and NRM are
given at 5 years.
Data analysis was performed on May 1, 2014. Median values and ranges are reported for
continuous variables, and percentages for categorical variables. The following variables were
tested in univariate analyses: gender, age and weight at UCBT, patient CMV serology prior to
transplantation, time interval between diagnosis and UCBT for patients transplanted in CR1
and time from diagnosis to relapse for children transplanted in CR2, cytogenetic risk group,
disease status at UCBT, year of UCBT, number of HLA disparities in the donor/recipient pair,
conditioning regimen with or without total body irradiation (TBI), use of ATG, previous
autologous HSCT and number of total nucleated cells infused per Kg of recipient body
weight. Variables that reached a p-value of 0.10 in univariate analysis, as well as number of
HLA disparities and median number of total nucleated cells infused were included in the final
Cox models
16.
P-values were two-sided. Statistical analyses were performed with SPSS
version 19 (Inc., Chicago, IL) and Splus (MathSoft, Inc., Seattle, WA).
1
Supplemental table 1. Patient, karyotype and transplant characteristics according to disease status at
time of UCBT (n= 293)
CR1 (n=114) CR2 (n=133) Advanced (n=46)
Patients
Gender (male), n(%)
Age (years), median (range)
Weight (kg), median (range)
50 (44)
2,3 (0,4-18)
13,0 (5-88)
80 (60)
6,5 (1-18)
24,0 (7-90)
21 (46)
4,9 (0,3-17)
17,0 (4-61)
Positive CMV serology, n(%)
59 (56)
60 (49)
16 (53)
Karyotypes
Favorable, n (%)
Intermediate risk, n (%)
Unfavorable, n (%)
10 (9)
47 (41)
57 (50)
37 (28)
54 (41)
42 (32)
4 (9)
31 (67)
11 (24)
101
21 (21)
55 (54)
25 (25)
114
15 (13)
96 (84)
3 (3)
108
123
18 (15)
50 (40)
55 (45)
129
49 (38)
79 (61)
1 (1)
127
40
5 (12)
15 (38)
20 (50)
46
15 (33)
28 (61)
3 (6)
45
18 (17)
57 (53)
19 (18)
8 (7)
6 (5)
114
93 (82)
21 (18)
73
52 (71)
21 (29)
6.4 (1-27)
19 (15)
87 (68)
13 (10)
6 (5)
2 (2)
128
111 (87)
17 (13)
102
72 (71)
30 (29)
4.4 (1-19)
7 (16)
24 (54)
2 (4)
6 (13)
6 (13)
43
36 (84)
7 (16)
35
24 (69)
11 (21)
4,8 (1-36)
2.5 (0,1-38)
1.7 (0.1-7)
1.8 (0.1-18)
Transplantation characteristics
HLA compatibility - (evaluable n)
Identical, n (%)
1 HLA disparity, n (%)
> 2 HLA disparities, n (%)
Conditioning regimen - (evaluable n)
including TBI, n (%)
including Bu, n (%)
Miscellaneous, n (%)
aGVHD Prophylaxis (evaluable n)
Including cyclosporine A
Alone
+ steroids
+ mycophenolate
Including methotexate
Miscellaneous
ATG/MoAb use (evaluable n)
Yes, n (%)
No, n (%)
G-CSF/GM-CSF Use (evaluable n)
Yes, n (%)
No, n (%)
Infused TNC, x 107/Kg, median (range)
Infused CD34+ Cells, x 105/Kg, median (range)
2
Supplemental table 2 : Univariate analysis of prognostic factors for UCBT in CR1
DFS
Relapse risk
(overall: 69±5%) (overall: 16±4%)
NRM
(overall : 15±3%)
%
17±5
13±5
21±6
20±6
15±5
16±5
17±5
13±5
p
0.69
Patient-related variables
Gender
Male
Female
Age (years)
< 2.3
≥ 2.3
Weight (Kg)
< 13
≥ 13
CMV
+
serology
-
n
50
64
57
57
48
54
59
47
%
72±7
65±6
75±6
61±7
75±6
61±7
72±6
60±7
p
0.64
%
18±5
15±5
15±5
18±5
88±5
75±6
11±4
27±7
p
0.71
Karyotype
Favorable
Intermediate
Unfavorable
n
10
47
57
%
60±15
67±7
73±6
p
0.50
%
10±10
20±6
15±5
p
0.8
%
30±15
15±5
13±5
p
0.30
Transplant-related
variables
Year of
≤ 2007
transplantation > 2007
HLA disparity
0-1
≥2
TBI
No
Yes
ATG/MoAb use No
Yes
Infused TNC
< 6.4
≥ 6.4
Infused CD34
< 2.5
≥ 2.5
Time from
< 5.4
diagnosis to
≥ 5. 4
transplant
n
%
p
%
p
%
p
59
55
76
25
99
15
21
93
51
53
47
47
57
57
69±6
66±7
62±6
76±8
72±5
45±13
61±11
70±5
62±7
70±6
62±7
68±7
67±6
0.96
19±5
13±5
20±5
12±7
16±4
22±12
19±9
16±4
16±5
19±6
18±6
17±6
21±6
0.43
12±4
20±6
18±5
12±7
12±3
37±14
22±6
22±3
21±6
11±4
20±6
15±5
13±5
0.31
69±6
0.15
0.22
0.44
0.34
0.08
0.45
0.54
0.72
0.70
13±5
0.63
0.12
0.04
0.3
0.6
0.67
0.6
0.9
0.3
0.11
0.75
0.41
0.83
0.04
0.89
0.12
0.45
0.57
18±5
3
Supplemental table 3. Multivariate analysis of prognostic factors for UCBT in CR1
Outcome
Non-relapse
mortality
Relapse
Disease free survival
Variable
>2 HLA mismatches
Infused TNC > 6.4 x
107/Kg*
Age of recipient
>2.3 years*
TBI
Favorable risk
karyotype
Intermediate risk
karyotype
Unfavorable risk
karyotype
Negative recipient
CMV sorology
> 2HLA mismatches
Infused TNC >6.4 x
107/Kg*
Favorable risk
karyotype
Intermediate risk
karyotype
Unfavorable risk
karyotype
Age of recipient
>2.3 years*
TBI
>2 HLA mismatches
Infused TNC >6.4 x
107/Kg*
Favorable risk
karyotype
Intermediate risk
karyotype
Unfavorable risk
karyotype
p
HR
0.41
0.23
0.60
0.45
95.0% IC
<
0.18
0.13
0.60
1.43
0.37
5.51
0.53
0.61
1.48
0.44
Reference group
4.97
0.34
0.45
0.09
2.32
0.58
0.63
0.13
3.17
0.07
2.49
0.92
6.71
0.32
0.79
0.52
1.14
0.15
0.43
1.88
2.99
0.81
Reference group
0.55
1.91
0.23
15.57
0.67
1.58
0.19
12.97
0.39
1.48
0.61
3.63
0.46
0.18
0.76
1.40
0.55
0.87
0.57
0.23
0.37
3.43
1.33
2.05
0.91
Reference group
0.67
0.76
0.21
2.69
0.76
0.82
0.23
2.95
>
1.98
1.64
* Median.
Abbreviations: UCBT. umbilical cord blood transplantation; 1st CR. first complete remission;
AML. acute myeloid leukemia; HLA. human leukocyte antigen; TNC. total nucleated cells; TBI.
total body irradiation; CMV. cytomegalovirus
4
Supplemental table 4: Univariate analysis of prognostic factors for UCBT in CR2
DFS
(overall : 48±4)
Patient related variables
Gender
male
female
Age (years)
<6.5
≥6.5
Weight (Kg)
< 24
≥24
CMV serology
+
Time from
<11
diagnostic to
≥11
1st relapse
(months)
n
80
53
67
66
16
106
60
63
59
60
%
51±6
43±7
50±6
46±6
54±13
48±5
45±7
52±6
33±6
63±6
p
0.42
Karyotype
Favorable
Intermediate
Unfavorable
n
37
54
42
%
67±8
39±7
42±8
Transplant-related
variables
Year of
≤ 2004
transplantation > 2004
Previous
No
autologous
Yes
transplantation
HLA disparity
0-1
≥2
TBI
No
Yes
ATG/MoAb use No
Yes
Infused TNC
< 4.4
≥ 4.64
Infused CD34
< 1.7
≥ 1.7
n
Relapse risk
(overall : 27±4)
%
24±4
30±4
26±3
27±4
29±4
25±4
26±4
31±4
43±6
17±5
p
0.20
p
0.07
%
17±6
27±6
36±8
%
p
62
71
113
20
38±6
58±6
46±5
59±11
0.05
68
55
80
50
17
111
64
64
61
61
55±6
38±7
45±6
54±7
59±12
47±5
48±6
49±6
48±7
46±7
0.04
0.94
0.67
0.34
0.00
0.45
0.14
0.42
0.87
0.60
NRM
(overall : 23±2)
%
23±3
23±3
17±3
28±4
17±3
28±4
22±3
20±3
28±5
25±6
p
0.93
p
0.19
%
17±6
38±7
23±7
p
0.19
%
p
%
p
33±4
22±3
31±4
5±5
0.85
31±4
17±3
21±2
39±10
0.01
28±3
26±4
32±5
18±6
25±7
27±3
25±4
28±4
27±4
27±4
0.58
18±3
31±5
20±3
31±5
22±6
22±3
25±4
22±3
26±4
22±3
0.01
0.62
0.12
0.61
0.00
0.05
0.05
0.78
0.41
0.55
0.18
0.02
0.56
0.92
0.06
0.09
0.89
0.37
0.25
5
ACKNOWLEDGEMENTS
We thanks the following Eurocord participating center:
Transplant center
CIC
PI (last name, name)
Italy - Palermo - Ospedale dei Bambini
109
Ziino, Ottavio
Brazil - Jau Sao Paulo - Hospital Amaral
Carvalho
France - Marseille - La Timone (pédiatrie)
180
Souza, Mair Pedro de. Mauad, Marcos
192
Michel, Gérard
Switzerland - Basel - University Hospital
202
The Netherlands - Leiden - University Hospital
Denmark - Copenhagen - Rigshospitalet
France - Paris - Saint-Louis
Belgium - Leuven - University Hospital
Gasthuisberg Dept. of Hematology
Sweden - Stockholm - Karolinska University
Hospital Children`s Hospital
203
206
207
209
Veelken, Joan Hendrik
Sengeloev, Henrik. Heilmann, Carsten
Socié, Gerard
Maertens, Johan. Uyttebroeck, Anne
212
Ljungman, Per. Winiarski, Jacek
United Kingdom - London Surrey Royal
Marsden Hospital
218
Potter, Michael
Finland - Helsinki University of Helsinki Hospital for Children & Adolescents
219
Vettenranta, Kim
United Kingdom - London - Royal Free and
University College Medical School
224
Thomson, Kirsty
France - Marseille - Paoli Calmettes (adulte)
230
Italy - Roma Univ.La Sapienza
232
France - Besançon - Saint Jacques
233
Blaise, Didier
Foa, Roberto
Deconinck, Eric
Poiré, Xavier
Belgium - Brussels - Cliniques Universitaires St. 234
Luc
Passweg, Jakob. von der Weid, Nicolas
Spain - Córdoba - Hosp. Reina Sofia
238
Gomez García, Pedro
The Netherlands - Utrecht - University Medical
Centre
Spain - Santander - Hospital U. Marqués de
Valdecilla
239
Petersen, Eefke. Bierings, Marc
242
Richard Espiga, Carlos
United Kingdom - London - Great Ormond
Street Hospital
243
Veys, Paul
Italy - Pescara - Ospedale Civile Department of 248
Hematology
Di Bartolomeo, Paolo
France - Nantes - Hotel Dieu
Israel - Jerusalem - Hadassah University
Hospital
Spain - Barcelona - Hospital Santa Creu i Sant
Pau
France - Poitiers - Jean Bernard
France - Bordeaux - Haut-Lévêque
France - Grenoble - Tronche CHU/Albert
Michallon
France - Clermont-Ferrand - Hotel Dieu
CHU/Jean Perrin
253
258
Chevallier, Patrice
Or, Reuven. Engelhard, Dan
260
Sierra, Jorge
264
267
270
Guilhot, Francois
Milpied, Noel
Cahn, Jean Yves
273
Bay, Jacques-Olivier
Italy - Genova - Institute G. Gaslini
274
Lanino, Edoardo
France - Lille - Claude Huriez
277
Yakoub-Agha, Ibrahim
Italy - Monza Ospedale San Gerardo Clinica
Pediatrica dell Universita di Milano Bicocca
279
Biondi, Andrea
6
Sweden - Lund - University Hospital
283
Italy - Padova - Clinica di Oncoematologia
Pediatrica
285
Lenhoff, Stig
Messina, Chiara
Italy - Roma - Ospedale S. Camillo
287
Majolino, Ignazio
Portugal - Porto - Inst. Portugues de Oncologia 291
do Porto
Campos, Antonio
Portugal - Lisboa - Inst. Portugues Oncologia
300
Abecasis, Manuel
Italy - Firenze - Azienda Ospedaliero
Universitaria Meyer - Ospedale di Careggi
304
Bosi, Alberto. Bambi, Franco
Italy - Torino - Ospedale Infantile Regina
Margherita Onco-Ematologia Pediatrica
305
Fagioli, Franca
Switzerland - Zürich - University Children s
Hospital
334
Güngör, Tayfun
Italy - Palermo - Ospedale V. Cervello
392
Scimè, Rosanna
Saudi Arabia - Riyadh - King Faisal Specialist
Hospital & Research Centre
397
Aljurf, Mahmoud. Ayas , Mouhab
Spain - Barcelona - Hospital Vall d`Hebron
422
Canada - Montréal - Ste-Justine Hospital
424
Sánchez de Toledo Codina, José. Diaz de
Heredia, Cristina
Bittencourt, Henrique
Czech Republic - Prague - University Hospital
Motol
452
Sedlacek, Petr
France - Nice - Archet
523
Rohrlich, Pierre-Simon
Italy - Pavia - Fondazione IRCCS Policlinico
San Matteo
557
Zecca, Marco
Israel - Tel-Hashomer - Edmond & Lily Safra
Children`s Hospital, Chaim Sheba Med Center
572
Toren, Amos
Spain - Málaga - Hospital Carlos Haya
576
Pascual Cascon, Maria Jesús
Turkey - Izmir - Ege University
621
Kansoy, Savas
Greece - Athens - Evangelismos Hospital
622
Karakasis, Dimitrios
France - Paris - Robert Debré
631
Dalle, Jean-Hugues
Germany - Düsseldorf Universitaetsklinikum
651
Meisel, Roland
Spain - Valencia Hospital Infantil La Fe
653
Fernandez Navarro, José Maria
Germany - Halle - Martin-Luther-Univ. HalleWittenberg
654
Koerholz, Dieter
France - Rennes - Pontchaillou
661
Lamy, Thierry
Spain - Valencia - Hospital Universitario La Fe
663
Sanz, Miguel A.
France - Strasbourg - Hautepierre (adulte)
672
Lioure, Bruno
7
France - Nancy - Brabois
676
Salmon, Alexandra
Russia - Moscow - Russian s Children s
Hospital
694
Maschan, Alexei
Australia Randwick Sydney Children s Hospital 698
O`Brien, Tracey
United Kingdom - Glasgow - Royal Hospital for 707
Sick Children
Gibson, Brenda E.
Australia - Sydney - The Children s Hospital at
Westmead
711
Shaw, Peter J.
Belgium - Liege - University of Liege
726
Beguin, Yves
Spain - Madrid - Niño Jesus Children`s Hospital 732
Diaz, Miguel Angel
Belgium - Gent - University Hospital Gent
744
Noens, Lucien. Bordon, Victoria
Greece - Athens - St. Sophia Children s
Hospital
752
Grafakos, Stelios
Israel - Petach-Tikva - Schneider Children s
Medical Center of Israel
755
Stein, Jerry
Italy - Roma - Rome Transplant Network
756
Arcese, William. Locatelli, Franco
Spain - Sevilla - Hospital Universitario Virgen
del Rocío
769
Espigado, Ildefonso
United Kingdom - Sheffield - Royal Hallamshire 778
Hospital
Snowden, John
Italy - Bologna - Azienda OspedalieroUniversitaria di Bologna
Pession, Andrea
790
Italy - Pisa - Azienda Ospedaliera Universitaria 795
Pisa
Favre, Claudio
France - Lyon - Debrousse (pédiatrie)
806
Bertrand, Yves
Hungary - Budapest - St. László Hospital
824
Kriván, Gergely
France - Rouen - Charles Nicolle- pédiatrie
932
Vannier, Jean-Pierre
Algeria-Oran-University Hospital of Oran
Department of Haematology and Cell Therapy
963
Bekadja, Mohamed Amine
France- Bordeaux -CHU Bordeaux Groupe
Hospitalier Pellegrin-Enfants
978
Jubert, Charlotte
France - Montpellier - Arnaud de Villeneuvepédiatrie
988
Sirvent, Anne
8
9