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Vanderson Rocha, MD, PhD Professor of Haematology- Oxford University
BMT unit, Churchill Hospital Oxford, UK
Scientific Director of Eurocord Paris, France
Outcomes of Double Unit Cord Blood Transplantation in patients with
malignant disorders: Eurocord Registry analysis
Eurocord Registry
General data base* overview
*Eurocord Registry status as off December, 31st, 2012
Eurocord registry database N or % Cord blood units / European CB units % 12 066 / 58% CBT cases / single% / double% 9 883 / 63% / 23%
European CBT cases 65% Countries / Centres / EBMT centres 51 / 577 / 297 Unrelated CBT cases 93% Children CBT cases 54%
Eurocord Registry at ABM Unrelated European CBT by recipient’s age and graft type
Children Adults
* Still collecting 2012 data
0
50
100
150
200
250
300
1990
19
94
1995
19
96
1997
19
98
1999
20
00
2001
20
02
2003
20
04
2005
20
06
2007
20
08
2009
20
10
2011
20
12
Double CBT
Single CBT *
0
50
100
150
200
250
300
350
400
1994
19
95
1996
19
97
1998
19
99
2000
20
01
2002
20
03
2004
20
05
2006
20
07
2008
20
09
2010
20
11
2012
Double CBT
Single CBT *
In children: 92% single CBT In adults: 47% double CBT
0
50
100
150
200
250
300
350
400
450
1990
1991
1992
1993
1994
1995
1996
1997
1998
1999
2000
2001
2002
2003
2004
2005
2006
2007
2008
2009
2010
2011
2012
MAC n=4674
RIC n=2629
* Still collecting data
Type of Conditioning Regimen per Year
*
*
Double UCBT in children
Preliminary Analysis
Patient characteristics (n=218)
Patient Characteristics Range
Median age, years 13 y 0.6-18
Median weight, kg 45 Kg ( 25-76)
Median year of transplant 2009 2002-2012
Median follow-up 21 months 3-111
Diagnosis
Malignant diseases – disease status at UCBT •Early: 31% • Intermediate: 31% •Advanced: 15%
Characteristic range
Conditioning MAC 76% RIC 24%
GvHD prophylaxis CsA+MMF 48% CsA+steroids 30% CsA+MMF+other 5% FK506+other 4% Other 13%
Use of ATG Yes 68% No 32%
Number of HLA mismatches 0 5% 1 37% ≥2 58%
Median collected TNC, x105/kg 5.1 2.15-44.29
Median infused TNC, x107/kg 5.1 0.98-34.2
Transplant and graft characteristics
Neutrophil Engraftment
at 60 days: 87%, n=218
Malignant disease: 90%, n=178, Non Malignant disease: 67%, n=40, p=0.001
Chimerism at 100 days available for 146/182 patients who engrafted, Mixed 10%, Full donor 90% (17 patients had long term persistance of both CBU)
Non engraftment
• 36 patients experienced primary graft failure – 27 died in a median time of 72 days after CBT. 5
had received a 2nd Tx (2 haplo, 2 dUCBT, 1 PBSC) – 9 are alive with a median FU of 18 months. 3 with
available information, had a subsequent Tx (2 CBT and 1 UD-BMT).
aGvHD grade II-IV
MAC: 42%, n=164
RIC: 34%, n=51
p=0.32
• 100 patients presented grade III-IV aGvHD
Acute leukemia: relapse
AML, n=48: 37%
ALL, n=101: 25%
p=0.19
Overall Survival
Non Malignant, n=40: 44%
Malignant, n=178: 47%
p=0.73
Overall Survival for acute leukemia
AML, n=48: 52+8%
ALL, n=101: 44+6%
p=0.54
Double UCBT in adults
Preliminary analysis
Patient characteristics
Patient Characteristics Range
Median age, years 46 y 18-76 Median weight, kg 71 kg 40-171 Median year of transplant 2009 1999-2012 Median follow-up 23 months 3-98
From 1999 to 2012, 1118 adult patients were transplanted with
double UCBT In 32 EBMT countries
Diagnosis (n= 1118)
Malignant diseases – disease status at UCBT •Early : 25% •Intermediate : 23% •Advanced: 38%
Non-malignant: 39/46 BMF
Transplantation and graft characteristics (n= 1118)
Characteristic range
Conditioning RIC 67% MAC 33%
GvHD prophylaxis CsA+MMF 73% CsA+steroids 13% CsA+MMF+other4% FK506+other 3% Other 7%
Use of ATG Yes 38% No 62%
Number of HLA mismatches 0/1 28% ≥2 72%
Median collected TNC, x105/kg 4.9 1.5-14.8
Median infused TNC, x107/kg 3.8 0.33-14.6
Neutrophil Engraftment (n= 1118)
Neutophil Engraftment at 60 days: 87+1%, n=1118
Chimerism at 100 days available for 881/1053 patients who engrafted, Mixed 14%, Full donor 86%
Lymphoid Mal, n=219: 89+2% Ac Leukemia, n=820: 87+2%
MDS/MPS, n=239: 82+3%
aGvHD grade II-IV (n= 1118)
BY HLA COMPATIBILITY BY CONDITIONING REGIMEN
2 HLA MM: 42+2%, n=666
0-1 HLA MM: 34+2%, n=274
p=0.25
MAC, n=350:34+2%
RIC, n=660: 32+2%
p=0.32
Relapse (n= 1118)
ACUTE LEUKEMIA OTHER MALIGNANCIES
N CI N CI
EARLY 267 21% 34 21%
INTERMEDIATE 242 29% 43 21%
ADVANCED 114 39% 281 30%
Mortality and causes of death (n= 681 out 1118)
Among 395 patients transplanted with advanced disease, 267 died in a median time of 108 days after CBT, of those 106, of the original disease
Disease free Survival Adults with malignancies (n= 1118)
p<0.001
Lymphoid Mal, n=219: 43+4%
Ac Leukemia, n=820: 39+2% MDS/MPS, n=239: 27+3%
DFS at 2 year by type of disease and conditioning regimen
MAC, n=388 RIC, n=711
Lymphoid Mal, n=26:40+11%
Ac Leukemia, n=286: 34+2%
MDS/MPS, n=72: 25+3%
Lymphoid Mal, n=181: 41+3%
Ac Leukemia, n=371: 41+3%
MDS/MPS, n=151: 23+4%
DFS at 2 year by disease status and conditioning regimen
MAC, n=388 RIC, n=711
Early , n=147: 44+5%
Intermediate, n=115: 36+5%
Advanced n=120: 18+4%
Early , n=224 46+5%
Intermediate, n=215: 44+4%
Advanced n=264: 27+4%
DFS- Multivariate analysis
HR 95%CI p value
Diagnosis: MDS vs acute leukemia
1.4 1.5- 1.95 0.02
Diagnosis: Lymphoid malignancies vs
acute leukemia
1.2 0.88- 1.7 0.22
Disease Status Remission vs not remission
0.51 0.38- 0.68 0.0001
Disease free Survival for acute leukemia (n=811)
• DFS at 2 year by type of disease
p=0.48
AML, n=499: 40+2%
ALL, n=313: 37+2%
Disease free Survival for acute leukemia (n=811)
DFS at 2 year by disease status, CR1
DFS at 2 year by disease status, CR2
AML, n=196: 50+4%
ALL, n=136: 48+2%
AML, n=175: 48+4%
ALL, n=129: 38+2%
Which are the risk factors associated with the double graft that can change one or
two units selection in dCBT ?
Risk factors of engraftment in dBCT
• Winner unit dose of CD3 cells? order of infusion? CD34 viable cells? HLA? others? • Engraftment Disease status? Conditioning regimen? Cell dose? TNC? CD34? CFU-GM?
Is there a number of nucleated cells or CD34 associated with outcomes in double
UCBT?
Patients and disease characteristics n= 430
Median (range) n
Children 41 (9%) 430
Adult 389 (91%)
Age (years)
Children 15 (4-18) 41
Adult 45 (18-67) 389
Weight (Kg)
Children 52 (14-88) 41
Adult 70 (40-120) 389
Positive CMV serology 205 (49%) 413
Diagnosis 241 (56%) 430
Acute leukemia 58 (13%)
MDS 131 (31%)
Other malignancies
Advanced Diseases 168 (40%) 419
Median Follow up (months) 12 (3-70)
*HLA A, B antigenic level - DRB1 allelic level
Transplant and Graft Characteristics n=430
Median (range) n
Conditioning Mieloablative 126 (30%) 418
GVHD Prophylaxis
418 CsA + Steroids 39 (9%)
CsA + MMF 307 (78%)
ALG/ATG before day 0 78 (22%) 395
HLA Matching *
428 6/6 5 (1%)
5/6 102 (24%)
4/6 297 (70%)
Pre-freezing (pf)
430 TNC (x107/Kg) 4.7 (2-27)
CD34 (x105/Kg) 1.7 (0.3-10)
Post-thawing (pt)
430 TNC (x107/Kg) 3.5 (0.8-22)
CD34 (x105/Kg) 1.2 (0.2-7)
Double UCBT (n=430) - Neutrophil Engraftment at 60 days
Number of pfCD34+
• CI Neutrophil Engraftment (NE): 81±2% • 346 pts (80%) achieved engraftment in a median time of 23 days
0 10 20 30 40 50 60
Days
0.0
0.2
0.4
0.6
0.8
1.0
Cum
ulat
ive
inci
denc
e of
neu
trop
hil e
ngra
ftmen
t
pf CD34 <1.7x105/kg 79+3%
pf CD34 >1.7x105/kg 83+3%
p = 0.03
Double UCBT (n=430)- Neutrophil Engraftment at 60 days
Number of ptCD34+ Number of ptCD34+
0 10 20 30 40 50 60
Days
0.0
0.2
0.4
0.6
0.8
1.0
Cum
ulat
ive
inci
denc
e of
neu
trop
hil e
ngra
ftm
ent
ptCD34 < 1.2x05/kg 76+3%
ptCD34 > 1.2x05/kg 85+2%
p = 0.04
0 10 20 30 40 50 60
Days0.
00.
20.
40.
60.
81.
0
Cum
ulat
ive
ince
denc
e of
neu
trop
hil e
ngra
ftm
ent
p = 0.006
ptCD34 < 0.9x05/kg 74+4%
ptCD34 > 0.9 and < 1.8 x05/kg 81+3%
ptCD34 > 1.8x105/kg 87+3%
0 20 40 60 80 100
Days0.
00.
20.
40.
60.
81.
0
Cum
ulat
ive
inci
denc
e of
tra
nspl
anta
tion-
rela
ted
mor
talit
y
Double UCBT – TRM at 100 days
CI 12 months of TRM: 16+2 %
pfCD34 > 1.2x05/kg 11+2%
pfCD34 <1.2x05/kg 18+3%
p = 0.02
Number of pfCD34+
0 20 40 60 80 100
Days
0.0
0.2
0.4
0.6
0.8
1.0
Cum
ulat
ive
inci
denc
e of
tra
nspl
anta
ntio
n-re
late
d m
orta
lity
Multivariate analysis -Double UCBT Summary
pf TNC pfCD34+ pt TNC pt CD34+ Others variables
Overall survival - - - -
Disease status at transplantation
Disease free survival - - - - Disease status
at transplantation
Neutrophil engraftment - 1.7x105/kg
(median) - 1.2x105/kg (4th percentile)
No other factor p=0.04 p=0.015
Transplantation-related mortality - 1.2X105/kg
(4th percentile) - HLA, MAC, age
p=0.004
Conclusions • Double Cord Blood Transplantation has extended the use
of Cord Blood Cells for Adults for whom the number of cells is not sufficient.
• Need of more data and follow-up • However despite a higher cell dose, graft failure is
around 10-15% (a higher CD34+ cell dose of both units seems to be an important factor to increase engraftment and decrease mortality)
• Acute GVHD seems to be increased • Mortality is associated with infections (delayed engraftment?,
delayed immune recovery?), GVHD and toxicity • MDS and advanced disease are factors associated with
decreased DFS rates
Acknowledgments
EBMT, CIBMTR Transplant Centers
(Data Managers, Nurses and Physicians) Cord Blood Banks and Netcord
Eliane Gluckman MD FRCP Project Leader
Vanderson Rocha MD, PhD
Scientific Director Annalisa Ruggeri, MD
Federica Giannotti , MD
Myriam Pruvost, PA
Fernanda Volt, MT Chantal Kenzey Data Manager
EUROCORD TEAM 2012-2013
Erick Xavier, MD
Luciana Tucunduva MD
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