The document analyzes data from the Eurocord Registry on outcomes of double unit cord blood transplantation, finding that higher pre-freezing CD34+ cell doses were associated with increased neutrophil engraftment and lower transplantation-related mortality, while higher post-thawing CD34+ cell doses were linked to higher engraftment rates; disease status at transplantation also impacted outcomes like disease free survival. The analysis included over 1,100 adult and over 200 pediatric transplants from the Eurocord database.

1. 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

2. 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%

3. 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
1994
1995
1996
1997
1998
1999
2000
2001
2002
2003
2004
2005
2006
2007
2008
2009
2010
2011
2012
Double CBT
Single CBT
*
0
50
100
150
200
250
300
350
400
1994
1995
1996
1997
1998
1999
2000
2001
2002
2003
2004
2005
2006
2007
2008
2009
2010
2011
2012
Double CBT
Single CBT *
In children: 92% single CBT In adults: 47% double CBT

4. 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
*
*

5. Double UCBT in children
Preliminary Analysis

6. 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

7. Diagnosis
Malignant diseases – disease status at UCBT
•Early: 31%
• Intermediate: 31%
•Advanced: 15%

8. 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

9. 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)

10. 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).

11. aGvHD grade II-IV
MAC: 42%, n=164
RIC: 34%, n=51
p=0.32
• 100 patients presented grade III-IV
aGvHD

12. Acute leukemia: relapse
AML, n=48: 37%
ALL, n=101: 25%
p=0.19

13. Overall Survival
Non Malignant, n=40: 44%
Malignant, n=178: 47%
p=0.73

14. Overall Survival for acute leukemia
AML, n=48: 52+8%
ALL, n=101: 44+6%
p=0.54

15. Double UCBT in adults
Preliminary analysis

16. 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

17. Diagnosis (n= 1118)
Malignant diseases – disease status at UCBT
•Early : 25%
•Intermediate : 23%
•Advanced: 38%
Non-malignant: 39/46 BMF

18. 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

19. 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%

20. 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

21. 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%

22. 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

23. 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%

24. 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%

25. 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%

26. 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

27. 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%

28. 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%

29. Which are the risk factors associated with
the double graft that can change one or
two units selection in dCBT ?

30. 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?

31. Is there a number of nucleated cells or
CD34 associated with outcomes in double
UCBT?

32. 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)

33. *HLA A, B antigenic level - DRB1 allelic level
Transplant and Graft Characteristics
n=430
Median (range) n
Conditioning Mieloablative 126 (30%) 418
GVHD Prophylaxis
418CsA + 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)
430TNC (x107
/Kg) 4.7 (2-27)
CD34 (x105
/Kg) 1.7 (0.3-10)
Post-thawing (pt)
430TNC (x107
/Kg) 3.5 (0.8-22)
CD34 (x105
/Kg) 1.2 (0.2-7)

34. 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
0.00.20.40.60.81.0
Cumulativeincidenceofneutrophilengraftment
pf CD34 <1.7x105/kg 79+3%
pf CD34 >1.7x105/kg 83+3%
p = 0.03

35. Double UCBT (n=430)- Neutrophil Engraftment at 60 days
Number of ptCD34+ Number of ptCD34+
0 10 20 30 40 50 60
Days
0.00.20.40.60.81.0
Cumulativeincidenceofneutrophilengraftment
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
Cumulativeincedenceofneutrophilengraftment
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%

36. 0 20 40 60 80 100
Days
0.00.20.40.60.81.0
Cumulativeincidenceoftransplantation-relatedmortality
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
0.00.20.40.60.81.0
Cumulativeincidenceoftransplantantion-relatedmortality

37. 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

38. 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

39. Acknowledgments
EBMT, CIBMTR
Transplant Centers
(Data Managers, Nurses and Physicians)
Cord Blood Banks and Netcord

40. 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