1. Il trapianto di sangue cordonale dopo
regime di condizionamento ad intensità ridotta
Franco Locatelli, MD
Oncoematologia Pediatrica
Fondazione IRCCS Policlinico San Matteo,
Università di Pavia

2. Eurocord Registry

3. Eurocord Registry

4. Eurocord Registry

5. Learning curve in UCBT for adults

6. Single UCBT in adults with malignancies N=557
1,0
Transplant related mortality according
to the period of CBT ,8
: 51%+/-5
: 34%+/-3 ,6
: 27%+/-3 ,4 ,2
p=0.002
Days 10 20 30 40 50 60 70 80 90
100 52

7. Overall survival after UCBT in adults by period of transplantation

8. Major factors changing outcomes after UCBT in adults
Increasing cell dose (double CB) and better donor choice
Decreasing HLA disparities (increasing greater inventory)
Better indications
Centre experience
Better surveillance, prophylaxis and treatment of infections
Modifications of GVHD prophylaxis and conditioning regimens 8

9. Neutrophil recovery after UCBT for adults with leukemias
by cell dose
> 3x107/kg (n=218) %
2-3 x107/kg (n=307) 83%
< x7/kg (n=295) 77%

10. Neutrophils recovery after single UCBT for adults with AL by number of infused CD34 cells
> 1.2x107/kg (n=160) %
< x7/kg (n=159) %
P=0.002

11. Major factors changing outcomes after UCBT in adults
Increasing cell dose (double CB) and better donor choice
Decreasing HLA disparities (increasing inventory of CBB)
Better indications
Centre experience
Better surveillance, prophylaxis and treatment of infections
Modifications of GVHD prophylaxis and conditioning regimens 11

12. Neutrophil recovery after UCBT for adults with leukemias
by number of HLA disparities
HLA 6/6 or 5/6 N= %
HLA 2/6 N= %
HLA 3 or 4/6 N= %

13. Major factors changing outcomes after UCBT in adults
Increasing cell dose (double CB)
Decreasing HLA disparities (increasing greater inventory)
Better indications
Better surveillance, prophylaxis and treatment of infections
Modifications of GVHD prophylaxis and conditioning regimens 13

14. Overall survival by status of the disease at transplant
in patients with Acute Leukemias
CR1 (n= 185) 47%
CR2 (n= 176) 38%
Advanced (n= 163) 20% 14

15. Major factors changing outcomes after UCBT in adults
Increasing cell dose (double CB)
Decreasing HLA disparities (increasing greater inventory)
Better indications
Better surveillance, prophylaxis and treatment of infections
Modifications of GVHD prophylaxis and conditioning regimens

16. Rationale for using RIC in patients given CBT
The mortality and morbidity associated with conventional myeloablative transplantation curtails the number of patients who can be treated with an allogeneiv HSCT;

17. Transplant-related mortality in RIC-HSCT compared to conventional HSCT
Diaconescu R, et al. Blood 2004; 104:

18. Rationale for using RIC in patients given CBT
The mortality and morbidity associated with conventional myeloablative transplantation curtails the number of patients who can be treated with an allogeneic HSCT;
The presence of residual host cells may also contribute to the reduction in incidence and severity of GvHD

19. Tolerant host and donor T cells
Mixed chimerism and tolerance
Hematopoietic stem cell engraftment:
donor HSC engraft in permissive hosts
recipient HSC persist due to reduced-intensity conditioning
erythrocytes
granulocytes
B cells
mixed chimerism
unbalanced chimerism:
less complete central deletion
donor and host
APC co-exist
Prevalence of host
APC
Prevalence of donor APC
Clonal deletion of
donor-reactive and
host-reactive
thymocytes
Peripheral tolerance:
anergy
regulatory T cells
Tolerant host and donor T cells
Donor-reactive T cells:
graft loss
Host-reactive T cells:
GVHD
Modified from: Sykes M. Immunity 2001; 14:417. 30

20. Eurocord Registry

21. Rejection ------ Engraftment -----
Immunosuppression
Toxicity
Myelosuppression
Rejection Engraftment ----- D C B A
Non-myeloablative: substantial autologous hematopoietic recovery. DLI usually required for complete donor engraftment (i.e. TBI 200 cGy).
As in A, but highly immunosuppressive. DLI occasionally required (i.e. TBI 200 cGy + Flu mg/m2).
Borderline myeloablative: with some autologous hematopoietic recovery. DLI occasionally required (i. e. Bu 8 mg/Kg + Flu mg/m2).
Myeloablative: with very rare autologous recovery. DLI not required (i.e . TBI 12 Gy + Cyclo 120 mg/Kg)
Adapted form: Barrett J. Br J Haematol 2000; 111:6-17.

22. Non-myeloablative regimen for UCBT in adults
Fludarabine 40mg/m2/day
2Gy
Endoxan 50mg/kg -8 -7 -6 -5 -4 -3 -2 -1
+14
+21
+100
+180
CSA ( level>200µg/L) - 3 to > +100
MMF (30mg/kg/day)- 3 to + 30
Eligibility:
High-risk hematological
malignancy
4-6/6 UCB
> 2.5 x 107 NC/kg (at collection)
G-CSF
(J Barker and J Wagner)

23. Chimerism after RIC in patients given CBT
Brunstein CG, et al. BLOOD 2007; 110:

24. EFS probability after RIC in patients given either 1 or 2 CB units
Brunstein CG, et al. BLOOD 2007; 110:

25. RIC before single unrelated
CBT for adults with hematological maligancies
An Eurocord-Netcord, SFGM-TC and Minnesota group
analysis 25

26. Patients and disease characteristics
Reduced Intensity conditioning regimen in Unrelated cord blood transplants for patients with hematological malignancies
(n=176)
Patients and disease characteristics
Transplants performed from with single units
Follow-up : months (3-80)
Median age: years ( 16-76)
Median weight: kg (40-116)
CMV+: %
Diagnosis
Previous autologous transplant: % (n=53)
Allo transplants 5% (n=8) 26

27. Disease Free Survival according to conditioning
51% CY+TBI 2GY+FLU
28% others P=
Months 27

28. Multivariate analysis for TRM
Type of conditioning ( FLU+EDX+TBI) HR= p=0.002
Nucleated cell dose >2.8 HR=0.46 p=0.06
Other variables included in the model (P<0.10)
status of the disease, diagnosis, age, HLA 28

29. B Rio on behalf of Eurocord-Netcord and SFGM-TC group analysis
Unrelated Cord Blood transplants in adults with hematological malignancies after
Cyclophosphamide-Fludarabine-TBI
reduced intensity conditioning regimen
B Rio on behalf of Eurocord-Netcord and SFGM-TC group analysis

30. Patients and disease characteristics
155 patients (96 single CBT and 59 double CBT) have data on outcomes and were analysed
Median Follow-up : months (1.6-56)
Median age: ,7 years ( 19-69)
Median weight: 65 kg (42-125)
CMV+: %
Previous Tx: auto: 35%(n=54)
allo: 1% (n=1)

31. Number of cord blood unrelated transplants/year
and type of graft after CY-Flu-TBI
Single CBT n=96
Double CBT n=59

32. Patients and disease characteristics
Diagnosis and status of the disease* at transplant
* For acute leukaemia, MDS, CML
Median time from diag to UCBT:
- acute leukemias 13,4 months (3,1 -144)
- others 42,3 months (4,7-187)

33. Graft characteristics
Single CBT n=96
Double CBT n=59
HLA match*
First CB unit
Second CB unit
6/6 2 1
5/6 24 17
4/6 32 38
3/6
missing -
HLA match*
Single CBT
6/6 5
5/6 26
4/6 57
3/6 4
2/6
missing 2
*-A and -B by low resolution and – DRB1 by high resolution typing

34. Non-myeloablative regimen for UCBT in adults
MMF (30mg/kg/day)- 3 to + 30
G-CSF
CSA ( level>200µg/L) - 3 to > +100 -3 -2 -1 -4 -8 -7 -6 -5
+14
+21
+100
+180
UCB
Eligibility:
High-risk hematological
malignancy
4-6/6 UCB
> 2.5 x 107 NC/kg (at collection)
Fludarabine 40mg/m2/day
Endoxan 50mg/kg
2Gy
(J Barker and J Wagner)

35. Conditioning GVHD prophylaxis
Cyclophosphamide – Fludarabine – TBI 2 Gy n= 145
4 Gy n=5
6 Gy n=5
Anti T antibodies (ATG/ALG or MonoAb) 3%
Hematopoietic growth factors (<Day 8) 46%
GVHD prophylaxis
CsA+MMF (94,8%)
CsA alone (2,6%)
CsA+pred+/-MMF (1,2%)
Other combinations (1,2%)

36. Graft characteristics n=155
All patients n=155
Single CBT n=96
Double CBT n=59
Median nucleated cells collected (107/Kg), range
4,1 (2,1-12,2)
n=151
3,8 (2,1-6,4)
n=96
4,6 (3,2-12,2)
n=55
Median nucleated cells infused (107/Kg), range
3,1 (0,6-7,9)
2,8 (0,6-6,4)
3,6 (1,1-7,9)
Median CD34 cells collected (106/Kg), range
1.5 ( )
n=147
1.4 ( )
n=95
1.6 ( )
n=52
Median CD34 cells infused (105/Kg), range
1.1 ( )
n=141
1.1 ( )
n=87
1.2 ( )
Median cell loss after thawing
25%
27%

37. Results Neutrophil recovery (n=124) Median days:19 days (1-48)
Platelet recovery (n=98) Median days:35 days (6-136)
Chimerism* at 3 months Chimerism* at 3 months
(available in 90% of the pts.) in patients with engraftment
*Still collecting data for double CBT cases

38. CI of Neutrophil Engraftment and Type of Graft
Double (n=59) 81%±5
Single (n=96) 79%±4

39. CI of Neutrophil Engraftment and Infused CD34+
≥1.1x105 CD34+ cells/kg (n=73) 84%±4
<1.1x105 CD34+ cells/kg (n=68) 75%±5
p= 0.02

40. CI of Neutrophil Engraftment and HLA disparity
0-1 HLA disparity (n=47) 94%±4
p= 0.03
≥ 2 HLA disparities (n=105) 73%±4

41. CI of Neutrophil Engraftment and Previous HSCT
Previous HSCT (n=55) 93%±4
No previous HSCT (n=100) 72%±5
p= 0.001

42. CI of aGVHD II-IV and Type of Graft
Double (n=59) 40%±7
Single (n=96) 35%±5

43. CI of TRM and Disease Status at UCBT AL, MDS and CML
p= 0.02
Advanced (n=21) 33%±11
Early (n=42) 13%±5
Intermediate (n=44) 10%±5

44. CI of TRM and Type of Graft
Double (n=59) 21%±6
Single (n=96) 15%±4

45. CI of TRM and ABO incompatibility
Major (n=65) 27%±6
Compatible or minor (n=89) 11%±4

46. CI of TRM and CMV serology
p= 0.05
CMV + (n=86) 23%±5
CMV - (n=57) 11%±4

47. CI of Relapse and Diagnosis
Other (n=122) 36%±5
Lymphomas/CLL (n=33) 17%±7

48. CI of Relapse and Type of Graft
Single (n=96) 36%±4
Double (n=59) 24%±7

49. DFS and Diagnosis p= 0.22 Lymphomas/CLL (n=33) 59%±9
Acute leukemias (n=91) 52%±6
MDS/CML/MM (n=31) 34%±12

50. EFS and Disease Status at UCBT AL, MDS, CML
p< 0.001
Intermediate (n=44) 58%±8
Early (n=42) 50%8
Advanced (n=21) 21%±10

51. DFS and Type of Graft
p= 0.53
Single (n= 96) 49%±5
Double (n=59) 56%±8

52. DFS and HLA disparity p= 0.002 0-1 HLA disparity (n=47) 70%±8
≥ 2 HLA disparities (n=105) 42%±5

53. Causes of Death (n=55)
Relapse 32
Transplant Related 23
GVHD 6
Infections 7
bact 2
viral 2
fungal 1
unk etiology 2
Hemorrhage 1
MOF+toxicities 9

54. Conclusions
Available evidence supports the use of CBT after RIC in adult patients either older than 45 years of age or not eligible to receive an allograft after a conventional preparative regimen.
The use of 2 units seems to decrease the risk of leukemia recurrence, although it remains to be definitively proved whether this translates into a better outcome.
Disease phase at time of transplantation is the most important factor predicting outcome. Better HLA matching of the CB unit(s) is associated with a better probability of DFS.
Particularly encouraging are the results obtained in patients with indolent lymphoproliferative disorders.

55. Eurocord team 2007-2008 Roel Willemze Eliane Gluckman Vanderson Rocha
Irina Ionescu
David Pacheco
Federico Garnier
Karim Boujedir
Wagnara Chaves
Andree Laure Herr
Adriene Madureira
Annalisa Ruggeri
Nabil Kabbara
Roel Willemze
Samir Nabhan
Juliana Rodrigues
Celso Arrais
Nabila Bechar
Anne Leger
Evelyne Thai