1. Cord Blood Transplantation: Are
the indications changing?
Daniel Weisdorf MD
University of Minnesota

2. Donor options
Matched siblings
Other relatives
Unrelated donors (URD)
Umbilical Cord Blood
Self (autologous)

3. Donor Choice Issues—beyond matched siblings
Age
Gender & match
Alloimmunization -- parity
CMV
HLA matching
Cell dose
Graft source & composition
Urgency

4. Donor Choice Issues: URD vs. UCB
Age UCB are the youngest
Gender & match ----
Alloimmunization -- parity UCB
CMV UCB
HLA matching URD better; UCB permissive
Cell dose UCB limiting
Graft source Different cell mix
& composition & function
Urgency UCB quickest

5. Here are the basics
• UCB engrafts children
and 1-2 UCB can engraft many adults
• Graft failure still limiting 10% of cases
– Crude graft assessments
– Cell dose & HLA match both matter
– HSC functional capacity is good
– Other genetic elements might be even better

6. NMDP Graft types
Adults 18+ years Pediatrics
BM
PBSC
UCB
BM
PBSC
UCB

7. Sib
42%
URD
48%
UCB
10%
AML HCT 2000-2011: Donor Type

8. Challenges in finding a donor?
• Family size
• Race
• Ethnicity
• Urgency

9. Too many HLA alleles &
way too many combinations
1968-2010Class I Alleles
Class II Alleles

10. Challenges in finding a donor?
• Family size
• Race
• Ethnicity
• Urgency
Served by UCB

11. UCB is permissive of HLA mismatch
Offers HCT opportunity for minorities

12. UCB is permissive of HLA mismatch
Offers HCT opportunity for minorities
*******
Double UCB HCT extends the graft pool
Offers HCT opportunity for larger adults

13. Mutual Tolerance
Each unit will not reject the
other

14. What we’ve observed about
UCB GVHD
• Less or same GVHD
– Moderate acute
– Uncommon grade III/IV acute GVHD
– Therapy responsiveness
• Less chronic GVHD
– Less frequent
– More Responsive to therapy

15. Acute GVHD
Days
CumulativeProportion
0.0
0.2
0.4
0.6
0.8
1.0
0 20 40 60 80 100
Double UCB 60% (52-68%)
Single UCB 33% (27-39%)
p < .01
27
33
Median onset
MacMillan, 2009
Single UCB 11% (7-15%)
Double UCB 21% (15-27%)
II-IV
III-IV

16. Ponce, BBMT, 2013
Acute GVHD after UCB HCT
Median onset
40 d
35 d

17. Acute GVHD: Maximum Stage
Patients with GVHD
0
10
20
30
40
50
Skin Stage Liver Stage Lower GI Stage
1 2 3 4 1 2 3 4 1 2 3
4
%Patientsw/MaximumStage
Single UCBT
Double UCBT
Skin Liver Lower GI
p<0.01

18. Ponce, BBMT, 2013
Acute GVHD after UCB HCT
80% GI
64% skin
18% liver

19. Steroid therapy of Acute GVHD
Overall Response (CR+PR):
Multivariate Analysis
Odds Ratio P value
(95% CI)
Donor Type
Marrow 1.0
UCB 1.6 (0.9-2.8) .13
MacMillan et al, Blood 2009

20. Steroid therapy of Acute GVHD
6 month Survival after Onset of GVHD:
Multivariate Analysis
Odds Ratio (95% CI)
of mortality P value
Donor Type
Marrow 1.0
UCB 0.6 (0.4-0.9) .02
Maximum Grade of GVHD
Grade II 1.0
Grade III 1.2 (0.7-2.1) .46
Grade IV 2.6 (1.5-4.5) <.01
Single Organ Involvement
No 1.0
Yes 0.8 (0.5-1.2) .28

21. Steroid therapy of Acute GVHD

22. Incidence of Chronic GVHD
All Patients
Months
Incidence
p = .12
0.0
0.2
0.4
0.6
0.8
1.0
0 2 4 6 8 10 12
Double
Single

23. Benefits of UCB:
perhaps best for older patients
• Less Chronic GVHD after UCB
– Earlier discontinuation of immunosuppression
– Lesser medical interventions day 100 – 1 year

24. 0
500
1000
1500
2000
2500
2000
2001
2002
2003
2004
2005
2006
2007
2008
2009
2010
2011
NumberofRecipentsbyAgeGroup
Year
Age at Transplant for AML: 2000-2011
>60
41 – 60
21 – 40
<21

25. 0%
20%
40%
60%
80%
100%
<21 21-40 41-60 >60
Age Group
AML: HCT Donor Type
UCB
URD
Sib
2000-2011

26. AML in remission; Age >50 RIC HCT
Minnesota, Paris, Nantes
n=35
82
80
Peffault de la Tour,
2013

27. Does UCB produce potent GVL?
• UCB graft vs. tumor
• Same relapse with single UCB vs. BM/PB
GVL not tied to GVHD
• Possibly less relapse with Double UCB
• More potent GVL
– Enhanced GVL from the losing graft
– Augmented antigen presentation
– Secretion of pro-inflammatory or enhancing
cytokines

28. Incidence of Relapse
Acute Leukemia in CR1 & CR2
Months
Incidence
p = .05
0.0
0.2
0.4
0.6
0.8
1.0
0 2 4 6 8 10 12 14 16 18 20 22 24
Double
Single
9% (0-21%)
30% (16-44%)
Verneris, Blood, 2009

29. Relapse
LFS
DUCB
M URD
MM URD
M Rel
M Rel
MM URD
M URD
DUCB
Outcome after Myeloablative HCT with Cy/TBI:
U Minn: FHCRC
Brunstein, Blood, 2010

30. Similar relapse risks after UCB or URD BM or
URD PBPC HCT for adults with acute leukemia
Relapse HR p = 0.86
4-6/6 UCB vs
8/8 BM
43/165 (26%) vs.
112/332 (34%)
0.85
(0.59-1.20)
0.35
4-6/6 UCB vs
7/8 BM 42/140 (30%)
0.84
(0.55-1.28)
0.42
4-6/6 UCB vs
8/8 PBPC 209/632 (33%)
0.85
(0.61-1.17)
0.31
4-6/6 UCB vs
7/8 PBPC 77/256 (30%)
0.91
(0.67-1.32)
0.63
Eapen, Lancet Oncology, 2010

31. LFS after BM, PB or UCB
Eapen, Lancet Oncology, 2010
BM M
PBPC M
UCB
PB MM
BM MM

32. Less relapse with 4/6 UCB than URD M
or MM BM for children with leukemia
Relapse RR p
BM M 1.00
BM MM vs BM M 0.77 (0.51-1.16) .22
UCB M vs BM M 0.68 (0.35-1.32) .25
UCB 5/6 high dose vs BM M 0.67 (0.43-1.02) .06
UCB 5/6 low dose vs BM M 0.72 (0.35-1.51) .39
UCB 4/6* any dose vs BM M 0.54 (0.36-0.83) .0045
Eapen, Lancet 2007
*UCB 4/6 6 month survivors RR 0.50 p= .0045
12 month survivors RR 0.41 p= .0001

33. EBMT: Similar outcomes with single or double UCB
Retrospective
BMT CTN: Similar outcomes with single or double UCB for
children: Big single vs double
So Much More to learn
1 UCB 2 UCB p
1 y OS 66% 71% .12
1 y DFS 64 68 .20
1 year
relapse
14% 12% .37
cGVHD 30% 32% .64
Wagner, BMT CTN, 2012

35. What don’t we know about UCB?
What could broaden the indications?
How to improve UCB engraftment
Homing & Adhesion to HSC niche
Ex vivo expansion for HSC or
committed progenitors
How to enhance immune reconstitution?
T cell dose
T cell progenitors
Mixed cell infusions

36. What approaches could broaden
the indications for UCB HCT
Specialized supportive care for HCT
UCB have slower engraftment: May need
Prolonged or different Antibiotics
Isolation--resist push to abandon HEPA
& protective isolation
Smarter (cheaper) transfusion support

37. Barriers limiting UCB use
• Morbidity and Costs
– Graft failure 10% have prolonged stay
• Rescue with 2nd graft 30% 1 year survival
– Costly supportive care
• Hospital days; Transfusions; Infections

38. Barriers limiting UCB use
• Morbidity and Costs
– Graft failure 10% have prolonged stay
• Rescue with 2nd graft 30% 1 year survival
– Costly supportive care
• Hospital days; Transfusions; Infections
& the graft $35-45,000 (x 2)
[poorly reimbursed]

39. To understand the indications
we must:
• Compare outcomes with:
–URD Haplo (BMT CTN 1101)
–6 month and 3 year survival
–Studies to Reduce Morbidity
• Infections
• GVHD
• Transfusions
• Duration of specialized HCT care
• QOL

40. To understand the indications
we must:
• Compare outcomes with:
–URD Haplo (BMT CTN 1101)
–6 month and 3 year survival
–Studies to Reduce Morbidity & Relapse
• Infections
• GVHD
• Transfusions
• Duration of specialized HCT care
• QOL