Cord Blood Transplantation: Are
the indications changing?
Daniel Weisdorf MD
University of Minnesota
Donor options
Matched siblings
Other relatives
Unrelated donors (URD)
Umbilical Cord Blood
Self (autologous)
Donor Choice Issues—beyond matched siblings
Age
Gender & match
Alloimmunization -- parity
CMV
HLA matching
Cell dose
Graft...
Donor Choice Issues: URD vs. UCB
Age UCB are the youngest
Gender & match ----
Alloimmunization -- parity UCB
CMV UCB
HLA m...
Here are the basics
• UCB engrafts children
and 1-2 UCB can engraft many adults
• Graft failure still limiting 10% of case...
NMDP Graft types
Adults 18+ years Pediatrics
BM
PBSC
UCB
BM
PBSC
UCB
Sib
42%
URD
48%
UCB
10%
AML HCT 2000-2011: Donor Type
Challenges in finding a donor?
• Family size
• Race
• Ethnicity
• Urgency
Too many HLA alleles &
way too many combinations
1968-2010Class I Alleles
Class II Alleles
Challenges in finding a donor?
• Family size
• Race
• Ethnicity
• Urgency
Served by UCB
UCB is permissive of HLA mismatch
Offers HCT opportunity for minorities
UCB is permissive of HLA mismatch
Offers HCT opportunity for minorities
*******
Double UCB HCT extends the graft pool
Offe...
Mutual Tolerance
Each unit will not reject the
other
What we’ve observed about
UCB GVHD
• Less or same GVHD
– Moderate acute
– Uncommon grade III/IV acute GVHD
– Therapy respo...
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-...
Ponce, BBMT, 2013
Acute GVHD after UCB HCT
Median onset
40 d
35 d
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
...
Ponce, BBMT, 2013
Acute GVHD after UCB HCT
80% GI
64% skin
18% liver
Steroid therapy of Acute GVHD
Overall Response (CR+PR):
Multivariate Analysis
Odds Ratio P value
(95% CI)
Donor Type
Marro...
Steroid therapy of Acute GVHD
6 month Survival after Onset of GVHD:
Multivariate Analysis
Odds Ratio (95% CI)
of mortality...
Steroid therapy of Acute GVHD
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
Benefits of UCB:
perhaps best for older patients
• Less Chronic GVHD after UCB
– Earlier discontinuation of immunosuppress...
0
500
1000
1500
2000
2500
2000
2001
2002
2003
2004
2005
2006
2007
2008
2009
2010
2011
NumberofRecipentsbyAgeGroup
Year
Age...
0%
20%
40%
60%
80%
100%
<21 21-40 41-60 >60
Age Group
AML: HCT Donor Type
UCB
URD
Sib
2000-2011
AML in remission; Age >50 RIC HCT
Minnesota, Paris, Nantes
n=35
82
80
Peffault de la Tour,
2013
Does UCB produce potent GVL?
• UCB graft vs. tumor
• Same relapse with single UCB vs. BM/PB
GVL not tied to GVHD
• Possibl...
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...
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
Bru...
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
...
LFS after BM, PB or UCB
Eapen, Lancet Oncology, 2010
BM M
PBPC M
UCB
PB MM
BM MM
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...
EBMT: Similar outcomes with single or double UCB
Retrospective
BMT CTN: Similar outcomes with single or double UCB for
chi...
What don’t we know about UCB?
What could broaden the indications?
How to improve UCB engraftment
Homing & Adhesion to HSC ...
What approaches could broaden
the indications for UCB HCT
Specialized supportive care for HCT
UCB have slower engraftment:...
Barriers limiting UCB use
• Morbidity and Costs
– Graft failure 10% have prolonged stay
• Rescue with 2nd graft 30% 1 year...
Barriers limiting UCB use
• Morbidity and Costs
– Graft failure 10% have prolonged stay
• Rescue with 2nd graft 30% 1 year...
To understand the indications
we must:
• Compare outcomes with:
–URD Haplo (BMT CTN 1101)
–6 month and 3 year survival
–St...
To understand the indications
we must:
• Compare outcomes with:
–URD Haplo (BMT CTN 1101)
–6 month and 3 year survival
–St...
Cord Blood Transplantation: Are the indications changing?
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Cord Blood Transplantation: Are the indications changing?

  1. 1. Cord Blood Transplantation: Are the indications changing? Daniel Weisdorf MD University of Minnesota
  2. 2. Donor options Matched siblings Other relatives Unrelated donors (URD) Umbilical Cord Blood Self (autologous)
  3. 3. Donor Choice Issues—beyond matched siblings Age Gender & match Alloimmunization -- parity CMV HLA matching Cell dose Graft source & composition Urgency
  4. 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. 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. 6. NMDP Graft types Adults 18+ years Pediatrics BM PBSC UCB BM PBSC UCB
  7. 7. Sib 42% URD 48% UCB 10% AML HCT 2000-2011: Donor Type
  8. 8. Challenges in finding a donor? • Family size • Race • Ethnicity • Urgency
  9. 9. Too many HLA alleles & way too many combinations 1968-2010Class I Alleles Class II Alleles
  10. 10. Challenges in finding a donor? • Family size • Race • Ethnicity • Urgency Served by UCB
  11. 11. UCB is permissive of HLA mismatch Offers HCT opportunity for minorities
  12. 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. 13. Mutual Tolerance Each unit will not reject the other
  14. 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. 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. 16. Ponce, BBMT, 2013 Acute GVHD after UCB HCT Median onset 40 d 35 d
  17. 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. 18. Ponce, BBMT, 2013 Acute GVHD after UCB HCT 80% GI 64% skin 18% liver
  19. 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. 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. 21. Steroid therapy of Acute GVHD
  22. 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. 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. 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. 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. 26. AML in remission; Age >50 RIC HCT Minnesota, Paris, Nantes n=35 82 80 Peffault de la Tour, 2013
  27. 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. 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. 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. 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. 31. LFS after BM, PB or UCB Eapen, Lancet Oncology, 2010 BM M PBPC M UCB PB MM BM MM
  32. 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. 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
  34. 34. 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
  35. 35. 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
  36. 36. 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
  37. 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 & the graft $35-45,000 (x 2) [poorly reimbursed]
  38. 38. 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
  39. 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 & Relapse • Infections • GVHD • Transfusions • Duration of specialized HCT care • QOL

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