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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 source & composition Urgency
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
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
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
1968-2010 Class 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 Offers HCT opportunity for larger adults
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 responsiveness
• Less chronic GVHD
– Less frequent – More Responsive to therapy
Acute GVHD
Days
Cum
ulat
ive
Prop
ortio
n
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
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 4
% P
atie
nts w
/ Max
imum
Sta
ge
Single UCBT
Double UCBT
Skin Liver Lower GI p<0.01
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 Marrow 1.0 UCB 1.6 (0.9-2.8) .13
MacMillan et al, Blood 2009
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
Steroid therapy of Acute GVHD
Incidence of Chronic GVHD All Patients
Months
Inci
denc
e
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 immunosuppression – Lesser medical interventions day 100 – 1 year
0
500
1000
1500
2000
2500
2000
2001
2002
2003
2004
2005
2006
2007
2008
2009
2010
2011
Num
ber o
f Rec
ipen
ts b
y A
ge G
roup
Year
Age at Transplant for AML: 2000-2011
>60 41 – 60 21 – 40 <21
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 • 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
Incidence of Relapse Acute Leukemia in CR1 & CR2
Months
Inci
denc
e
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
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
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
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 (0.51-1.16) .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
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
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
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
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
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]
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
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