cord blood transplantation: are the indications changing?
TRANSCRIPT
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Cord Blood Transplantation: Are the indications changing?
Daniel Weisdorf MD University of Minnesota
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Donor options Matched siblings Other relatives Unrelated donors (URD) Umbilical Cord Blood Self (autologous)
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Donor Choice Issues—beyond matched siblings Age Gender & match Alloimmunization -- parity CMV HLA matching Cell dose Graft source & composition Urgency
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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
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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
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NMDP Graft types
Adults 18+ years Pediatrics
BM
PBSC
UCB
BM
PBSC
UCB
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Sib 42%
URD 48%
UCB 10%
AML HCT 2000-2011: Donor Type
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Challenges in finding a donor?
• Family size
• Race • Ethnicity • Urgency
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Too many HLA alleles & way too many combinations
1968-2010 Class I Alleles Class II Alleles
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Challenges in finding a donor?
• Family size
• Race • Ethnicity • Urgency
Served by UCB
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UCB is permissive of HLA mismatch Offers HCT opportunity for minorities
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UCB is permissive of HLA mismatch Offers HCT opportunity for minorities ******* Double UCB HCT extends the graft pool Offers HCT opportunity for larger adults
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Mutual Tolerance
Each unit will not reject the other
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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
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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
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Ponce, BBMT, 2013
Acute GVHD after UCB HCT
Median onset 40 d
35 d
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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
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Ponce, BBMT, 2013
Acute GVHD after UCB HCT
80% GI 64% skin 18% liver
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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
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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
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Steroid therapy of Acute GVHD
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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
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Benefits of UCB: perhaps best for older patients
• Less Chronic GVHD after UCB
– Earlier discontinuation of immunosuppression – Lesser medical interventions day 100 – 1 year
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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
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0%
20%
40%
60%
80%
100%
<21 21-40 41-60 >60 Age Group
AML: HCT Donor Type
UCB URD Sib
2000-2011
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AML in remission; Age >50 RIC HCT Minnesota, Paris, Nantes
n=35 82 80
Peffault de la Tour, 2013
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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
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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
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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
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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
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LFS after BM, PB or UCB
Eapen, Lancet Oncology, 2010
BM M PBPC M UCB PB MM BM MM
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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
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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
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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
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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
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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
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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]
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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
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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