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