Pr Eliane Gluckman , MD, FRCP,

Hospital Saint Louis, University Paris-

Diderot, France

Should Haplo-identical transplantation

be preferred to cord blood in patients

without a matched donor?

Disclosure of Interest: Nothing to Disclose

Why do we ask the question ?

• Unrelated cord blood transplant is clinically validated and reproducible with numerous single center and registry based studies

• Haplo-related transplants have been pionneered in the 70s, but most results were provided by single centers and few large series are published

• New technologies have been recently introduced with promising results

The ideal stem cell source

• Immediate availability

• Few HLA restriction

• Absence of risk for the donor

• Applicable to all diseases and all ages

• Associated with rapid lympho hematopoietic recovery, potent graft versus malignancy effect, little risk of acute and chronic GVH and high disease free survival

Cord blood transplantation advantages

• More than 25 years experience

• High quality cord blood banks: Immediate availability, absence of donor risk, HLA mismatch accepted

• General applicability for children and adults with malignant and non malignant disorders

• Outcome data collection through international registries

• Survival outcomes comparable to other sources of stem cells

• Use extended in older populations with reduced intensity conditioning and double cord blood transplant

• Exciting new results for improving engraftment and immune reconstitution

1988 First Cord Blood Transplant

1992-93 Establishment of Cord Blood Banks (NY, Paris, Milan and Dusseldorf )

1995 Establishment of Eurocord group

1998 Large series of UCBT= cell dose and HLA

2002 Use of cord blood cells in adults with promising results

2006 More adults than children transplanted with cord blood cells

2008 Allele matched UBMT compared to UCBT

2010 HLA C typing and outcomes

2013 HLA allele level typing

Past and Present of Cord Blood Transplants

Number of stem cell donors and cord blood units worldwide

Total donors: 22,387,367

Data from BMDW - Bone Marrow Donors Worldwide

21,798,409 stem cell donors 588,958 CBU’s

Eurocord Database

• 10509 cord blood transplantations were performed from 1988 to September 2013 in 52 countries and 580 centres

298 EBMT 7745 cases (74%)

282 Non-EBMT 2764 cases (24%)

7%

93%

related n=765 unrelated n=9699

53% 47%

children (age

Related and Unrelated UCBT in Children and Adults per Year

0

100

200

300

400

500

600

0

100

200

300

400

500

600

700

Eurocord, n=8667 CIBMTR, n=9617

Adult, n=4202 Children, n=4465

Adult, n=4019 Children, n=5598

0 200 400 600 800 1000 1200

16- 30 y

30- 39 y

40- 49 y

50- 59 y

>60 y

1171

780

719

805

477

1103

736

790

752

433

Single and double UCBT: distribution of age for adult patients

Eurocord

CIBMTR

35% adults>50 years

Unrelated UCBT performed in EBMT centers by recipient’s age and graft type

Children (

Type of conditioning for unrelated UCBT performed in EBMT centers

MAC RIC

Children (

59%

14%3% 3% 1%

20%

Acute leukemia

MDS /MPD

Lymphomas

Plasma cell disorders / SolidtumorsBone Marrow Failure Sd

Other non malignantdisorders

Children Adults

10%2%11%

7%

11%

9% 3%47%

Acute leukemia

MDS / MPD

Lymphomas / Solid tumors

Bone Marrow Failure Sd

Hemoglobinopathy

Immune Deficiency

Metabolic Disorder

Histiocytosis / Others

Transplants by diagnosis

Malignant: 50± 1%; n=1159

Non-malignant: 63 ± 2%; n=1113

■

■

P

Single and Double UCBT in EBMT centers: AML, ALL, MDS

Children: 2-y OS

2006-2011 (N=1210)

2000-2005 (N=555)

1996-1999 (N=170)

@2 years 43±2%

@2 years 37±4%

@2 years 56±2%

p

Single and Double UCBT in EBMT centers, n=2768

Adult, 2-y OS according to disease:

MDS/MPS: 25± 3%; n=380

Plasma cell disorder : 44 ± 6%; n=94

Lymphoma : 44 ± 3%; n=329

Acute leukemia 38 ± 2%; n=1685

Chronic leukemia 40 ± 3%; n=268

■ ■

■ ■

■

p=0.017

New clinical developments

• Single versus double UCBT

• New conditioning

• Criteria of donor choice

• Ex vivo expansion

Overall Survival - Adequate Dose Single vs. Double UCBT -

Adju

ste

d P

robability,

%

Months

0 6 12 36 24 18

100

0

20

40

60

80

0

100

20

40

60

80

Double UCBT, 32%

Single UCBT, TNC ≥2.5 x 107/kg, 33%

30

HR 0.92, p=0.62

Scaradavou ; Blood 2013

p=0.03

Group 1: sUCBT-CyTBI12: 30±7%, n=68

Group 2: sUCBT-BuFluTT+ATG: 46±6%, n=88

Group 3: dUCBT-CyFluTBI12: 48±6%, n=83

2 years- LFS after MAC sUCBT and dUCBT in adults with AL in CR1, n=239

Ruggeri ; Leukemia 2013

2 years- LFS after RIC sUCBT and dUCBT

in adults with AL in CR1, n=212

32 ± 3%

51 ± 5%

p=0.03

In multivariate analysis, double CBT was associated with improved LFS rates [p=0.04 HR=0.64 (0.41-0.99)]

dUCBT, n=136

sUCBT, n=76

Rocha ; ASH 2012

Criteria of donor choice

Lesser vs. Allele-level HLA-match

3/8 4/8 5/8 6/8 7/8 8/8

4/6 11% 31% 49% 10% __ __

5/6 1% 8% 22% 44% 25% __

6/6 __ __ 4% 18% 24% 54%

Eapen, EBMT 2013

Neutrophil Recovery - Allele-level Matched at A, B, C, DRB1 -

100

0

20

40

60

80

0

100

20

40

60

80

Incid

ence,

%

Days

0 30 10 5

8/8 (71%)

15 20 25

3/8 (53%)

4/8 (56%)

5/8 (58%)

6/8 (66%)

7/8 (62%)

P=0.005

Eapen, EBMT 2013

Neutrophil Recovery - Allele-level Matched at A, B, C, DRB1 -

Odds R

atio

HLA-Match

7/8 6/8 3/8

3.00

0.00

1.00

2.00

0.00

3.00

1.00

2.00

5/8 4/8

0.72 0.86

0.56 0.55 0.45

P=0.005

Eapen, EBMT 2013

Non-Relapse Mortality - Allele-level Matched at A, B, C, DRB1 -

Incid

ence,

%

Years

0 1 2 3

100

0

20

40

60

80

0

100

20

40

60

80

6/8 (26%)

4/8 (37%)

5/8 (34%)

3/8 (41%)

7/8 (26%)

8/8 (9%)

P

Non-Relapse Mortality - Allele-level Matched at A, B, C, DRB1 -

Hazard

Ratio

HLA-Match

7/8 6/8 3/8

10.00

0.00

2.00

4.00

6.00

8.00

1.00

0.00

10.00

2.00

4.00

6.00

8.00

1.00

5/8 4/8

2.79 2.69

3.60 3.48

4.61

P

RISK FACTORS - HIGHER MORTALITY

Factors Non Relapse Mortality

Overall Mortality

Age, > 16 years HR 1.62

HR 1.43

ALL HR 1.35 HR 1.26

Active disease at transplant

HR 1.68 HR 2.98

TNC ≤3 x 107/kg HR 1.51 HR 1.35

Period 2000-2004

HR 1.51 HR 1.35

Eapen, EBMT 2013

Non-Relapse Mortality - 7/8 Allele-level HLA-Matched: Effect of TNC -

Incid

ence,

%

Years

0 1 2 3

100

0

20

40

60

80

0

100

20

40

60

80

7/8, TNC> 5 x 107/kg (20%)

7/8, TNC ≤3 x 107/kg (45%)

7/8, TNC > 3 – 5 x 107/kg (24%)

8/8 (9%)

Eapen, EBMT 2013

Non-Relapse Mortality - Effect of mismatch at single HLA-locus -

HR P-value

HLA-A match vs. mismatch 117 vs. 117

3.05 0.002

HLA-B match vs. mismatch 31 vs. 117

1.26 0.72

HLA-C match vs. mismatch 40 vs. 117

3.04 0.01

HLA-DRB1 match vs. mismatch 66 vs. 117

2.93 0.005

Eapen, EBMT 2013

Best HLA-match Allele-level match at HLA-A, -B, -C and –DRB1

Select units with TNC ≥ 3 x 107/kg

7/8 and 6/8 are better tolerated than 5/8 or 4/8 HLA-matched transplants

Avoid 3/8 HLA-matched transplants

Absence of HLA-C typing match at HLA-B HLA-C at confirmatory typing TNC in excess of minimum required does not lower NRM

Eapen, EBMT 2013

Comparative Studies of cord blood transplant with other

stem cell sources

Ad

juste

d P

ro

bab

ilit

y,

%

0

20

40

60

80

100

12 24 60 48 36 0

CB matched (n=35) 60%

CB 1-Ag MM >3.5x107/kg (n=157) 45%

BM matched (n=116) 38%

CB 2-Ag MM (n=267) 33%

CB 1-Ag MM >3.5x107/kg (n=44) 35%

Eapen M et al Lancet. 2007, 369:1947-54

Survival and LFS are similar after UCBT compared to unrelated bone marrow in children with acute leukemias

Impact of Stem Cell Source in Adults with Acute Leukemia, n=1280

Leukemia-free Survival

-Adjusted for Disease Status at Transplantation-

Pro

bability,

%

Years

0

100

0

20

40

60

80

90

10

30

50

70

0

100

20

40

60

80

90

10

30

50

70

CB, 33%

12 24 24 36

BM matched, 41%

PBPC matched, 39%

Not in remission at HCT, RR 2.40, p

Leukemia-Free Survival

by Donor Type

Minnesota FHRC study

Cum

ula

tive P

roport

ion

SIB MM URD

MUD DUCB

0.0

0.2

0.4

0.6

0.8

1.0

0 1 2 3 4 5

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Years post-transplantation

Matched Sibling*

MUD

MMUD

DUCB

1.0

0.83 (0.62-1.11)

1.04 (0.70-1.53)

1.00 (0.73-1.37)

P=.20

P=.85

P=.99

Brunstein C, Blood 2010

RIC Leukemia-Free Survival

Pro

bability,

%

Months

0 6 12 36 24 18

100

0

20

40

60

80

90

10

30

50

70

0

100

20

40

60

80

90

10

30

50

70

30

MMUD: 25%

MUD: 31%

dCB, TCF: 26%

dCB, other: 9%

P=0.017 MUD vs. dCB other 0.68 (0.47 – 0.99) 0.046

Brunstein C, Eapen M, Blood 2012

Similarities between UCBT and haplo identical related transplant

Cord blood Haplo identical

HLA mismatch 0,1,2 mismatches 2,3 mismatches

Availability 15-30 days 15-30 days

GVHD limited limited

Immune reconstitution Delayed Delayed

Indications Malignant and non malignant

Malignant and non malignant

Age Children and adults Children and adults

Conditioning Myeloablative or non myeloablative

Myeloablative or non myeloablative

Differences between UCBT and haplorelated BMT

UCBT Haplo

Type of graft Cryopreserved cord blood Mobilized PBSC and or BM

Limitation of Graft acquisition

Cell dose Poor mobilization

Graft manipulation None None or In vitro T cell depletion

Donor safety No problem G-CSF toxicity + harvest

Cell dose TNC CD34 T lymphocytes

>0.3x108/kg >0.2x106/kg >0.4x107/kg

>9x108/kg >7x106/kg varies

GVH prophylaxis Standard Standard +in vivo T cell depletion or non for T depleted

Cost of the graft 20-30,000 US $ Cost of G-CSF, graft harvest and manipulation

Controversies-UCBT

• Sustainability and quality of cord blood banks

• UCBT is associated with delayed engraftment and immune reconstitution

• No possibility to perform DLI, but GVL after UCBT is high and immunotherapy is possible

Controversies-Haplo

• Criteria of donor choice

• Indications and conditioning: small series, heterogeneity

• Stem cell source

– GCSF primed BM or PBSC or both

– Effect of cell dose and graft composition

– T deplete or not?

• GVHD prophylaxis

– None

– Post HSCT cyclophosphamide, rapamycin, multi drugs (ATG + MTX + CSA + MMF + basiliximab)

• Single center experience :

Outcome data and long term follow up are not yet available

Conclusion • HLA mismatched HSCT transplants are feasible and there is

no shortage of donors

• Is MUD=CB=Haplo? All retrospective studies in children and adults with acute leukemia showed that alternative sources such as UBMT, UCBT or Haplo, can be used to treat a number of patients with some different outcomes, but similar LFS

• Comparative registry-based studies are needed

• Collaborative protocols should explore new methods to improve results

• The ultimate choice of the SC source depends on expertise and policy of each center