Unrelated Cord Blood Transplantation In Adults with Hematological Malignancies Eurocord Results

Vanderson Rocha, MD, PhD Professor of Haematology- Oxford University

BMT unit, Churchill Hospital Oxford, UK

Scientific Director of Eurocord Paris, France

Unrelated Cord Blood Transplantation

In adults with Hematological Malignancies

Eurocord Results

UCBT for adults with Malignancies

• Eurocord Registry update • Indications

• Survey on outcomes for specific diseases

• Survey on outcomes of elderly patients in Europe and USA • Conditioning regimen

• Complications (engraftment)

Eurocord Registry Update • 12.066 CBU shipped for transplantation (283, 2%, not used): 11.783 CBU used for: • 9.883 CBT from 1988 to 2012 in 51 countries and 577 centres 293 EBMT 6958 cases (75%) 267 Non-EBMT 2379 cases (25%)

54%

46%

Children n=5071 (54%) Adult n=4265 (46%)

8%

92%

Related n=708 (8%)

Unrelated n=8618 (92%)

Eurocord Registry

N°of European CBUs shipped by year*

* 215 CBUs not infused are included in the bar chart

0

100

200

300

400

500

600

700

800

900

1990

1991

1992

1993

1994

1995

1996

1997

1998

1999

2000

2001

2002

2003

2004

2005

2006

2007

2008

2009

2010

2011

2012

Year of shipment

N of CBUs

1990 3 1991 1 1992 2 1993 1 1994 5 1995 15 1996 30 1997 58 1998 92 1999 123 2000 145 2001 192 2002 167 2003 187 2004 298 2005 440 2006 590 2007 695 2008 823 2009 813 2010 878 2011 817 2012 813

N=7188

Eurocord Registry Unrelated European CBT by recipient’s age and graft type

Children Adults

* Still collecting 2012 data

0

50

100

150

200

250

300

1990

19

94

1995

19

96

1997

19

98

1999

20

00

2001

20

02

2003

20

04

2005

20

06

2007

20

08

2009

20

10

2011

20

12

Double CBT

Single CBT *

0

50

100

150

200

250

300

350

400

1994

19

95

1996

19

97

1998

19

99

2000

20

01

2002

20

03

2004

20

05

2006

20

07

2008

20

09

2010

20

11

2012

Double CBT

Single CBT *

In children: 92% single CBT In adults: 47% double CBT

CELL DOSE

Children, n=2354 Adult, n=1337

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

TNC (x10^7) of CBU Used for Single Transplants

Indication for Unrelated UCBT in adults

0

100

200

300

400

500

600

700

21%

39%

14%

8%

1%

12%

2% 3%

17%

37%

14%

5% 4%

15%

4% 4%

Single, n= 1735

Double, n= 1752

Age distribution for adult patients

0 200 400 600 800 1000 1200

16- 30 y

30- 39 y

40- 49 y

50- 59 y

>60 y

1103

736

790

752

433

N=1185

2 Years Survival in Adults (single and double unrelated CBT)

2 Years Survival in Adults (single and double unrelated CBT) with Acute Leukemia (n=1552) by disease status

CR1 (n= 636)- 48%

CR2 (n= 557)- 41%

More advanced (n= 359)-12%

Unrelated CBT- Outcomes and Risk factors for specific diseases

Clinical Results of Unrelated CBT in Adults

n Median FU (m/y)

Outcomes Favourable Risk Factors

Ref

Lymphoid malignancies

104 18 m DFS: 41% Chemosensitive disease Low-dose TBI Cell dose>2x107/Kg

JCO, 2009

MDS

108

25 m DFS: 30% low-risk disease Leukemia, 2010

Acute leukemia- KIR

218

14 m

LFS: KIR-MM: 55% KIR-M: 31%

KIR-ligand incompatibility HLA 0/1 mismatch

Leukemia 2009

Acute leukemia- RIC

155

18 m

LFS: 51%

Disease Status HLA 0/1 mismatch

Not published

ALL 421 24 m LFS CR1: 39% CR2: 31% Adv: 8%

Disease Status, age<35 No use of ATG

Submitted 2013

AML

604 24 m LFS: CR1: 43% CR2: 38% Adv: 11%

Disease Status, no previous autologous transplant, TBF (MAC) Disease status, age<48 years and TCF (RIC)

Not published

Outcomes of unrelated cord blood transplant for adults with acute lymphoblastic

leukemia: a survey conducted by Eurocord and the ALWP/EBMT

L Tucunduva, A Ruggeri , G Sanz, S Furst, B Rio, G Socié, W Arcese, M Michallet, I Yakoub-Agha, J Cornelissen, J Sanz, P Montesinos, D Purtill, E

Gluckman, M Mohty and V Rocha

BMT Tandem Meetings CIBMTR / ASBMT Salt Lake City 13-17 February/2013

No conflict of interest to disclose

Patient and disease characteristics n=421

Characteristics CR1,

n=195 CR2,

n= 136Not CRn= 90

Median age at UCBT, years (range) 35 (18-64) 26 (18-76) 30 (18-60)Age ≥35 years at diagnosis 48% 25% 31%

Immunophenotype B 71% 74% 63%T 20% 21% 35%

Other 9% 5% 2%WBC count at diagnosis

median (range) 16 (0.6-456) 11 (0.2-624) 13 (0.7-515)≥30x109/L 40% 32% 39%≥100x109/L 14% 14% 24%

Cytogenetics very high risk 57% 23% 28%

high risk 5% 2% 8%standard risk 38% 75% 63%

Median time from diagnosis to UCBT, months (range) 7 (3-39) 31 (2-96) 16 (3-113)

Median time from diagnosis to first relapse, months (range) na 27 (3-140) 13 (2-138)

Transplant characteristics

Characteristics CR1,

n=195 CR2,

n= 136Not CRn= 90

Type of UCB graft single 57% 54% 70%double 43% 46% 30%

TNC x107/Kg; median (range) 4.0 (1.8-9.4) 4.1 (1.5-9.0) 3.8 (1.8-9.2)HLA matching No mismatch 4% 1% 0%1 mismatch 32% 23% 26%

2-3 mismatches 64% 76% 74%Type of conditioning

RIC 28% 24% 18%MAC 72% 76% 82%

Other n=30 (29%)

Cy+Flu+TBI

n=73 (71%)

Conditioning

MAC n=314 RIC n=103

Cy+TBIn=80(44%)

Cy+Flu+TBIn=63 (35%)

Othern=36

Cy+Bu n=10 (8%)

Cy+Bu+Thio n=27 (21%)

Bu+Flu+Thio n=78 (62%)

Other n=11 (9%)

Cy+Thio n=1

Cy+Bu+Thio n=1

Cy+Flu n=3

Flu+Mel n= 1

Cy+Flu+Mel n=2

Cy+Flu+Thio n=1Bu+Flu n=1

Cy+Bu+Flu n= 2

Bu+Flu+Thio n=8

Flu+other n=4

Cy+Bu+Flu+ARAC+amsa

crine n=1

GVHD prophylaxis

MAC RIC

0

10

20

30

40

50

60

70

80

0

20

40

60

80

100

120

• Use of ATG in conditioning regimen

p<0.0001

Results - 2y LFS all patients

CR1 39±4%(n=195)

CR2 31±4% (n=136)

not in CR 8±3% (n=90)

p<0.0001

Results - 2y LFS all patients

no ATG 42±4% (n=132)

ATG 23±3% (n=239)

p<0.0001

Results - 2y LFS

MAC RIC

no ATG 39±6% (n=72)

ATG 23±3% (n=212)

no ATG 47±6% (n=62)

ATG 33±10% (n=25)

p=0.02 p=0.04

Multivariate analysis for LFS

• Variables tested in the model: -- age (≥35 vs <35 years) -- remission status (CR1 and CR2 vs advanced) -- median collected TNC (equal or superior vs inferior 4.0x107/kg) -- conditioning (RIC vs MAC) -- type of graft (single vs double) -- use of ATG in conditioning regimen (yes vs no)

Variable HR 95% IC p value

age ≥35 y 1.3 1.1-1.7 0.03

not in CR at UCBT 2.5 2.0-3.3 <0.0001

ATG 1.5 1.1-2.0 0.009

Factors associated with decreased LFS

Clinical Results of Unrelated CBT in Adults

n Median FU (m/y)

Outcomes Favourable Risk Factors

Ref

Lymphoid malignancies

104 18 m DFS: 41% Chemosensitive disease Low-dose TBI Cell dose>2x107/Kg

JCO, 2009

MDS

108

25 m DFS: 30% low-risk disease Leukemia, 2010

Acute leukemia- KIR

218

14 m

LFS: KIR-MM: 55% KIR-M: 31%

KIR-ligand incompatibility HLA 0/1 mismatch

Leukemia 2009

Acute leukemia- RIC

155

18 m

LFS: 51%

Disease Status HLA 0/1 mismatch

Not published

ALL 421 24 m LFS CR1: 39% CR2: 31% Adv: 8%

Disease Status, age<35 No use of ATG

Submitted 2013

AML

604 24 m LFS: CR1: 43% CR2: 38% Adv: 11%

Disease Status, no previous autologous transplant, TBF (MAC) Disease status, age<48 years and TCF (RIC)

Not published

Cord blood transplantation for adult with acute myeloid leukaemia:

a survey on behalf of Eurocord and ALWP-EBMT

Annalisa Ruggeri, William Arcese, Guillermo Sanz, Bernard Rio, Noel Milpied, Sabine Furst, Josep Ribera, Alberto Bosi, Emmanouel Nikiforakis,

Eliane Gluckman, Mohamad Mohty, Myriam Labopin and Vanderson Rocha

16th Congress of the European Hematology Association (EHA) London - 11/06/2011


UCBT for AML Patients and disease characteristics, n= 604

60% single and 40% adults

CR1, n=229 CR>=2, n=228 Adv, n=147

Median age at UCBT (years) 40 (18-66) 42 (18-68) 41 (22-67)

Male 109 (49%) 109 (48%) 71 (48%)

Positive pts CMV serology 130 (63%) 133 (64%) 74 (64%)

High risk cytogenetic n=192 n=190 n=114

115 (60%) 94 (49%) 63 (55%)

Interval diagnosis-UCBT 6 months 22 months 13 months

Previous HSCT (auto/allo) 12 (5%) 77 (34%) 44 (32%)

Median Follow-up 24 (range 3-120) months

UCBT for AML Transplant characteristics, n=604

• MAC • RIC

MAC: TBI dose > 6Gy, Busulfan dose >8 mg/Kg or IV BU>9.6 mg/kg

CyFluTBI-2Gy 72%

Other Flu-Based 15%

Other 13% BuFluTT

34%

BuCy 10% BuCyTT

5%

CYTBI-12Gy 16%

CyFluTBI-12Gy 11%

Other Bu-Based 12%

Other 12%

UCBT for AML- MAC LFS

MAC- 2y LFS by disease status, n=293

Disease Status (Remission) HR 2,11- 95%CI 1,56- 2,87, p=<0,0001

No Previous HSCT HR 2,19 -95%CI 1,58- 3,04, p=<0,0001 Multivariate analysis (LFS- MAC)

CR1: 51%

CR2 and CR3:37%

Adv: 14% p<0.0001

UCBT for AML- RIC LFS

RIC- 2y LFS by disease status, n=289

Disease Status (Remission) HR 2,5- 95%CI 1,73- 3,59, p=<0,0001

Age<48y HR 1,45 -95%CI 1,16- 2,06, p=0,02 CyFluTBI2Gy HR 1,67 -95%CI 1,18- 2,37, p=0,004

Multivariate analysis (LFS- RIC)

CR2 and CR3 : 47%

CR1: 38%

Adv: 9% p<0.0001

Changing trends of UCBT for hematological malignancies

in patients older than 50 years:

a Eurocord- CIBMTR survey

Annalisa Ruggeri, Mary Eapen,

Luciana Tucunduva, Fernanda Volt, Mary Horowitz, Vanderson Rocha, Daniel Weisdorf and Eliane Gluckman


UCBT in Children and Adults per Year

0

100

200

300

400

500

600

2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 0

100

200

300

400

500

600

700

2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011

Eurocord, n=9470 CIBMTR, n=9617

Adult, n=4354 Children, n=5116

Adult, n=4019 Children, n=5598

Single and double UCBT: distribution of age for adult patients

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 Eurocord

CIBMTR

Study Objective

Survey of patients more than 50 years of age reported to Eurocord and CIBMTR

• Period 2005 - 2011 • Hematologic malignancies

N = 1529 n = 848 (N. America) n= 681 (Europe) Median follow up: 24 months

0

100

200

300

400

500

600

50- 59 y 60- 69 y 70+ y

Eurocord

CIBMTR

64%

36%

60%

37%

3%

Age distribution

8%

42%

20%

3%

6%

12%

7% 1% 1%

8%

52% 14%

3%

8%

14% 1%

ALL AML MDS/MPD CML CLL NHL HD PCD Solid Tumor BMFS

Diagnosis

Eurocord

CIBMTR

Transplant characteristics

Graft Type Conditioning Regimen

0% 10% 20% 30% 40% 50% 60% 70% 80% 90%

100%

Eurocord, n=681 CIBMTR, n=848

Double UCBT Single UCBT

0% 50% 100%

50- 59 y- CIBMTR

50- 59 y- Eurocord

60- 69 y- CIBMTR

60- 69 y- Eurocord

52%

77%

72%

93%

48%

23%

21%

7%

■ RIC ■ MAC

29%

71%

39%

61%

Overall Survival - Acute Myeloid Leukemia -

Eurocord, n=262

42±5%

40±6%

11±5%

■ CR1, n=117

■ CR2, n=91

■ Advanced, n=154

Overall Survival - Acute Myeloid Leukemia -

Prob

abili

ty,

%

Years 0

100

0

20

40

60

80

90

10

30

50

70

0

100

20

40

60

80

90

10

30

50

70

1 2

CR1 (N=213) CR2 (N=107) Relapse (N=89)

CIBMTR, n=409

Overall Survival -AML by disease status and conditioning-

Eurocord, n=257

46±4%

33±10% 30±12%

6±4%

■ CR and MAC, n=29

■ CR and RIC, n=176

■ Rel and MAC, n=17

■ Rel and RIC, n=35

Overall Survival - Acute Myeloid Leukemia –

Prob

abili

ty,

%

Years 0

100

0

20

40

60

80

90

10

30

50

70

0

100

20

40

60

80

90

10

30

50

70

1 2

CR and MAC (N=112) CR and RIC (N=191) Rel and MAC (N=49) Rel and RIC (N=31)

CIBMTR, n=373

Overall Survival - Myelodysplastic Syndrome -

Eurocord, n=138

28±6% 25±6%

■ 50-59 yrs, n=83

■ +60 yrs, n=55

Overall Survival - Myelodysplastic Syndrome -

Prob

abili

ty,

%

Years 0

100

0

20

40

60

80

90

10

30

50

70

0

100

20

40

60

80

90

10

30

50

70

1 2

50-59 yrs (N=62) 60+ yrs (N=44)

CIBMTR, n=106

0

50

100

150

200

250

300

350

1990

1994

1995

1996

1997

1998

1999

2000

2001

2002

2003

2004

2005

2006

2007

2008

2009

2010

2011

Type of Conditioning Regimen in Single and Double UCBT Single UCBT, n=4946 Double UCBT, n=1841

*

* Still collecting data

MAC n=3581 RIC n=1365

MAC n=644 RIC n=1197

*

No Flu Based (n=1471) 86 %

Fludarabine based MAC (n=384) 91%

60 50 40 30 20 10 0

1,0

,8

,6

,4

,2

0,0

Neutrophil recovery after single UCBT for patients with malignant disorders after myeloablative conditioning regimen (n=1946)

p< 0.0001

Conditioning regimen Myeloablative

Analyze the impact of TT, iv BU, F+ATG (TBF-ATG) on long

term outcomes after single unit UCBT compared to other MAC regimens in adults with leukemias in remission

H Bittencourt et al. # 377, Oral session EBMT

Thiotepa-Busulfan-Fludarabine versus Cyclophosphamide-based

Myeloablative Conditioning Regimen

In Remission

Early Stage (n=147)

Characteristics Group 1, sUCBT

Cy-based n=93

Group 2, sUCBT Bu+Flu+TT

n=54

Age (years) 33(18-54) 32 (19-51) HLA match – 4/6 51(56%) 28(53%) Acute Leukemia* 79(85%) 52 (96%)

Median TNC after thawing (107Kg) 2.5 (0.6-7.6) 2.3 (1.4-4.9)

GVHD Prophylaxis: CSA+Steroids

ATG

78(84%) 83(89%)

38 (70%) 48(89%)

Year of UCBT* 2003 (2000-2007) 2006 (2005-2008)

* P<0.05 Besides ABO major incompatibility (P=0.02), there was no other differences among the 2 groups for patients disease and UCBT

characteristics (gender, weight, CMV status, previous autologous HSCT, CD34+ infused cells)

EFS at 5 years Early Stage

Group 1: sUCBT-Cy-based: 28%

Group 2: sUCBT-BuFluTT: 41%

BuFluTT associated with better event-free survival in multivariate analysis HR 0.64 (CI95%:0.41-0.99 – P=0.04)

P=0.07

DFS: 32%

TBF Single UCBT vs

other MAC single UCBT vs

TBI+CY+Flu double UCBT

What are the results ?

p=0.03

Group 1: sUCBT-CyTBI12: 30±7%, n=68 (Cell dose 2.9)

Group 2: sUCBT-BuFluTT+ATG: 46±6%, n=88 (Cell dose 3.1)

Group 3: dUCBT-CyFluTBI12: 48±6%, n=83 (Cell dose 3.7)

LFS at 2 years MAC sUCBT and dUCBT in adults with AL in CR1

Which is the “best” RIC for UCBT?

Disease Free Survival according to conditioning after single and double UCBT for malignancies in

adults ( n=155)

Months

28% others

51% CY+TBI 2GY+FLU (n=101)

P= 0.0002

0 10 20 30

0.0

0.2

0.4

0.6

0.8

1.0

Months

Pro

babi

lity

Relapse

2 year estimate: 46%

Phase II trial in France on the use of TCF–RIC in UCBT for AML ( n=79)

Cumulative Incidence of Relapse

Rio B et al

Should we include Thiotepa or increase TBI in the RIC ?

PROBABILITY OF ENGRAFTMENT

• The Probability Density to engraft describes the probability to engraft at each time point from CBT, also considering competing events (ie early deaths)

• The engraftment probability peaks at +21, the median halves at +31 (20%) and drops to 5% at day 42

-0.0050

0.0000

0.0050

0.0100

0.0150

0.0200

0.0250

0.0300

0.0350

0.0400

0 5 10 15 20 25 30 35 40 45 50 55 60 65 70 75 80 85 90

20% 5%

The area under the curve beyond each time points represents the residual probability to engraft

Conclusions

Single and unrelated cord blood with myeloablative or

reduced intensity conditioning regimens are feasible procedures and have extented the use of allo transplants for patients without a HLA matched donor

Graft failure and delayed neutrophil recovery are still

problems to be circumvent in the field of UCBT Analysis of risk factors in specific diseases are important with

the aim to improve final outcomes.

Leukemia-free Survival after Single UCBT – MAC in adults with leukemias

- Transplantation in Remission -

Pro

bab

ilit

y, %

100

0

20

40

60

80

90

10

30

50

70

Months 0 6 12 18 24 8/8 matched BM 246 177 139 99 82 7/8 matched BM 106 69 46 35 31 8/8 matched PBPC 452 316 220 143 112 7/8 matched PBPC 166 89 66 45 36 4/6-6/6 matched UCB 123 77 47 30 24

8/8 BM, 52%

7/8 BM, 41%

8/8 PBPC, 50%

PBPC 39%

4-6/6 UCB, 44%

Eapen et al; Lancet Oncol 2010

Eliane Gluckman MD FRCP Project Leader

Vanderson Rocha MD, PhD

Scientific Director Annalisa Ruggeri, MD

Federica Giannotti , MD

Myriam Pruvost, PA

Fernanda Volt, MT Chantal Kenzey Data Manager

EUROCORD TEAM 2012-2013

Erick Xavier, MD

Luciana Tucunduva, MD

Unrelated Cord Blood Transplantation In Adults with Hematological Malignancies Eurocord Results

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