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

BMT unit, Churchill Hospital Oxford, UK

Scientific Director of Eurocord Paris, France

Outcomes of Double Unit Cord Blood Transplantation in patients with

malignant disorders: Eurocord Registry analysis

Eurocord Registry

General data base* overview

*Eurocord Registry status as off December, 31st, 2012

Eurocord registry database N or % Cord blood units / European CB units % 12 066 / 58% CBT cases / single% / double% 9 883 / 63% / 23%

European CBT cases 65% Countries / Centres / EBMT centres 51 / 577 / 297 Unrelated CBT cases 93% Children CBT cases 54%

Eurocord Registry at ABM 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

0

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1990

1991

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1995

1996

1997

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1999

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2004

2005

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2008

2009

2010

2011

2012

MAC n=4674

RIC n=2629

* Still collecting data

Type of Conditioning Regimen per Year

*

*

Double UCBT in children

Preliminary Analysis

Patient characteristics (n=218)

Patient Characteristics Range

Median age, years 13 y 0.6-18

Median weight, kg 45 Kg ( 25-76)

Median year of transplant 2009 2002-2012

Median follow-up 21 months 3-111

Diagnosis

Malignant diseases – disease status at UCBT •Early: 31% • Intermediate: 31% •Advanced: 15%

Characteristic range

Conditioning MAC 76% RIC 24%

GvHD prophylaxis CsA+MMF 48% CsA+steroids 30% CsA+MMF+other 5% FK506+other 4% Other 13%

Use of ATG Yes 68% No 32%

Number of HLA mismatches 0 5% 1 37% ≥2 58%

Median collected TNC, x105/kg 5.1 2.15-44.29

Median infused TNC, x107/kg 5.1 0.98-34.2

Transplant and graft characteristics

Neutrophil Engraftment

at 60 days: 87%, n=218

Malignant disease: 90%, n=178, Non Malignant disease: 67%, n=40, p=0.001

Chimerism at 100 days available for 146/182 patients who engrafted, Mixed 10%, Full donor 90% (17 patients had long term persistance of both CBU)

Non engraftment

• 36 patients experienced primary graft failure – 27 died in a median time of 72 days after CBT. 5

had received a 2nd Tx (2 haplo, 2 dUCBT, 1 PBSC) – 9 are alive with a median FU of 18 months. 3 with

available information, had a subsequent Tx (2 CBT and 1 UD-BMT).

aGvHD grade II-IV

MAC: 42%, n=164

RIC: 34%, n=51

p=0.32

• 100 patients presented grade III-IV aGvHD

Acute leukemia: relapse

AML, n=48: 37%

ALL, n=101: 25%

p=0.19

Overall Survival

Non Malignant, n=40: 44%

Malignant, n=178: 47%

p=0.73

Overall Survival for acute leukemia

AML, n=48: 52+8%

ALL, n=101: 44+6%

p=0.54

Double UCBT in adults

Preliminary analysis

Patient characteristics

Patient Characteristics Range

Median age, years 46 y 18-76 Median weight, kg 71 kg 40-171 Median year of transplant 2009 1999-2012 Median follow-up 23 months 3-98

From 1999 to 2012, 1118 adult patients were transplanted with

double UCBT In 32 EBMT countries

Diagnosis (n= 1118)

Malignant diseases – disease status at UCBT •Early : 25% •Intermediate : 23% •Advanced: 38%

Non-malignant: 39/46 BMF

Transplantation and graft characteristics (n= 1118)

Characteristic range

Conditioning RIC 67% MAC 33%

GvHD prophylaxis CsA+MMF 73% CsA+steroids 13% CsA+MMF+other4% FK506+other 3% Other 7%

Use of ATG Yes 38% No 62%

Number of HLA mismatches 0/1 28% ≥2 72%

Median collected TNC, x105/kg 4.9 1.5-14.8

Median infused TNC, x107/kg 3.8 0.33-14.6

Neutrophil Engraftment (n= 1118)

Neutophil Engraftment at 60 days: 87+1%, n=1118

Chimerism at 100 days available for 881/1053 patients who engrafted, Mixed 14%, Full donor 86%

Lymphoid Mal, n=219: 89+2% Ac Leukemia, n=820: 87+2%

MDS/MPS, n=239: 82+3%

aGvHD grade II-IV (n= 1118)

BY HLA COMPATIBILITY BY CONDITIONING REGIMEN

2 HLA MM: 42+2%, n=666

0-1 HLA MM: 34+2%, n=274

p=0.25

MAC, n=350:34+2%

RIC, n=660: 32+2%

p=0.32

Relapse (n= 1118)

ACUTE LEUKEMIA OTHER MALIGNANCIES

N CI N CI

EARLY 267 21% 34 21%

INTERMEDIATE 242 29% 43 21%

ADVANCED 114 39% 281 30%

Mortality and causes of death (n= 681 out 1118)

Among 395 patients transplanted with advanced disease, 267 died in a median time of 108 days after CBT, of those 106, of the original disease

Disease free Survival Adults with malignancies (n= 1118)

p<0.001

Lymphoid Mal, n=219: 43+4%

Ac Leukemia, n=820: 39+2% MDS/MPS, n=239: 27+3%

DFS at 2 year by type of disease and conditioning regimen

MAC, n=388 RIC, n=711

Lymphoid Mal, n=26:40+11%

Ac Leukemia, n=286: 34+2%

MDS/MPS, n=72: 25+3%

Lymphoid Mal, n=181: 41+3%

Ac Leukemia, n=371: 41+3%

MDS/MPS, n=151: 23+4%

DFS at 2 year by disease status and conditioning regimen

MAC, n=388 RIC, n=711

Early , n=147: 44+5%

Intermediate, n=115: 36+5%

Advanced n=120: 18+4%

Early , n=224 46+5%

Intermediate, n=215: 44+4%

Advanced n=264: 27+4%

DFS- Multivariate analysis

HR 95%CI p value

Diagnosis: MDS vs acute leukemia

1.4 1.5- 1.95 0.02

Diagnosis: Lymphoid malignancies vs

acute leukemia

1.2 0.88- 1.7 0.22

Disease Status Remission vs not remission

0.51 0.38- 0.68 0.0001

Disease free Survival for acute leukemia (n=811)

• DFS at 2 year by type of disease

p=0.48

AML, n=499: 40+2%

ALL, n=313: 37+2%

Disease free Survival for acute leukemia (n=811)

DFS at 2 year by disease status, CR1

DFS at 2 year by disease status, CR2

AML, n=196: 50+4%

ALL, n=136: 48+2%

AML, n=175: 48+4%

ALL, n=129: 38+2%

Which are the risk factors associated with the double graft that can change one or

two units selection in dCBT ?

Risk factors of engraftment in dBCT

• Winner unit dose of CD3 cells? order of infusion? CD34 viable cells? HLA? others? • Engraftment Disease status? Conditioning regimen? Cell dose? TNC? CD34? CFU-GM?

Is there a number of nucleated cells or CD34 associated with outcomes in double

UCBT?

Patients and disease characteristics n= 430

Median (range) n

Children 41 (9%) 430

Adult 389 (91%)

Age (years)

Children 15 (4-18) 41

Adult 45 (18-67) 389

Weight (Kg)

Children 52 (14-88) 41

Adult 70 (40-120) 389

Positive CMV serology 205 (49%) 413

Diagnosis 241 (56%) 430

Acute leukemia 58 (13%)

MDS 131 (31%)

Other malignancies

Advanced Diseases 168 (40%) 419

Median Follow up (months) 12 (3-70)

*HLA A, B antigenic level - DRB1 allelic level

Transplant and Graft Characteristics n=430

Median (range) n

Conditioning Mieloablative 126 (30%) 418

GVHD Prophylaxis

418 CsA + Steroids 39 (9%)

CsA + MMF 307 (78%)

ALG/ATG before day 0 78 (22%) 395

HLA Matching *

428 6/6 5 (1%)

5/6 102 (24%)

4/6 297 (70%)

Pre-freezing (pf)

430 TNC (x107/Kg) 4.7 (2-27)

CD34 (x105/Kg) 1.7 (0.3-10)

Post-thawing (pt)

430 TNC (x107/Kg) 3.5 (0.8-22)

CD34 (x105/Kg) 1.2 (0.2-7)

Double UCBT (n=430) - Neutrophil Engraftment at 60 days

Number of pfCD34+

• CI Neutrophil Engraftment (NE): 81±2% • 346 pts (80%) achieved engraftment in a median time of 23 days

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pf CD34 <1.7x105/kg 79+3%

pf CD34 >1.7x105/kg 83+3%

p = 0.03

Double UCBT (n=430)- Neutrophil Engraftment at 60 days

Number of ptCD34+ Number of ptCD34+

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Days

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ptCD34 < 1.2x05/kg 76+3%

ptCD34 > 1.2x05/kg 85+2%

p = 0.04

0 10 20 30 40 50 60

Days0.

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60.

81.

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p = 0.006

ptCD34 < 0.9x05/kg 74+4%

ptCD34 > 0.9 and < 1.8 x05/kg 81+3%

ptCD34 > 1.8x105/kg 87+3%

0 20 40 60 80 100

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Double UCBT – TRM at 100 days

CI 12 months of TRM: 16+2 %

pfCD34 > 1.2x05/kg 11+2%

pfCD34 <1.2x05/kg 18+3%

p = 0.02

Number of pfCD34+

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Multivariate analysis -Double UCBT Summary

pf TNC pfCD34+ pt TNC pt CD34+ Others variables

Overall survival - - - -

Disease status at transplantation

Disease free survival - - - - Disease status

at transplantation

Neutrophil engraftment - 1.7x105/kg

(median) - 1.2x105/kg (4th percentile)

No other factor p=0.04 p=0.015

Transplantation-related mortality - 1.2X105/kg

(4th percentile) - HLA, MAC, age

p=0.004

Conclusions • Double Cord Blood Transplantation has extended the use

of Cord Blood Cells for Adults for whom the number of cells is not sufficient.

• Need of more data and follow-up • However despite a higher cell dose, graft failure is

around 10-15% (a higher CD34+ cell dose of both units seems to be an important factor to increase engraftment and decrease mortality)

• Acute GVHD seems to be increased • Mortality is associated with infections (delayed engraftment?,

delayed immune recovery?), GVHD and toxicity • MDS and advanced disease are factors associated with

decreased DFS rates

Acknowledgments

EBMT, CIBMTR Transplant Centers

(Data Managers, Nurses and Physicians) Cord Blood Banks and Netcord

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