Outcomes Using Single and Double Unit

Cord Blood Transplant Grafts

Vanderson Rocha, MD, PhD Eurocord

Hôpital Saint Louis, Paris

Overcoming the Cell Dose Limitation If no single graft is big enough then …

HLA A & B: Ag level HLA DRB1: Allele level

4/6

-8 -7 -6 -5 -4 -3 -2 -1 0

TBI

MMF CSA

G-CSF

FLU

CY

FLU

CY

FLU

DUCBT

Use of Unrelated Stem Cell Sources in the U.S. for 2006 - 2010

Age ≤ 16 yrs Age > 16 yrs

0

20

40

60

80

100

2006-2010 2006-2010

Bone Marrow (BM)Peripheral Blood (PB)Cord Blood - singleCord Blood - multiple

Tran

spla

nts,

%

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

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400

1994

19

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05

2006

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2008

20

09

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20

11

2012

Double CBT

Single CBT *

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

Should Transplantation of Two Cord Blood Units be the Standard for

Adults?

Approximately 80 - 85% of cord blood transplants in the U.S. and 50% in Europe, infuse two units

Practice variation Likely that some of these patients may have

had an adequately dosed single unit Majority with TNC (sum of unit 1 & 2) in

excess of 3 x 107/kg

Should Transplantation of Two Cord Blood Units be the Standard for

Adults? Ideal study design Randomized trial Each patient has an adequately dosed single

unit Randomized to receive one or two units

A similar trial in children / adolescents ( J Wagner and J Kurtzberg)

None planned in adults – feasibility

Minnesota Studies

• Double UCBT promotes engraftment, achieving rates comparable to single UCBT with adequate cell doses: mechanism unknown

immune mediated or additive effect? • Risk of grade 2-4 aGVHD is higher after double

UCBT (although no difference in risk of grade 3-4 aGVHD)

• Risk of cGVHD is similar

• Reduced risk of relapse is associated with – Double UCBT – Early disease status (CR1 & 2) – No Benefit from aGVHD

Overall Survival CR1 & CR2

Years

Prob

abili

ty

p = .16 0.0

0.2

0.4

0.6

0.8

1.0

0 1 2 3

I I

I I I I

I I I I

I I I I

I I I I I I I I I I I I I I I I I I I

Double

Single 72% (56-88%)

47% (51-75%)

Other studies in USA and Europe?

Study Design

Used data reported to observational registries CIBMTR; N = 327 NYBC; N = 79

All single units contained TNC ≥2.5 x 107/kg

Lower TNC limit for 1 unit CBTs: BMT CTN 0501

Almost all two UCB unit transplants TNC ≥3 x 107/kg ≈10% of 1 unit TNC < 1.5 x 107/kg

Study Population

N = 303 recipients of double UCBT N = 106 recipients of single UCBT AML or ALL Transplant period: 2002 – 2009 Several differences b/w two groups Single UCB recipients were younger,

more likely to be in relapse, MAC conditioning regimen, 6/6 or 5/6 HLA-matched to donor, lower TNC and transplanted prior to 2005

Neutrophil Recovery - Adequate Dose Single vs. Double UCBT -

Inci

denc

e, %

Months 0 1 2 6 4 3

100

0

20

40

60

80

0

100

20

40

60

80 Single UCBT, advanced 71%

Single UCBT, early/intermediate, 81%

Double UCBT, advanced, 65%

Double UCBT, early/intermediate, 81%

5

Early/Intermediate: CR1, CR2 Advanced: Relapse

Grade II-IV Acute GVHD - Adequate Dose Single vs. Double UCBT -

Inci

denc

e, %

Months 0 2 4 12 8 6

100

0

20

40

60

80

0

100

20

40

60

80

Double UCBT early period, 58%

Single UCBT early period, 18%

Double UCBT later period, 31%

Single UCBT later period, 27%

10

Early period: 2000-2004 Later period: 2005 -2009

P<0.001

Chronic Graft vs. Host Disease - Adequate Dose Single vs. Double UCBT -

Inci

denc

e, %

Months 0 6 12 36 24 18

100

0

20

40

60

80

0

100

20

40

60

80

Single UCBT, TNC ≥2.5 x 107/kg , 24%

Double UCBT, 31%

30

HR 1.33, p=0.27

Transplant-related Mortality - Adequate Dose Single vs. Double UCBT -

Inci

denc

e, %

Months 0 6 12 36 24 18

100

0

20

40

60

80

0

100

20

40

60

80

Single UCBT, TNC ≥2.5 x 107/kg, 38%

Double UCBT, 32%

30

HR 0.91, p=0.63

Relapse - Adequate Dose Single vs. Double UCBT -

Inci

denc

e, %

Months 0 6 12 36 24 18

100

0

20

40

60

80

0

100

20

40

60

80

Double UCBT, 36%

Single UCBT, TNC ≥2.5 x 107/kg, 32%

30

HR 0.90, p=0.64

Relapse - Myeloablative Conditioning -

Inci

denc

e, %

Months 0 6 12 36 24 18

100

0

20

40

60

80

0

100

20

40

60

80

30

SUCBT, advanced, 42%

SUCBT, early/intermediate, 24%

DUCBT, advanced, 46%

DUCBT, early/intermediate 20%

Early/Intermediate: CR1, CR2 Advanced: Relapse

Relapse - Reduced Intensity Conditioning -

Inci

denc

e, %

Months 0 6 12 36 24 18

100

0

20

40

60

80

0

100

20

40

60

80

30

Single UCBT advanced, 67%

Single UCBT early/intermediate, 46%

Double UCBT advanced, 64%

Double UCBT early/intermediate, 48%

Early/Intermediate: CR1, CR2 Advanced: Relapse

Overall Survival - Adequate Dose Single vs. Double UCBT -

Adj

uste

d Pr

obab

ility

, %

Months 0 6 12 36 24 18

100

0

20

40

60

80

0

100

20

40

60

80

RR

Double UCBT, 32%

Single UCBT, TNC ≥2.5 x 107/kg, 33%

30

HR 0.92, p=0.62

SUMMARY

These data confirm Infusing 2 UCB units overcomes the cell

dose barrier Thereby making this treatment accessible

to a substantial number of adults Survival after transplantation using a

single unit (adequate dose) is comparable to that after two units

Outcomes After Double Unit Unrelated Cord Blood

Transplantation (UCBT) Compared with Single UCBT in

Adults

with Acute Leukemia in Remission

An Eurocord and Acute Leukemia Working Party–EBMT Collaboration Study

Double versus Single UCBT in Adults with AL by conditioning regimen

Selection criteria • First single or double UCBT performed in transplant centers in

Europe • Transplants performed from 2005-2011 • Adults ≥ 18 years old with AML or ALL in first or second CR • Single CBU with adequate TNC at collection (>2.5x107/Kg) • Two different analysis : Myeloablative or Reduced Intensity

Conditioning Regimen MAC: 402 patients (241 sUCBT and 161 dUCBT) RIC : 360 patients (229 dUCBT and 131 sUCBT)

Outcomes After Double UCBT Compared with

Single UCBT in Adults

with Acute Leukemia in Remission after

Myeloablative Conditioning Regimen

Selection Criteria

• Adult patients with ALL and AML, in CR1

•UCBT from 2005 to 2011 in EBMT centers

• Single and double UCBT

• Myeloablative conditioning regimen

239 patients were evaluable

Patients and disease characteristics, n=239

Patients Characteristics AL in CR1, n=239 Median Follow-up 24 (3-74) months

Median age at UCBT (years) 34 (18-63) Diagnosis, n

AML ALL

138 101

High risk cytogenetics T(9;22), n

FLT3/ITD, n

56% 42 26

Interval diagnosis-UCBT 180 days Single UCBT 156 (61%)

Double UCBT 83 (39%) •There were no statistical differences between single and double UCBT for those characteristics

Characteristics, n=239 • Pts were transplanted with sUCBT (n=156) or dUCBT

(n=83) • Type of MAC was statistically associated with outcomes

therefore pts were analyzed in 3 different groups: – Group 1: sUCBT with TBI-based+Cy (+Flu) (n=68) (performed in

42 transplant centers (TC)), – Group 2: sUCBT with Bu+Flu+Thiotepa (n=88) (performed in 23

TC) and – Group 3: dUCBT with Cy+TBI+Flu (n=83) (performed in 47 TC)

Group 1, sUCBT- TBI based+Cy

(+Flu) 28% Group 2,

sUCBT- Bu+Flu+Thio

tepa 37%

Group 3, dUCBT-

Cy+TBI+Flu 35%

Type of Graft and Conditioning Regimen, n=239

Graft Characteristics Group 1, sUCBT TBI-based+Cy

n=68

Group 2, sUCBT Bu+Flu+Thio

n=88

Group 3, dUCBT Cy+TBI+Flu n=83

HLA match* 6 and 5 out of 6 31% 30% 26%

4 out of 6 69% 70% 74%

Median TNC after thawing (107Kg) 2,9 (1,5- 8) 3 (1,2- 6) 3,7 (1,3- 6)

Median CD34+ cells after thawing (105Kg) 1,2 (0,3- 7) 1,6 (0,3- 15) 1,5 (0,2- 7)

ATG use before day 0 70% 90% 40%

*HLA A, B antigenic level - DRB1 allelic level

No statistical differences were found among the 3 groups for patients disease and transplant characteristics (diagnosis, risk, gender, weight, CMV status, year of UCBT, time from diagnosis to UCBT, cytogenetic risk class, number of HLA disparities)

however patients in group 2 were older than in group 1 and 3 (median age 38 vs 33 vs 31 years) (p=0.03).

0 10 20 30 40 50 60

Days

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Cum

ulat

ive

Inci

denc

e of

Neu

troph

il R

ecov

ery

Group 1Group 2Group 3

Neutrophil Engraftment- MAC sUCBT and dUCBT in adults with AL in CR1

Cumulative incidence (CI) of 60 day neutrophil recovery: 87±3%

Median time: 22 (10-82) days

Group 1: sUCBT-CyTBI12: 82±4%, n=68

Group 2: sUCBT-BuFluTT+ATG: 87±4%, n=88

Group 3: dUCBT-CyFluTBI12: 89±32, n=83

0 10 20 30 40 50 60

Months

0.0

0.2

0.4

0.6

0.8

1.0

Cum

ulat

ive

Inci

denc

e of

Rel

apse

Group 1Group 2Group 3

Relapse at 2-year- MAC sUCBT and dUCBT in adults with AL in CR1

CI of relapse: 19±3%

Group 1: sUCBT-CyTBI12: 25±4%, n=68

Group 2: sUCBT-BuFluTT+ATG: 18±3%, n=88

Group 3: dUCBT-CyFluTBI12: 16±3%, n=83

No factors associated with RI in the multivariate analysis

TRM at 1-year- MAC sUCBT and dUCBT in adults with AL in CR1

CI of TRM: 33±3%

Group 1: sUCBT-CyTBI12: 38±6%, n=68

Group 2: sUCBT-BuFluTT+ATG: 33±4%, n=88

Group 3: dUCBT-CyFluTBI12: 29±3%, n=83

0 2 4 6 8 10 12Months

0.0

0.2

0.4

0.6

0.8

1.0

Cum

ulat

ive

Inci

denc

e of

TR

M

Group 1Group 2Group 3

Outcomes, MAC sUCBT and dUCBT in adults with AL in CR1

Outcome Group 1, sUCBT TBI-based+Cy

n=68

Group 2, sUCBT Bu+Flu+Thio

n=88

Group 3, dUCBT Cy+TBI+Flu

n=83 p value

Neutrophil Recovery 82±3% 89±2% 87±4% 0,001

Grade II- IV acute GVHD 30±3% 20±3% 45±3% 0, 001

Chronic GVHD 27±4% 29±5% 29±4% 0,34 2-year Relapse

Incidence 25±4% 18±3% 16±3% 0,22

1-year NRM 44±4% 33±4% 36±4% 0, 46 2-year LFS 30±7% 46±6% 48±4% 0, 005

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

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

ALL diagnosis

HR 1,45- 95%CI 1,3- 2 p=0.04

Age>35y HR 1,45 -95%CI 1,16- 2,06 p=0,04

Group1 CT: sUCBT-CyTBI12

HR 1,62 -95%CI 1,18- 2,52, p=0,03

Factors associated with lower LFS

LFS – Multivariate analysis MAC sUCBT and dUCBT in adults with AL in CR1

• Overall Survival

• Causes of death, n=106

OS at 2-year- MAC sUCBT and dUCBT in adults with AL in CR1

Group 1: sUCBT-CyTBI12: 33±6%, n=68

Group 2: sUCBT-BuFluTT+ATG: 53±6%, n=88

Group 3: dUCBT-CyFluTBI12: 56±6%, n=83

0 5 10 15 20 25 30 35 40

Interstitial pneumonitis

VOD

Hemorrhage

Rejection

Cardiac toxicity

ARDS

Unknown

Multiorgan failure

infections

Relapse

GvHD

No statistical difference by causes of deaths among the 3 groups, p= 0.45

UCBT after Myeloblative Conditioning regimen

Comparison after single UCB intrabone injection and

dUCBT in patients with hematological malignant disorders.

An Eurocord-EBMT analysis

Vanderson Rocha, Myriam Labopin, Annalisa Ruggeri, Marina Podestà, Dolores Caballero, Francesca Bonifazi, Rovira Montserrat, Andrea Gallamini,

Gerard Socie, E Nikiforakis, Mauricette Michalet, E Deconinck, Mohamad Mohty, Andrea Bacigalupo, Eliane Gluckman,and Francesco Frassoni

Transplantation 2013

10 20 30 40 50 60

0.0

0.2

0.4

0.6

0.8

IB-CBT N=87 Median days: 23

d-UCBT N=149 Median days: 28

P=0.001

90%

90%

days

Intrabone single UCBT (IB-CBT) versus DoubleUCBT (d-UCBT) after MAC in patients with hematological malignancies

Cumulative Incidence of PMN recovery (>= 500)

0 30 60 90 120 150 180

0.0

0.2

0.4

0.6

0.8

Cumulative Incidence of Platelets recovery (>=20.000)

81%

65%

P<0.001

days

IB-CBT N=87

d-UCBT N=149

Intrabone single UCBT (IB-CBT) versus DoubleUCBT (d-UCBT) after MAC in patients with hematological malignancies

Disease Free Survival

months

47%

37%

Intrabone single UCBT (IB-CBT) versus DoubleUCBT (d-UCBT) after MAC in patients with hematological malignancies

IB-CBT N=87

d-UCBT N=149

Outcomes After Double UCBT Compared with

Single UCBT in Adults

with Acute Leukemia in Remission after

Reduced Intensity Conditioning Regimen

Comparative Retrospective Registry Based Analysis

Selection criteria • First single or double UCBT performed in transplant centers in Europe • Adults ≥ 18 years old with AML or ALL in CR • Single CBU with adequate TNC at collection (>2.5x10e7/Kg) • Reduced intensity conditioning regimen

• From 2005-2011, 360 patients (229 dUCBT and 131 sUCBT) were transplanted in 10 countries (63 transplant centers)

• AML, n=283, ALL, n=77 • CR1, n=212, CR2, n=148

RIC, Single vs Double UCBT

CR1 n=212

sUCBT dUCBT p

N 76 136 Age (y) Median 52 52 0.6 Range 18-67 18-67

Weight (Kg) Median 64 67 0.07 Range 42-100 40-100

Female Gender 60% 51% 0.05 CMV + 68% 60% 0.86 Median year of UCBT 2008 2009 0.03

RIC –dUCBT versus sUCBT in AL CR1 Patients characteristics

N 76 136

Conditioning CyFluTBI2Gy 68% 87% <0.001

ATG/ALG 35% 21% 0.04

GVHD Prophylaxis <0.001 CsA +MMF+ Corticosteroids 78% 88% Median follow-up time (mo) 23 (1-86) 23 (1-73)

RIC –dUCBT versus sUCBT in AL CR1 Transplant Characteristics

sUCBT dUCBT p

N 76 136 HLA match 0.8 (HLA-A,-B by serology and DRB1 low resolution) 6/6 or 5/6 26% 28% 4/6 or 3/6 74 % 72% Nucleated cells at collection x107/kg 3.9 5 <0.001 Range 2.6- 6.4 2.9- 9.4

Nucleated cells at infusion x107/kg 3.1 4 <0.001 Range 1.1- 6.5 1.1-9.4

RIC –dUCBT versus sUCBT in AL CR1 Donor characteristics

sUCBT dUCBT p

Results

RIC sUCBT versus dUCBT for adults with AL in CR1 Neutrophil recovery

76± 2%

82 ± 3% dUCBT, n=136

sUCBT, n=76

p=0.86

Chimersim Full donor sUCBT 85% dUCBT 81% p=0.6

RIC sUCBT versus dUCBT for adults with AL in CR1 100 day CI of Acute GVHD II-IV

35± 5%

35 ± 4%

p=0.92

dUCBT, n=136

sUCBT, n=76

RIC sUCBT versus dUCBT for adults with AL in CR1 Acute GVHD II-IV

Single UCBT, n=76 Double UCBT, n=136

0 50%

I 14%

II 17%

III 12%

IV 7%

0 46%

I 16%

II 28%

III 8%

IV 2%

grade III-IV, p=0.06

RIC sUCBT versus dUCBT for adults with AL in CR1 Acute GVHD II-IV

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

Single Double Single Double Single Double

Grade IV

Grade III

Grade II

Grade I

Grade 0

Skin Liver GI

RIC sUCBT versus dUCBT for adults with AL in CR1 2-year CI of Chronic GVHD

12± 5%

21± 4%

p=0.15

dUCBT, n=136

sUCBT, n=76

RIC sUCBT versus dUCBT for adults with AL in CR1 2 years Non-Relapse Mortality

30 ± 6%

28 ± 4%

p=0.87

dUCBT, n=136

sUCBT, n=76

RIC sUCBT versus dUCBT for adults with AL in CR1 2 years Relapse incidence

38 ± 6%

21 ± 4%

p=0.03

In a multivariate analysis adjusted for differences and risk factors Double CBT was associated with decreased relapse [p=0.01 HR=0.74 (0.58-0.93)]

dUCBT, n=136

sUCBT, n=76

2 years- LFS after RIC sUCBT and dUCBT in adults with AL in CR1

32 ± 3%

51 ± 5%

p=0.03

In a multivariate analysis adjusted for differences and risk factors Double CBT was associated with improved LFS rates [p=0.04 HR=0.64 (0.41-0.99)]

dUCBT, n=136

sUCBT, n=76

2 years- LFS after RIC sUCBT and dUCBT in adults with AL in CR2, n=148

48 ± 3%

40 ± 6%

p=0.32

dUCBT, n=93

sUCBT, n=55

Leukemia-Free Survival - Double Cord Blood Transplant -

Prob

abili

ty,

%

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%

Brunstein et al; Blood 2012

Algorithm for UCBT in adults by cell dose, disease and type of conditioning

• If a single cord blood unit contains < than 2.5x107/kg 1) Double UCBT 2) Intrabone injection (in MAC) 3) Other protocols (intrabone injection, haplo-cord, expansion…

but minimum cell dose has to be determine 1.5x107/kg) • If single unit > 2.5x107/kg , and MAC, BU+TT+FLU+ATG

is a good option • If single unit (> 2.5x107/kg) patients with 1CR, probably

double UCBT is better with the aim to decrease relapse. Should we intensify the conditioning regimen?

Summary • Use of two partially HLA mismatched UCB units has

extended transplantation to larger recipients that would otherwise be denied transplantation for lack of an UCB donor.

• Single ( cell dose and IvBU+TT+FLU) and double have similar outcomes in MAC, however the use of double in RIC using the TBI+CY+FLU seems better in AL CR1

• Delayed engraftment requires further research to reduce its associated NRM

• Additional studies are needed to better understand the biology of the low relapse rate in recipients of 2 UCB units.

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