umbilical cord blood - comtecmed · overcoming post-transplant leukemia relapse donor versus...

William Arcese University of Rome “Tor Vergata”Rome Transplant Network

Berlin 8-11 September 2011

Which is the donor of choice if no MUD is available?

Umbilical Cord Blood

Which is the donor of choice if no MUD is available?

Patient Population :Adult Patients Candidated to Allogeneic Transplantfor Acute Leukemia (AML, ALL)

Underutilization of SCT from MUD

• From 2000 to 2006, out of 151,000 qualifying for an unrelated donor SCT only

64,720 (43%) received one. van Rood and Oudshoorn, BMT 2008.

• 763 searches started and 349 (46%) transplants from MUDs performed in Italy.

Italian Bone Marrow Donor Registry 2009.

>50% of the searches do not end in a transplant

CB HaploHLA typing of A+B+DRB1(DNA) ~80% 100%

Median search time <1mos <1mos

Major limiting factors to acquisition Cell Dose _

Rearranging date of cell infusion Easy Easy

Potential for Immunotherapy No (?) Yes

Potential Viral Transmission No Yes

Risk for Congenital diseases Yes No

Risk to donor No Yes

Advantages and Disadvantages

Policy and Expertise of each Centersignificantly affect the final choice of the stem cell source and allogeneic transplant procedure

Which is the donor of choice if no MUD is available?

Which is the donor of choice if no MUD is available?

Umbilical Cord Blood UnitAvailability

Prediction of the percentage of patients requesting a donor (2000 consecutive patients) at the Anthony Nolan Register finding at least one donor for each predefined donor size inventory according to match categories

Cord Blood Bankminimal pre-freezing TNC count 90x107

Inventory 50.000Cryopreserved CB Units

At least 1 CB Unit 5/6 HLA Matched Antigens for 70% of patients with a median b.w. of 55 Kg (range 44-75)

S. Querol et al., Haematologica, 2011

Italian Cord Blood Network (ITCBN) At 31st March 2011

Unrelated CB Units

6.7% of the World Inventory

126.903

33.091

Collected

Cryopreserved

Probability of finding a single CB Unit + MUD

Single Unit CB + MUD identified: 494/674

months

Prob

abilit

y

3 m 46%

6 m 73%12 m 83%

0.00

0.20

0.40

0.60

0.80

1.00

0 6 12 1

8 2

4 3

0 3

6

IBMDR, Italy

No Alternative Donor

54%

27%

Haplo ?

Center Policy for Cord Blood TransplantNumber of Total Nucleated Cells

Number of CD 34+ Cells

Number of CFCs

Single CB Unit Transplant

Double CB Unit Transplant

IntraBone CB Unit Transplant

Single CB Unit + HLA-MM Stem Cell Transplant

Single CB Unit + Mesenchymal Cell Transplant

Ex vivo Expanded Cord Blood Cells

●

●

●

●

●

●

●

●

●

Policy and Expertise of each Centersignificantly affectthe final choice of cord blood as stem cell source for allogeneic transplant

Which is the donor of choice if no MUD is available?

By adopting different selection criteria according with different transplant procedures, ~ 100% of patients can be transplanted with umbilical cord blood

Which is the donor of choice if no MUD is available?

Cord Blood vs Haploidentical Transplants

ResultsMACMyeloAblative Conditioning

RICReduced Intensity Conditioning

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

Which is the donor of choice if no MUD is available?

Tregs + Tcons T-Cell Depleted Haploidentical HSCT University of PerugiaM.Martelli, F. Aversa, A. Velardi

TCR α/β+ cell Depletion for Haploidentical TransplantationBambino Gesù Hospital F. Locatelli, A. Moretta, L. Moretta

HSV-TK engineered T-lymphocyte infusionCD34+ selected HaploidenticalTransplantationSan Raffaele Scientific InstituteFabio Ciceri

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

Which is the donor of choice if no MUD is available?

Number of CBT by year reported to Eurocord

Related n=616Unrelated n=6424

*Still collecting data

EUROCORD

*

Which is the donor of choice if no MUD is available?

Cord Blood vs Haploidentical Transplants

Results

MACMyeloAblative Conditioning

Impact of Stem Cell Source on Myeloablative Transplant Outcomes in

Adults with Acute Leukemia

Mary Eapen MD MSCenter for International Blood and Marrow Transplant Research

Medical College of Wisconsin

Donor-recipient HLA match

Graft source Matched Mismatched

BM (N=472) 70% 30%

PBPC (N=888) 71% 29%

CB (N=165) 6% 19% (1-locus)75% (2-loci)

Eapen et al; Lancet Oncol 2010

Leukemia-free Survival

Eapen et al; Lancet Oncol 2010

Pro

bab

ilit

y,

%100

0

20

40

60

8090

10

30

50

70 4-6/6 UCB, 44% in

Remission

0 6 12 18 24 Months

0 6 12 18 24

Pro

bab

ilit

y,

%

100

0

20

40

60

8090

10

30

50

70

4-6/6 UCB, 15%

NOT in Remission

Impact of the use of Fludarabine or CY based Myeloablative Conditioning

after CBT in adults with leukemiasH Bittencourt, S Nabhan et al. on behalf of Eurocord

Overall Survival after MAC UCBT by type of conditioning regimen in patients with leukemia

Impact of the use of Fludarabine or CY based MAC after CBT in adults with leukemias

Flu-MAC 52%

CY-MAC 38%

p=0.04

CY-MAC 28%

Flu-MAC 6%p=0.70

Early and intermediate disease

Advanced disease

Multivariate analysis for OS : Fludarabine (HR: 0.52; CI95%:0.27-0.97 – p=0.04)

Overall SurvivalNumber of Patients 231Age (years) 33 (18-

55)Disease AML 87

(38%) ALL 85 (37%) MDS/MPD 59 (25%)Disease status at CBT

Early and intermediate

149 (64%) Advanced 82 (36%)Previous Autologous

HSCT31 (13%)TNC at Infusion

(x107/kg)2.5 (0.58-7.6)

GETH-RTN Protocol 2008(TBF-MAC protocol)

GVH prophylaxisATG + CSA + MMF or Prednisone

EudraCT Code 2008-000927-24

Thiotepa 5 mg/kg/d iv in 4 hs TT TT

Busilvex 3.2 mg/kg iv in 3 hs BU BUBU

Fludarabine 50 mg/m2/d iv in 1 h

FLU

FLU

FLU

Thymoglobulin 2 mg/kg/d ATG

ATG

ATG

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

CBT

UCBT for AML Transplant characteristics

Conditioning Regimens n=573

-Reduced Intensity - Cy+Flu+TBI, n

282 (49%)211

-Myeloablative - TT+Bu+Flu, n

- Cy+TBI, n - Cy+Bu, n

- Cy+Flu+TBI, n

291 (51%)98543431

Use of Anti-thymocyte globulin 49%GVHD prophylaxis n=551

- CsA + MMF ± steroids- CsA ± steroids

- Other

58%28%14%

Outcomes of Adult Patients with AMLreceiving

Thiotepa-Busulfan-Fludarabine and

Single Cord Blood (n=98) or Unmanipulated Haploidentical Bone Marrow (n=45)

Transplant

CR1+CR2 (n=77)

months

Ove

rall

Surv

ivalCBT

in 98 AMLEUROCORD

2-year Overall Survival 63±8%

8±7% Advanced (n=21)

Haplo BMTin 45 AMLRome Transplant NetworkPescara Transplant Team

2-year Overall Survival

CR1 + CR2 n=34

ADVANCED n=11

64±8% at 1 yr 59%±9

18±12%p= 0.019

2-year Disease Free Survival

Advanced (n=21)

CR1+CR2 (n=77)

p=<0.001

45±7%

8±7%

Dis

ease

Fre

e Su

rviv

al

months

2-year Disease Free Survival

CBTin 98 AMLEUROCORD

Haplo BMTin 45 AMLRome Transplant NetworkPescara Transplant Team

Cr1+Cr2 (n=34)

ADVANCED (n=11)

61±9 % at 1 yr49±9%

9 ±9 % p= 0.007

Results from Other Hematopoietic Stem Cell Sources should be compared with Those from Cord Blood Transplants Conditioned with TBF-mac Regimen(Thiotepa-i.v.Busulfan-Fludarabine)

Myeloablative Conditioning Regimen

The “NK cell alloreactivity” in HLA Mismatched Transplant

Donor Recipient HLA NK cell Target

KIR2DL2/3

KIR3DL1

HLA-Bw4 B51

KIR2DL1

HLA-C group 2 Cw2

HLA-C group 2 Cw2

HLA-Bw4 B27

HLA-C group 1Cw1

HLA-C group 2Cw4

missing HLA-C group 1

A potentially NK alloreactive donor occurs in nearly 50% of transplant pairs

Overcoming Post-transplant Leukemia Relapse

Donor versus recipient NK cells alloreactivity induces a potent graft versus AML effect in the absence of GVHD.

Donor versus recipient NK cell alloreactivity,as predicted by the HLA typing, should become a major criterion for donor selection.

A potentially NK alloreactive donor appears to be the best alternative donor.

Controversial inCord Blood Transplant

NK alloreactivity in AML

Ruggeri et al, Blood 1999; Science 2002; Blood 2007;

HSCT ProgrammeUniversity of Perugia

0.06

0.300.18

0.67

NK alloreactive (n=21)

Non

- NK

alloreactive (n=30)

NK alloreactive (n=30)

Non

-NK

alloreactive (n=31)0

.0

0.2

0.4

0.6

0.8

1.0

P = 0.02Su

rvi

val

A B

0 2 4 6 8 10

0.0

0.2

0.4

0.6

0.8

1.0

Years

P = 0.04

Chemoresistant relap

se

Any

remission

0 2 4 6 8 10Ye

ars

Confirmed inT-cell depleted Haploidentical Transplant

Undefined inUnmanipulated Haploidentical Transplant

EUROCORD n=218YESWillemze R. et al., Leukemia, 2009

Minnesota n=257NOBrunstein CG et al., Blood 2009

Which is the donor of choice if no MUD is available?

Cord Blood vs Haploidentical Transplants

Results

RICReduced Intensity Conditioning

Reduced Intensity Conditioning

Mycophenolate - 3 to + 30

G-CSF until ANC >2500/uL

CSA - 3 to + 100

Fludarabine 200 mg/m2

-3

-2

-1

-4

-8

-7

-6

-5

-9

7 14

21

280

sTBI 200 cGy

Day +28 BMBx

Cytoxan 50 mg/kg

Eligibility:• < 70 yrs• Heme malignancy• High risk for TRM age > 45 extensive prior Rx poor fitness

Single UCB

Double UCBHLA mismatched UCBT

University of Minnesota

Impact of Stem Cell Source on RIC Transplant Outcomes in Adults with

Acute Leukemia

Mary Eapen MD MSCenter for International Blood and Marrow Transplant Research

Medical College of Wisconsin

Leukemia-Free SurvivalPr

obab

ility

, %

Months0 6 12 362418

100

0

20

40

60

80

90

10

30

50

70

0

100

20

40

60

80

90

10

30

50

70

Fk10_49.ppt

30

Double CB (n=121), TCF: 26%

Double CB (40), other: 9%

P=0.017

Reduced Intensity Conditioning Regimen after single unrelated CBT for adults with hematological maligancies

An Eurocord-Netcord, SFGM-TC and Minnesota group analysis

Disease Free Survival according to Conditionings

months

28% other conditionings

51% TCF: sTBI 2GY+CY+FLU

p= 0.0002

Reduced Intensity Conditionings in CBT(n=176)

Multivariate analysis for DFS

•Type of conditioning (TCF: sTBI 2GY +CY+FLU):

HR= 0.53 p<0.001

•Early and intermediate phase of the disease: HR= 0.63 p=0.02

Other variables included in the model (p<0.10) status of the disease, diagnosis, age

Reduced Intensity Conditionings in CBT(n=176)

RESULTS OF CORD BLOOD TRANSPLANTATION

AFTER REDUCED INTENSITY CONDITIONING

IN ADULTS WITH HEMATOLOGICAL MALIGNANCY

Bernard RIO et al.ON BEHALF OF EUROCORD AND SFGM-TC

Unpublished

Event Free Survival

51%+/-4

Single (n= 96) 56% ±8

Double (n=59) 49% ±5

Overall

by Type of Graft

(n=155)

ConditioningTCF: sTBI 2GY +CY+FLU

Results from Other Hematopoietic Stem Cell Sources should be compared with Those from Cord Blood Transplants Conditioned with TCF-ric Regimen(sTBI 2GY +CY+FLU)

Reduced Intensity Regimen

Fare clic per modificare lo stile del sottotitolo dello schema

Do we know the best option  for alternative donor transplant: MUD vs CB vs Haplo?

NO

Fare clic per modificare lo stile del sottotitolo dello schema

Ospedale Sant’Andrea

Ospedale Campus Biomedico

Ospedale SanGiovanni-Addolorata

Ospedale Sant’Eugenio

Ospedale Bambino Gesù

Istituto Regina Elena

Policlinico UniversitarioTor Vergata

Ospedale S. Eugenio

Coordinator: William Arcese

University “Tor Vergata”, Rome

ROME

JACIE Metropolitan Transplant Program

Coordinator: William Arcese

University “Tor Vergata”, Rome

JACIE Metropolitan Transplant Program

Allogeneic Transplant PolicyAIMIdentification of a suitable donor for the majority of eligible patients in order to perform an allogeneic transplant in adequate timing

Strategy for alternative stem cell donor search in adults with malignant disorders

High resolution HLA typing

Simultaneous searchCord Blood Banks

NC dose collected to be increased with number of mismatchessingle CB Unit>2.5x107/kg NC > 3.5x107/kg NC>1x105/kg CD34 >2x105/kg CD34HLA: 0-1/6 HLA: 2/6

Bone Marrow donor registries

HLA 8/8 loci<8/8 or >3 months (delay for AL)

MUDTransplant

UNMANIPULATEDHAPLOIDENTICAL BMT

Prospective Randomized StudyCB vs Haplo

1st

2nd

3rd

Different GVHD Prophylaxis

MTX + CSA ATG + MTX + CSA ATG + MMF + CSA ATG + MTX + CSA + MMF+Basiliximab

Identical Conditioning RegimenGETH-RTN 2008 Protocol TBF-mac or TBF-ric

MUDMatchedUnrel. Donor

UCBUmbilicalCord Blood

HRDHaploidenticalRelated Donor

HLAIdentical Sibling

POLICY IN ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANT

Eligible Patientsn = 428

Not EligibleN= 34

ALGORITHM OF ALLOGENEIC HSC TRANSPLANTCandidates to Transplant

n = 462

HAPLOn = 54

Scheduledn = 16

CBn = 50

MUDn = 73

HLA Id. Sib.N = 146

Transplanted n = 339/428 (80%)

Too Earlyn = 13 (4.6%)

Evaluable for alternative donor Identification n = 269/282 (95%) No Donor Identified

n = 25 (9%)

Alternative Donor Identifiedn = 244/269 (91%)

Total Donor Identified n = 390/428 (91%)

Alternative Donor transplantsn = 193/244 (79%)

No Transplantn = 51/244 (21%)

HLA Identical Siblingn = 146 (34%)

Search for Alternative Donorn = 282/428 (66%)

Arcese et al., Curr. Opin. in Hemat., 2011

C O R D B L O O D T R A N S P L A N T A T IO N A N DIMMU N O B IOL OG Y O F HA E MA T O P O IE T ICS T E M C E L L T R AN S P L A N T

R OME , IT A L Y O c to b e r 2 7 -2 9 , 2 0 1 1

P r e s id e n t: E . G lu c k m a n

L o c a l O r g a n ize r s : W . A r c e s e , F . L o c a te l l i , P . R e b u l la

I m m u n o b io lo g y W o r k in g P a r ty :A . M a d r ig a l , A . T o u b e r t, A . V e la r d i , E . B a u d o u x , C . N a v a r r e te

Acknowledgements

Franco LocatelliOspedale Bambino Gesù

Ospedale S. Eugenio

Paolo De FabritiisOspedale Sant’Eugenio

Concetta PettiIstituto Regina ElenaGiuseppe AvvisatiUniversità Campus Biomedico

Luciana AnninoOspedale San Giovanni

Bruno MonarcaOspedale Sant’Andrea