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