Umbilical Cord Blood

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




           Umbilical Cord Blood

                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?




Patient Population :
Adult Patients Candidated to Allogeneic Transplant
for 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
Advantages and Disadvantages

                             CB          Haplo
HLA 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
Which is the donor of choice if no MUD is available?




Policy and Expertise of each Center
significantly affect the final choice of the
stem cell source and allogeneic transplant
procedure
Which is the donor of choice if no MUD is available?




        Umbilical Cord Blood Unit
        Availability
 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 Bank
minimal pre-freezing TNC count
90x107
           Inventory
           50.000
           Cryopreserved 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
33.09         Cryopreserved
1
                       Collecte
                       d
                     126.90
6.7% of the          3
World Inventory
   Probability of finding a single CB Unit + MUD

Single Unit CB + MUD identified: 494/674
                     No Alternative Donor
                                                Haplo ?
                 1
                 .
                 0                   27                    12 m 83%
                 0
                 0
                 .
                                     %             6 m 73%
                      54
   Probability




                 8
                 0
                 0    %
                 .
                 6                          3 m 46%
                 0
                 0
                 .
                 4
                 0
                 0
                 .
                 2
                 0
                 0
                 .     0         6          1        1      2    3     3
                 0
                 0
                                            2
                                                  months
                                                     8      4    0     6


                                                                IBMDR, Italy
Center Policy for Cord Blood Transplant
     ● Number 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
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


Policy and Expertise of each Center
significantly affect
the final choice of cord blood as stem cell
source for allogeneic transplant
Which is the donor of choice if no MUD is available?


Cord Blood vs Haploidentical
Transplants

Results
    MAC                      RIC
    MyeloAblative            Reduced Intensity
    Conditioning             Conditioning
Which is the donor of choice if no MUD is
available?




● Haplo-related transplants have been
 pionneered since the 70s but most
 results were provided by single
 centers and few large series are
 published.
Tregs + Tcons
T-Cell Depleted Haploidentical HSCT
University of Perugia
M.Martelli, F. Aversa, A. Velardi



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



HSV-TK engineered T-lymphocyte infusion
CD34+ selected HaploidenticalTransplantation
San Raffaele Scientific Institute
Fabio Ciceri
Which is the donor of choice if no MUD is
available?



● Unrelated cord blood transplant is
 clinically validated and reproducible
 with numerous single center and
 registry based studies.
      EUROCORD
Number of CBT by year reported to Eurocord


                         Related
                         n=616
                         Unrelated
                         n=6424




                                               *



                                             *Still collecting
                                             data
Which is the donor of choice if no MUD is available?


Cord Blood vs Haploidentical
Transplants

Results
    MAC
    MyeloAblative Conditioning
   Impact of Stem Cell Source on
Myeloablative Transplant Outcomes in
    Adults with Acute Leukemia

                       Mary Eapen MD MS
Center 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
          100
           90
           80

                                  4-6/6 UCB,
Probability,




           70
           60
           50                     44%             in
           40
                                                  Remissio
%




           30
           20                                     n
           10
            0
             0          6    12           18
24        100
               90
               80
               70
                                                  NOT in
Probability,




               60
               50                                 Remissio
               40                 4-6/6 UCB,      n
%




                                  15%
               30
               20
               10
                0
                    0   6   12       18        24 Eapen et al;
Impact of the use of Fludarabine or CY based
         Myeloablative Conditioning
     after CBT in adults with leukemias
           H Bittencourt, S Nabhan et al.
           on behalf of Eurocord
        Impact of the use of Fludarabine or CY based MAC after
        CBT in adults with leukemias
        Overall Survival after MAC UCBT by type of conditioning regimen
        in patients with leukemia

      Overall Survival
    Early and intermediate                 Advanced
                                  Number of Patients       231
    disease                                disease
                                  Age (years)              33 (18-
                                  Disease                  55)
               Flu-MAC 52%           AML                   87
                                     ALL                   (38%)
                                                           85
                                     MDS/MPD               (37%)
                                                           59
              CY-MAC 38%          Disease status at CY-MAC (25%)
                                                    CBT
                                                    28%
                                     Early and             149
    p=0.04                        intermediate
                                     Advanced
                                       p=0.70              (64%)
                                                           82
                                                     Flu-MAC 6%
                                  Previous Autologous      (36%)
                                                           31
                                  HSCT Infusion
                                  TNC at                   (13%)
                                                           2.5 (0.58-7.6)
                                  (x107/kg)
Multivariate analysis for OS : Fludarabine (HR: 0.52;
GETH-RTN Protocol 2008
(TBF-MAC protocol)
                         EudraCT Code 2008-000927-24


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

Busilvex 3.2 mg/kg iv in 3 hs              BU    BU    BU


Fludarabine 50 mg/m2/d iv in 1             FL    FL    FL
                                           U     U     U
h

Thymoglobulin 2 mg/kg/d                          AT    AT   AT
                                                 G     G    G
                      Days       -7   -6    -5   -4    -3   -2   -1   0

GVH prophylaxis
ATG + CSA + MMF or Prednisone
UCBT for AML
Transplant characteristics
    Conditioning Regimens           n=573
          -Reduced Intensity        282 (49%)
              - Cy+Flu+TBI, n          211

            -Myeloablative          291 (51%)
             - TT+Bu+Flu, n            98
                 - Cy+TBI, n           54
                 - Cy+Bu, n            34
              - Cy+Flu+TBI, n          31

   Use of Anti-thymocyte globulin     49%
         GVHD prophylaxis            n=551
  - CsA + MMF ± steroids              58%
  - CsA ± steroids                    28%
  - Other                             14%
   Outcomes of Adult Patients with AML
                receiving
      Thiotepa-Busulfan-Fludarabine
                   and
Single Cord Blood (n=98) or Unmanipulated
    Haploidentical Bone Marrow (n=45)
                Transplant
                                                                 CR1+CR2 (n=77)


2-year Overall Survival                                                           63±8%

CBT




                                         Overall Survival
in 98 AML                                                                 8±7%
EUROCORD
                                                                           Advanced (n=21)


                                                                  month
                                                                  s
                                                            2-year Overall Survival
    64±8% at 1 yr                  59%
                  CR1 + CR2 n=34
                                   ±9                       Haplo BMT
                           p=
                                                            in 45 AML
            18±12%                                          Rome Transplant Network
       ADVANCED n=11
                           0.019                            Pescara Transplant Team
2-year Disease Free Survival                                           CR1+CR2 (n=77)




                                           Disease Free Survival
CBT                                                                                     45±7%


in 98 AML                                                                                    p=<0.001
EUROCORD                                                                      8±7%

                                                                         Advanced (n=21)

                                                                         months




                                                                   2-year Disease Free Survival
         61±9 % at 1 yr
                                49±9%                              Haplo BMT
                     Cr1+Cr2 (n=34)                                in 45 AML
                                p= 0.007
                                                                   Rome Transplant Network
         9 ±9 %                                                    Pescara Transplant Team
        ADVANCED (n=11)
    Myeloablative Conditioning Regimen

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)
The “NK cell alloreactivity” in HLA Mismatched Transplant

                   Donor                 Recipient
           HLA             NK cell             Target

        HLA-C group 2                         HLA-C group 2
        Cw2                   KIR2D           Cw2
                              L1

  HLA-C group 1                             HLA-C group 2
  Cw1                        KIR2DL         Cw4
                             2/3
                                            missing
                                            HLA-C group 1
           HLA-Bw4            KIR3D               HLA-Bw4
             B27                                    B51
                              L1

            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.
                             NK alloreactivity in AML
                           Confirmed in
                           T-cell depleted Haploidentical
                           Transplant
            1         A
                     Chemoresistan            1    A      remissio  Ruggeri et al,
            .
                     t relapB                 .
                                                   n      n
                                                   y alloreactive Blood 1999;
           00                                00
           .              se                 .     NK
           8                                 8     (n=30)
           0                                 0                   0.67
                                                                       Science 2002;
   Survi




                    P=
           .        0.04                     .  P=
   val




           6                                 6
           0
           .
                        NK alloreactive
                        (n=21)          0.30
                                             0
                                             .
                                                0.02
                                                                      Blood 2007;
           4
           0                                         4
                                                     0                            0.18
           .                                  0.06   .       N   N
                                                                  -
                                                                          alloreactive
                                                                                                        HSCT Programme
           2
           0        N-   N     alloreactive          2
                                                     0       o   K        (n=31)                        University of Perugia
           .        o    K     (n=30)                .       n
                0   2
                    n    4     6    8         1          0       2    4       6          8   1
           0                                  0      0
                             Ye                                             Ye               0
                             ars                                            ars

 Undefined in
 Unmanipulated Haploidentical Transplant

ROCORD           n=218
  Controversial in                                                                               Minnesota            n=257
ES                                                                                               NO
  Cord Blood Transplant
lemze R. et al., Leukemia, 2009
                                                                                                 Brunstein CG et al., Blood 2009
Which is the donor of choice if no MUD is available?


Cord Blood vs Haploidentical
Transplants

Results
RIC
Reduced Intensity Conditioning
    Reduced Intensity Conditioning
                                                                                Single UCB
                                                 HLA mismatched UCBT
                                                                                Double UCB

    Cytoxan        Fludarabine         sTBI                                                  Day +28
    50 mg/kg       200 mg/m2           200 cGy                                               BMBx




-    -    -    -   -     -   -     -      -      0            7          1            2          28
9    8    7    6   5     4   3     2      1                              4            1
                                 CSA - 3 to + 100
Eligibility:                     Mycophenolate - 3 to + 30
• < 70 yrs

• Heme malignancy

• High risk for TRM                                  G-CSF until ANC >2500/uL
    age > 45
    extensive prior Rx
    poor fitness

                                                                      University of Minnesota
    Impact of Stem Cell Source on
RIC Transplant Outcomes in Adults with
           Acute Leukemia

                        Mary Eapen MD MS
 Center for International Blood and Marrow Transplant Research
                   Medical College of Wisconsin
                       Leukemia-Free Survival
                 100                                                             100
                                                                  P=0.017
                 90                                                              90

                 80                                                              80

                 70                                                              70
Probability, %




                 60                                                              60

                 50                     Double CB (n=121), TCF:                  50

                 40
                                        26%                                      40

                 30                                                              30

                 20                                                              20

                 10        Double CB (40),                                       10
                           other: 9%
                   0                                                             0
                       0         6      12     18      24     30            36
                                              Months

                                                                                 Fk10_49.ppt
  Reduced Intensity Conditioning Regimen
after single unrelated CBT
for adults with hematological maligancies

    An Eurocord-Netcord, SFGM-TC and Minnesota
    group
    analysis
Reduced Intensity Conditionings in CBT
(n=176)
     Disease Free Survival according to Conditionings




                51% TCF: sTBI
                2GY+CY+FLU


                      28% other
                      conditionings
           p=
           0.0002
                           months
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
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



                       Unpublishe
                       d
Event Free Survival
      Overal                by Type of
      l                     Graft

                              Single (n= 96)
        51%                   56% ±8
        +/-4   (n=155
               )          Double
                          (n=59)
                          49% ±5




          Conditioning
          TCF: sTBI 2GY
       Reduced Intensity Regimen

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)
Do we know the best option
  for alternative donor transplant:


MUD vs CB vs Haplo?
    Fare clic per modificare lo stile del sottotitolo dello schema




                         NO
JACIE Metropolitan Transplant Program
                                                                                                  Coordinator:
                                                                                             William Arcese
                                                                            University “Tor Vergata”, Rome

                                Ospedale
                                Sant’Andrea



                                                                                                  O
                                                                                                  s
                                                                                                  p
                                                                                                  e
                                                                                                  d


                                                              ROME
                                                                                                  a
                                                                                                  l
                                                                                                  e

                                                                                                  S
                                                                                                  .


         Fare clic per modificare lo stile del sottotitolo dello schema                           E
                                                                                                  u
                                                                                                  g
               Ospedale                                                                           e
               Bambino Gesù                     Ospedale                                          n
                                                SanGiovanni-Addolorata                            i
                                                                                                  o
                                                                                            Policlinico Universitario
                                                                                            Tor Vergata


        Istituto Regina Elena



                                 Ospedale
                                 Sant’Eugenio
                                                                         Ospedale
                                                                         Campus Biomedico
JACIE Metropolitan Transplant Program            Coordinator:
                                                    William Arcese
                                   University “Tor Vergata”, Rome




Allogeneic Transplant Policy
AIM
Identification 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 search
       Cord Blood
                                                               Bone Marrow donor
       Banks
                                                               registries

NC dose collected to be increased with
                                           2nd
                                                   <8/8 or >3 months    HLA 8/8 loci
number of mismatches
                                                   (delay for AL)
single CB Unit
                                                                              1st
>2.5x107/kg NC  > 3.5x107/kg
NC
>1x105/kg CD34 >2x105/kg                                 3rd            MUD
CD34                                                                   Transplant
               Randomized
ProspectiveHLA: 2/6
HLA: 0-1/6
Study                                      UNMANIPULATED
CB vs Haplo
     POLICY IN ALLOGENEIC HEMATOPOIETIC STEM
     CELL TRANSPLANT
    Identical Conditioning Regimen
               GETH-RTN 2008 Protocol
               TBF-mac or TBF-ric



HLA          MUD                UCB                 HRD
Identical    Matched            Umbilical           Haploidentical
Sibling      Unrel. Donor       Cord Blood          Related Donor



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



      Different GVHD Prophylaxis
ALGORITHM OF ALLOGENEIC HSC TRANSPLANT
                                  Candidates to Transplant
                                  n = 462
   Not Eligible
   N= 34
                                       Eligible Patients
                                       n = 428                           HLA Identical Sibling
                                                                         n = 146 (34%)
                                 Search for Alternative Donor
       Too Early                 n = 282/428 (66%)
       n = 13 (4.6%)
                       Evaluable for alternative donor Identification
No Donor Identified    n = 269/282 (95%)
n = 25 (9%)
                              Alternative Donor Identified                     Total Donor Identified
                              n = 244/269 (91%)                                n = 390/428 (91%)
    No Transplant
    n = 51/244 (21%)
                                 Alternative Donor transplants
                                 n = 193/244 (79%)


         Scheduled      MUD               CB                 HAPLO      HLA Id. Sib.
         n = 16         n = 73                               n = 54     N = 146
                                          n = 50

                                    Transplanted
                                    n = 339/428 (80%) 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 D
                               IMMU N O B IO L O G Y O F
                               HA E MA T O P O IE T IC
                               S T E M C E L L T RAN S P L AN T

                 R O ME , IT A L Y
                     O c t o b e r 2 7 -2 9 , 2 0 1 1

P r e s i d 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 ll a

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

    Franco Locatelli
    Ospedale Bambino Gesù
    Paolo De Fabritiis
O
s   Ospedale Sant’Eugenio
p
e
d   Concetta Petti
a
l
    Istituto Regina
e
S
    Elena
.   Giuseppe Avvisati
E
u   Università Campus Biomedico
g
e
n
i
    Luciana Annino
o
    Ospedale San Giovanni

    Bruno Monarca
    Ospedale

				
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