1 Emanuele Angelucci stem cell transplantation in thalassaemia by xiagong0815

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									Plenary 4 - New Scientific Developments
Stem
cell and cord blood transplantation in
            thalassaemia
       2nd Pan-European Conference on
             Haemoglobinopathies
              Berlin, 13-14 March 2010

                                       Emanuele Angelucci
                                       Cagliari Hematology
                                “A. Businco” Cancer Centre
         Plane of the presentation

● History of transplantation in Thalassemia
● Current results
  ● HLA id sibling
  ● MUD
  ● Related Cord Blood
  ● Experimental approach
● Current position of transplantation in the
  treatment of Thalassemia
         Plane of the presentation

● History of transplantation in Thalassemia
● Current results
  ● HLA id sibling
  ● MUD
  ● Related Cord Blood
  ● Experimental approach
● Current position of transplantation in the
  treatment of Thalassemia
  First transplant for Thalassemia

● December 2, 1981 at the FHCRC in Seattle
 Figure 2. Numbers of hemopoietic stem cell transplants performed for thalassemia through the years
           in centers of the European Registry for Blood and Marrow Transplantation (EBMT)




                          Angelucci, E. et al. Haematologica 2008;93:1780-1784




Copyright ©2008 Ferrata Storti Foundation
  Figure 3. Numbers of hemopoietic stem cell transplantations performed for thalassemia through the
       years in centers of the European Registry for Blood and Marrow Transplantation (EBMT)




                          Angelucci, E. et al. Haematologica 2008;93:1780-1784




Copyright ©2008 Ferrata Storti Foundation
      Figure 1. Results of hemopoietic stem cell transplantation in 900 consecutive patients, aged 1-35
              years, transplanted from an HLA identical sibling in Pesaro since December 1981




                          Angelucci, E. et al. Haematologica 2008;93:1780-1784




Copyright ©2008 Ferrata Storti Foundation
         Plane of the presentation

● History of transplantation in Thalassemia
● Current results
  ● HLA id sibling
  ● MUD
  ● Related Cord Blood
  ● Experimental approach
● Current position of transplantation in the
  treatment of Thalassemia
         Plane of the presentation

● History of transplantation in Thalassemia
● Current results
  ● HLA id sibling
  ● MUD
  ● Related Cord Blood
  ● Experimental approach
● Current position of transplantation in the
  treatment of Thalassemia
Haemoglobinopathy Retrospective Study
Overall Survival ( # 1086 Patients)
 Haemoglobinopathy Retrospective Study
Disease Free Survival (# 1086 Patients)
Haemoglobinopathy Retrospective Study
 Overall Survival by Class of Risk




   Class 1        Class 2            Class 3
BMT in Adult Thalassemia
                         (BU14 CY90)
                           median follow-up: 4 years (1.7-6.8)
                1


               0.8               THALASSEMIA-FREE SURVIVAL
 PROBABILITY




                                                                     67%
               0.6


               0.4
                                 TRANSPLANT-RELATED MORTALITY
                                                                     27%
               0.2
                                  REJECTION
                                                                         8%
                0
                     0    1       2        3       4        5    6   7
                                               YEARS
         Plane of the presentation

● History of transplantation in Thalassemia
● Current results
  ● HLA id sibling
  ● Matched Unrelated Donor
  ● Related Cord Blood
  ● Experimental approach
● Current position of transplantation in the
  treatment of Thalassemia
                                                            Figure 1.




                                   GITMO 2002 data. Blood 2002;99:4350-4356


Copyright ©2002 American Society of Hematology. Copyright restrictions may apply.
                        50 Class 1 and 2 Thalassemia patients
                Unrelated BMT for Thalassemia
              Class 1 and Class 2 (n=50; median age 8 yrs (2-17)


              1.0
                                     Overall survival                     94% (87-100)
              0.9                 *Thalassemia free survival              88% (78-97)
              0.8
                                   Thalassemia free survival              82% (71-94)
              0.7

              0.6

              0.5

              0.4
Probability




              0.3

              0.2

              0.1

              0.0
                    0         1            2               3          4                  5
                                                Years


                                                               * Including 3 second transplants
Unrelated BMT for Thalassemia
  Class 3 younger, age <17 years; n=38
Unrelated BMT for Thalassemia
   Class 3 adult patients, age >17 years; n=27




                                          La Nasa et al. Bone Marrow Transplant, 2005
Figure 1. Influence of HLA-DPB1 mismatches on the outcome of UD-SCT for beta-thalassemia




                                Fleischhauer, K. et al. Blood 2006;107:2984-2992




Copyright ©2006 American Society of Hematology. Copyright restrictions may apply.
OS after HLA identical sibling donor for patients with Thalassemia or SCD
according to bone marrow (n=389) or cord blood (n=70) stem cell source



                                                          CB   Deaths n=3     96±3%
           Probability of overall survival (%)


                                                          BM   Deaths n=18   95±1%




                                                 p=0.92
                                                                                           months




                                                                                      ASBMT meeting Feb 15 2008
   Disease Free survival after HLA identical sibling donor bone marrow
   or cord blood for patients with SCD (n=156) or Thalassemia (n=303)




                   Probability of disease free survival (%)
                                                              SCD (n=156)      ev n=13                     92±2%


                                                              Thalassemia (n=303)   ev n=47                 84±2%
In multivariate
analysis
Stem cell source
Disease
Age at T
Year at T




                                                               p=0.04                    Ev= deaths or graft failure     months


  SICKLE CELL DISEASE : ONLY FACTOR ASSOCIATED WITH BETTER DFS

                                                                                                                 ASBMT meeting Feb 15 2008
         Plane of the presentation

● History of transplantation in Thalassemia
● Current results
  ● HLA id sibling
  ● MUD
  ● Related Cord Blood
  ● Experimental approach
● Current position of transplantation in the
  treatment of Thalassemia
    Non-myeloablative HCT for SCD
                                         Minimal Toxicity               Reduced Intensity
                                            Regimen                        Regimen
No. of Patients                                   11*                           12**
Age (median, years)                      10 (range, 3 – 30)             22 (range, 2 – 56)
Conditioning Regimen                 Flu(90-150)/TBI (200) [5];     Flu(175)/BU(8)/ATG/TLI (500)[5];
(dose) [No. of patients]           Flu(125-150)/ATG/TBI (200)[6]     Flu (120)/Mel(140)/ATG [2]; Flu
                                                                   (120)/Mel(140)/Campath-1H (100)[2]
                                                                     Flu(120)/CY(120) [1]; Flu/BU [2]


Source of Stem Cells                     Marrow (9); PBSC (2)      Marrow (6); PBSC (6); UCB (1)
(HLA-ID siblings)
Graft rejection/disease                           10                               3
recurrence
GVHD                                 1 (Gr I), chronic, none              4 (Gr II-IV),
                                                                       chronic, 3 (2 fatal)
Deaths                                           none                              2
Event-free survival                              1 (9%)                       7 (58%)
   *includes 2 patients with thalassemia major
   **includes 1 patient with thalassemia major                          Walters MC. ASH 2005
          Unrelated Cord Blood
      Transplantation for Thalassemia
•   Provenience:        14 centers (Taiwan, Singapore, USA)
•   Patients:           38
•   Disease:            Thal=36, SCD=2
•   Median age:         6 yrs (range 0.3-20)
•   Risk classes:       class 1=19; class 2=4; class 3 =1;
                        unknown=14
•   HLA disparity:      most patients were mismatched for 1 or 2 antigens
•   Conditioning:       BUCYATG
•   GvHD prophylaxis:   CSA+ methylprednisolone
•   Alive and Well:      30
•   Disease-free:       25
•   Died:               8
•   OS:                 77%± 7% (87% ± 7% for experienced centers)
•   DFS:                65% ± 8% (77% ± 9% for experienced centers)
•   Median follow-up:   257 days (1-1,760 d)

                                      Tan JP et al: Blood 2006, p.167a, abstr. 554
Figure 2 Hemopoietic Stem Cell Transplant from related haploidentical donor. MIH experience
                           on 22 patients of different classes.




                                     Sodani, P. et al. Blood 2010;115:1296-1302




Copyright ©2010 American Society of Hematology. Copyright restrictions may apply.
         Plane of the presentation

● History of transplantation in Thalassemia and
  SCD
● Current results
  ● HLA id sibling
  ● MUD
  ● Related Cord Blood
  ● Experimental approach
● Current position of transplantation in the
  treatment of Thalassemia
      Figure 4. Kaplan-Meier survival curves in 977 medically treated patients with thalassemia in Italy




                          Angelucci, E. et al. Haematologica 2008;93:1780-1784



Copyright ©2008 Ferrata Storti Foundation
          Current position of transplantation in
              the treatment of thalassemia.


●    Transplantation remains today the only definitive curative therapy
    for thalassemias and other hemoglobinopathies.


● The development of oral chelators did not change this position.
  However, this has not settled the debate on how this curative but
  potentially lethal treatment stands vis-à-vis a medical, non-
  curative therapy for adult and advanced disease patients.
          Current position of transplantation in
              the treatment of thalassemia.

●    Transplantation technologies have improved substantially during
    recent years and their outcome ismuch better today than it was in
    the ‘80s.



                                 OS %              DFS %
         early                     95                89
         Advanced                  87                80
         Adults                  65 - 70           65 - 70
         Current position of transplantation in
             the treatment of thalassemia.

● We should make our best effort to further reduce transplant
  related mortality and to extend the opportunity of transplant even
  to patients lacking an HLA identical donor and those without
  modern healthcare resources.
● This is the challenge for the definitive cure of thalassemias and
  hemogobinopathies in the third millennium.
Thank you for your attention




                        Emanuele Angelucci
                        Cagliari Hematology
                 “A. Businco” Cancer Centre

								
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