1. Role of ATG in Allogeneic HSCT ZiYi Lim National University Cancer Institute Singapore 3rd BTG – Hong Kong 24th Feb 2012

3. Allogeneic Transplants for Age > 20yrs, Registered with the CIBMTR by Donor Type and Graft Source -
Number of Transplants
Slides 11: Among patients older than 20, there has also been an increase in the number of unrelated donor transplants which surpassed the number of related donor transplants. Mobilized peripheral blood progenitor cells is the most common graft source for unrelated donor transplants in this age group. In 2008 and 2009, utilization of umbilical cord blood in adults reached 11% of all unrelated donor transplants. *
* Data incomplete

4. Improvements in HSCT outcomes
Changes in conditioning regimens
Improved HLA-typing
Improvements in supportive care
24-Apr-17

5. Unmanipulated
marrow
T-cell Depletion
Relapse
GVHD
Intensity of conditioning

6. Father of ATG? 1899 Ground rat spleens > injected into guinea pigs
Hyperimmune serum > agglutinate and destroy rat leukocytes
Elie Metchnikoff ( )

7. ATG Polyclonal antibodies
Produced by immunizing rabbits/horses with human thymocyte/lymphocyte cell suspensions
Bind to broad array of surface antigens
Apoptosis
Complement dependent cell lysis
T cells, (B cells/NK cells/DCs at higher doses)
Down modulation of surface molecules
PB and lymphoid tissue
Down regulation of inhibitory T cell activity
Inhibits adhesion molecules/leukocyte inflitration

8. ATG/ALG formulations Generic Name Producer Horse ALG (Lymphoglobulin)
Rabbit ATG (Thymoglobulin)
Genzyme, Sangstat, France
Rabbit ATG (Fresenius)
ATG Fresenius, Germany
Horse ATG Pharmacia
ATGAM, Pharacia Upjohn, USA

9. Horse ATG
Rabbit ATG

10. ATG preparations used: issues
Different sources and immunogens used
Multiple target antigens: immune response, adhesion and cell trafficking, heterogeneous cell pathways
Batch-to-batch variability
Doses and duration of therapy vary considerably and have not been systematically compared.
Young: 10 vs 28 day study, no sig difference, but trend for more rapid, more frequent and more CRs
Killick, 14 patients, one PR only, using 1/3 dose (5mg/mg horse ATG)

11. Use of ATG in Unrelated Adult Donor HSCT

12. Early Studies
Weiden PL, Doney K, Storb R, Thomas ED. Antihuman thymocyte globulin for prophylaxis of graft-versus-host disease. A randomized trial in patients with leukemia treated with HLA- identical sibling marrow grafts. Transplantation. 1979;27:
Ramsay NKC, Kersey JH, Robinson LL, et al. A randomized study of the prevention of acute graft versus host disease. N Engl J Med. 1982;306:

13. 109 patients with haematological malignancies
All received cyclophosphamide/TBI conditioning
GvHD prophylaxis with CyA
2 trials:
Trial A: ATG (3.75 mg/kg x D-4,-3) vs no ATG
Trial B: ATG (3.75 mg/kg x D-5 to -2) vs no ATG

14. Impact of ATG on Grade III-IV aGvHD
Overall Survival

15. Causes of Death on Overall Cohort

16. Update of original Italian randomised study
75 patients surviving more than 100 days (ATG 38 vs non ATG 37)
Median follow-up 5.7 years
Assessment of
long-term risk of chronic GVHD
chronic lung dysfunction
quality of life

17. ATG use associated with a lower incidence of cGvHD
ATG and impact on Overall Survival

18. Use of ATG in Related Adult Donor HSCT

19. FBATG Sibling Allograft protocol for patients
Pilot Study
FBATG Sibling Allograft protocol for patients
with high risk AML/MDS
Retrospective analysis on 62 patients with high risk AML/MDS
HLA-matched sibling donor RIC HSCT
41 patients received alemtuzumab (20mg x 5 days intravenously) followed by cyclosporin A post-transplant.
21 patients received ATG (total 6mg/kg over 3 days intravenously)
2 yrs OS:
56.1%+/-8% vs 73.7%+/-10%, p=0.25

20. Pilot Study FBATG Sibling Allograft protocol for patients with high risk AML/MDS
2 yrs TRM
(19.5%+/-7% vs 10.6% +/- 7%, p=0.43)
2 yrs Relapse
(28.4%+/-15% vs 51.5%+/-8%, p=0.04)
Patients who received ATG had a significantly higher incidence of chronic extensive GvHD (34% vs 6%, p=0.03).
Significantly larger proportion of patients receiving alemtuzumab required subsequent DLI therapy (68% vs 19%)

21. Use of ATG in Alternative donor HSCT

22. Donor Source
Regimen
ATG
Outcomes
Lee KH 2011
Haplo-related
(n=83)
Flu-Bu-ATG
3mg/kg x4d
aGvHD 20%
cGvHD 34%
OS 45%
Sanz J 2012
Single UCBT
(n=88)
Flu-Bu-Thio-ATG
2mg/kg x4d
aGvHD 24%
cGvHD 24%
5-yr DFS 11-44%
Ciurea SO 2010
(n=26)
Flu-Mel_Thio-ATG
1.5mg/kg x4d
aGvHD 7%
cGvHD 14%
Lu DP 2006
(n=135)
Bu Cy2 -ATG
2.5mg/kg x4d
aGvHD 40%
cGvHD 55%
2-yr LFS 64%

23. Marked increased risk of EBV-related complications with addition of ATG to nonmyeloablative conditioning prior to UCB transplantation Brunstein et al. Blood 2006; 108:

24. Protocol Standard: Cyclo+ Busulphan or TBI and ALG in 174 (73%)
ALG 15mg/kg bd x 3 days
RIC: cyclo/fludarabine/TBI 200cG in 30 (32%) after 2002
Post Tx immune suppression: CSA/MMF (50%); CSA/MP (49%)

25. Results
15/335 developed EBV-related complications at median of D+133 (52-407)
4 viraemia; 11PTLD
5/9 treated with rituximab responded to treatment survived

26. Brunstein, C. G. et al. Blood 2006;108:2874-2880
Figure 1. Cumulative incidence of Epstein-Barr virus-related complications
Brunstein, C. G. et al. Blood 2006;108:
Copyright ©2006 American Society of Hematology. Copyright restrictions may apply.

27. Figure 2. Kaplan-Meier probability of overall survival
Brunstein, C. G. et al. Blood 2006;108:
Copyright ©2006 American Society of Hematology. Copyright restrictions may apply.

28. Summary ATG effective in reducing acute and chronic GvHD
Differences between ATG/ALG preparations and lack of comparative data
Balance of ATG usage depends on trade off between anticipated risks and benefits of T-cell depletion
Use of ATG and dose of ATG dependent on both donor and host factors
More studies are required to determine optimum timing and dose of ATG