Transcript cord day

Role of ATG in Allogeneic
HSCT
ZiYi Lim
National University Cancer Institute
Singapore
3rd BTG – Hong Kong
24th Feb 2012
Allogeneic Transplants for Age > 20yrs,
Registered with the CIBMTR
1992-2009
- by Donor Type and Graft Source 13,000
12,000
Number of Transplants
11,000
10,000
Related BM/PB
Unrelated BM
Unrelated PB
Unrelated CB
9,000
8,000
7,000
6,000
5,000
4,000
3,000
2,000
1,000
0
1992-93
1994-95
1996-97
1998-99
2000-01
2002-03
2004-05
2006-07
*
2008-09
* Data incomplete
Improvements in HSCT outcomes
Changes in conditioning regimens
Improved HLA-typing
Improvements in supportive care
13-Apr-15
4
T-cell Depletion
Relapse
Unmanipulated
marrow
GVHD
Father of ATG?
1899
• Ground rat spleens
> injected into
guinea pigs
• Hyperimmune
serum >
agglutinate and
destroy rat
leukocytes
Elie Metchnikoff
(1845-1916)
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
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
Horse ATG
Rabbit ATG
ATG preparations used: issues



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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.
Use of ATG
in
Unrelated Adult Donor HSCT
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;27:227- 230.
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;306:392-397
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
Impact of ATG on Grade III-IV aGvHD
Overall Survival
guest on February 17, 2012. For personal use only.
ATG FOR GVHD PROPHYLAXIS
Causes of Death
on Overall Cohort
2945
Figure 4. Causes of death in 109 patients randomized to receive no ATG
(n 5 53), 7.5 mg/kg ATG (n 5 29), or 15 mg/kg ATG (n 5 27). Acute GVHD was the
cause of death in 36% of patients not receiving ATG, 28% of patients receiving 7.5
mg/kg ATG, and 11% of patients receiving 15 mg/kg ATG. Infections were, on the
contrary, more frequent in patients receiving high-dose ATG.
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
ATG use associated with a lower incidence of cGvHD
ATG and impact on Overall Survival
Use of ATG
in
Related Adult Donor HSCT
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
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%)
Use of ATG
in
Alternative donor HSCT
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-ThioATG
2mg/kg x4d
aGvHD 24%
cGvHD 24%
5-yr DFS 1144%
Ciurea SO
2010
Haplo-related
(n=26)
Flu-Mel_ThioATG
1.5mg/kg x4d
aGvHD 7%
cGvHD 14%
Lu DP 2006
Haplo-related
(n=135)
Bu Cy2 -ATG
2.5mg/kg x4d
aGvHD 40%
cGvHD 55%
2-yr LFS 64%
Marked increased risk of EBV-related
complications with addition of ATG to
nonmyeloablative conditioning prior to UCB
transplantation
Brunstein et al. Blood 2006; 108: 2874-2880
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%)
Results
15/335 developed EBV-related
complications at median of D+133 (52407)
4 viraemia; 11PTLD
5/9 treated with rituximab responded to
treatment survived
Figure 1. Cumulative incidence of Epstein-Barr virus-related complications
Brunstein, C. G. et al. Blood 2006;108:2874-2880
Copyright ©2006 American Society of Hematology. Copyright restrictions may apply.
Figure 2. Kaplan-Meier probability of overall survival
Brunstein, C. G. et al. Blood 2006;108:2874-2880
Copyright ©2006 American Society of Hematology. Copyright restrictions may apply.
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