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Role of ATG in Allogeneic Role of ATG in Allogeneic HSCTHSCT
ZiYi LimZiYi LimNational University Cancer InstituteNational University Cancer Institute
SingaporeSingapore
33rdrd BTG – Hong Kong BTG – Hong Kong2424thth Feb 2012 Feb 2012
Allogeneic Transplants for Age Allogeneic Transplants for Age 20yrs,20yrs,Registered with the CIBMTR Registered with the CIBMTR
1992-20091992-2009- by Donor Type and Graft Source -- by Donor Type and Graft Source -
Num
ber
of
Tra
nsp
lants
*
* Data incomplete
0
1,000
2,000
3,000
4,000
5,000
6,000
7,000
8,000
9,000
10,000
11,000
12,000
13,000
1992-93 1994-95 1996-97 1998-99 2000-01 2002-03 2004-05 2006-07 2008-09
Related BM/PBUnrelated BMUnrelated PBUnrelated CB
Improvements in HSCT Improvements in HSCT outcomesoutcomes
Changes in conditioning regimensChanges in conditioning regimens
Improved HLA-typingImproved HLA-typing
Improvements in supportive careImprovements in supportive care
21 Apr 202321 Apr 2023 44
Elie Metchnikoff Elie Metchnikoff (1845-1916)(1845-1916)
18991899
• Ground rat spleens Ground rat spleens > injected into > injected into guinea pigsguinea pigs
• Hyperimmune Hyperimmune serum > serum > agglutinate and agglutinate and destroy rat destroy rat leukocytesleukocytes
Father of ATG?
ATGATG
Polyclonal antibodiesPolyclonal antibodies
Produced by immunizing rabbits/horses with human Produced by immunizing rabbits/horses with human thymocyte/lymphocyte cell suspensionsthymocyte/lymphocyte cell suspensions
Bind to broad array of surface antigensBind to broad array of surface antigens
ApoptosisApoptosis– Complement dependent cell lysisComplement dependent cell lysis– T cells, (B cells/NK cells/DCs at higher doses)T cells, (B cells/NK cells/DCs at higher doses)
Down modulation of surface moleculesDown modulation of surface molecules– PB and lymphoid tissuePB and lymphoid tissue– Down regulation of inhibitory T cell activityDown regulation of inhibitory T cell activity– Inhibits adhesion molecules/leukocyte inflitrationInhibits adhesion molecules/leukocyte inflitration
ATG/ALG formulationsATG/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
ATG preparations used: issuesATG preparations used: issues
Different sources and immunogens used Different sources and immunogens used Multiple target antigens: immune response, Multiple target antigens: immune response,
adhesion and cell trafficking, heterogeneous adhesion and cell trafficking, heterogeneous cell pathwayscell pathways
Batch-to-batch variabilityBatch-to-batch variability Doses and duration of therapy vary Doses and duration of therapy vary
considerably and have not been systematically considerably and have not been systematically compared.compared.
Early StudiesEarly 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 malignanciesAll 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
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
Pilot StudyFBATG 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 StudyPilot StudyFBATG Sibling Allograft protocol for patients FBATG Sibling Allograft protocol for patients
with high risk AML/MDSwith 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%)
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
Haplo-related(n=26)
Flu-Mel_Thio-ATG
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 Marked increased risk of EBV-related complications with addition of ATG to complications with addition of ATG to
nonmyeloablative conditioning prior to UCB nonmyeloablative conditioning prior to UCB transplantationtransplantation
Brunstein et al. Blood 2006; 108: 2874-2880Brunstein et al. Blood 2006; 108: 2874-2880
ProtocolProtocol
Standard: Cyclo+ Busulphan or TBI and Standard: Cyclo+ Busulphan or TBI and ALG in 174 (73%)ALG in 174 (73%)
ALG 15mg/kg bd x 3 daysALG 15mg/kg bd x 3 days
RIC: cyclo/fludarabine/TBI 200cG in 30 RIC: cyclo/fludarabine/TBI 200cG in 30 (32%) after 2002(32%) after 2002
Post Tx immune suppression: CSA/MMF Post Tx immune suppression: CSA/MMF (50%); CSA/MP (49%)(50%); CSA/MP (49%)
ResultsResults
15/335 developed EBV-related 15/335 developed EBV-related complications at median of D+133 (52-complications at median of D+133 (52-407)407)
4 viraemia; 11PTLD4 viraemia; 11PTLD
5/9 treated with rituximab responded to 5/9 treated with rituximab responded to treatment survivedtreatment survived
Copyright ©2006 American Society of Hematology. Copyright restrictions may apply.
Brunstein, C. G. et al. Blood 2006;108:2874-2880
Figure 1. Cumulative incidence of Epstein-Barr virus-related complications
Copyright ©2006 American Society of Hematology. Copyright restrictions may apply.
Brunstein, C. G. et al. Blood 2006;108:2874-2880
Figure 2. Kaplan-Meier probability of overall survival
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