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

T-cell DepletionUnmanipulated

marrow

Relapse GVHDIntensity of conditioning

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

Horse ATG Rabbit ATG

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.

Use of ATG Use of ATG

in in

Unrelated Adult Donor HSCTUnrelated Adult Donor HSCT

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

Impact of ATG on Grade III-IV aGvHD

Overall Survival

Causes of Death on Overall CohortCauses of Death on Overall Cohort

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 Use of ATG

in in

Related Adult Donor HSCTRelated Adult Donor HSCT

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%)

Use of ATG Use of ATG

in in

Alternative donor HSCTAlternative 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-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