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 - 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

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

Unmanipulated marrow T-cell Depletion Relapse GVHD Intensity of conditioning

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 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)

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

Causes 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 in Related Adult Donor HSCT

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

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-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%

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 (52-407) 4 viraemia; 11PTLD 5/9 treated with rituximab responded to treatment survived

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;108:2874-2880 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