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  

 

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