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ATGs: how many??

This study explores the use of ATG-Fresenius in reducing the risk of GvHD and facilitating engraftment in allogeneic stem cell transplantation. It also discusses the potential side effects and compares different treatment approaches.

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ATGs: how many??

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  1. ATGs: how many?? ATG Fresenius: rabbit serum containing polyclonal antibodies against the ALL-T leukemia line Jurkat. TMG Genzyme: rabbit serum containing polyclonal antibodies against human thymocytes.

  2. Antibodies specificities ATG/ALG CD mAb inhibitions SourceFl-labeled CD mAb-50% inhibition point in μg/ml of ATG/ALG CD2 CD3 CD4 CD5 CD7 CD8 ATG AM 130 550 280 1100 150 190 (ATG horse Upjohn) Merieux rabbit 40 230 400 20 70 30 Merieux horse 60 600 400 70 125 130 Fresenius 180 4400 >5000 200 240 1700 MALG 460 1000 1400 500 220 300 (horse ATG Minnesota) Bourdage et al., Transplantation 1995;59:1194-1200

  3. ATG-F / TMG-G: Different spectrum of specifities against co-stimulation molecules activity Activities anti CTLA - 4 ATG - F ++++ TMG - S ++ anti CD 86 ATG - F +++ anti CD 28 TMG - S +++ anti CD 80 ATG - F ++++ TMG - S - Pistillo et al., Transplantation 2000

  4. ATG–F administration schedule (BO) Total dose 15 mg/kg 3 mg/kg CsA - MTX -6 -5 -4 -3 -2 -1 0 Total dose 30 mg/kg 10 mg/kg CsA - MTX -6 -5 -4 -3 -2 -1 0

  5. Prophylaxis of chronic GvHD with or without anti T-lymphocyte globulin (ATG-F) prior allogeneic peripheral stem cell transplantation from HLA-identical sibling after myeloablative conditioning in patients with acute leukemia: A randomised phase III study Primary endpoint: reduction of cGVHD from 60% to 35% Sample size: 60/arm Study medication: ATG-Fresenius 10 mg/kg on days -3-2-1

  6. EUDRACT-Number 2005-005719-83 (ATGfamily study) Sponsor: University Hospital Hamburg Protocol Coordinator Germany: Nicolaus Kröger Hamburg Protocol Coordinator Italy: Francesca Bonifazi Bologna Scientific Committee:Nicolaus Kröger, Axel R. Zander, Frank Schulz-Kindermann Ernst Holler, Hermann Einsele, Jürgen Finke, Rainer Schwerdtfeger, Michael Schleuning Gerhard Ehninger, Martin Bornhäuser, Hans-Jochem Kolb, Hans-Jochem Kolb Francesca Bonifazi, Giuseppe Bandini, Arnon Nagler, Wolfang Bethke Statistics: Dr. Hinke, Germany Data Management: Andreas Voelp C.R.0. DataLog Clinical monitoring Pharmalog/R. Dautermann

  7. Levels of plasma ATG (active) and blood lymphocytes

  8. ‘ mean channel value of fluorescence arbitrary units

  9. Half time of Jurkat-reactive antibodies 8 patients after 30 mg/kg ATG-Fresenius days -3, -2, -1.

  10. Preparative regimen Tot. dose 7.5 mg 800 Gy ATG – G 800 cGy CsA/MMF From Lowsky et al., 2005

  11. ATG-G levels From Lowsky et al., 2005

  12. Intracellular interleukin-4 Comparison of Intracellular Cytokine Production. From Lowsky et al., 2005

  13. Effect of ATG prior to allogeneic stem cell transplantation After Tx To reduce risk of GvHD Before Tx To facilitate engraftment

  14. NMA GVHD after NMA Vs MA AlloSCT: MA Skin Morbidities involving the skin, liver, and gut after nonmyeloablative conditioning compared with myeloablative conditioning. Liver Gut Figura 2 Overall Acute Chronic Mielcarek et al. Blood 2003

  15. From Sala-Torra et al., 2008

  16. Linfomi.Ric GVHD ACUTA E CRONICA: ATG VS NON ATG (BO) Nr. pazienti

  17. I ATG-G 10 mg/KG 200 Gy FK / MTX 3/16 graft failure - 4 - 1 0 II ATG-G 10 mg/KG 450 Gy no graft failure more infections more relapse FK / MTX G-csf - 1 - 7 -10 0 I and II treatment plans From Toor et al., 2008

  18. Hematopoietic Stem Cell Transplantation in a canine model cATG-G 2-5 mg/kg 100 Gy Csa /MMF - 12 - 7 0 From Diaconescu et al., 2005

  19. From Diaconescu et al., 2005

  20. Preparative regimen Tot. dose 7.5 mg 800 Gy ATG – G 800 cGy CsA/MMF From Lowsky et al., 2005

  21. Lymphoid and myeloid engraftment From Lowsky et al., 2005

  22. T-cell engraftment From Lowsky et al., 2005

  23. Conclusioni • Utilizzo ATG non sarebbe indicato, in quanto riduce la GVHD, soprattutto cronica, diminuendo la GvL. • Utilizzo ATG indicato in quanto necessario per favorire l‘attecchimento, il chimerismo completo, elementi di primaria importanza ai fini del successo (eradicazione della malattia) del trapianto. La tossicità è minima. Gli ATG concorrono a realizzare dei condizionamenti “ridotti” evitando l’impiego di farmaci citotossici/immunosoppressivi. • Poiché il punto 2 è molto più importante del punto 1, gli ATG devono essere usati nei regimi “a intensitàridotta”.

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