Differential Elimination of Anti-Thymocyte Globulin of Fresenius and Genzyme Impacts T-Cell Reconstitution After Hematopoietic Stem Cell Transplantation.

Lisa V E Oostenbrink,Marianne Ifversen,Robbert G M Bredius,Anja M Jansen-Hoogendijk,Cornelia M Jol-Van Der Zijde,Marco W Schilham,Katrine Kielsen,Maarten J D Van Tol,Arjan C Lankester,Klaus G Müller,Astrid G S Van Halteren

doi:10.3389/fimmu.2019.00315

Lisa V E Oostenbrink, Marianne Ifversen + Show 9 more

Open Access

https://doi.org/10.3389/fimmu.2019.00315

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Abstract

Anti-thymocyte globulin (ATG) is a lymphocyte depleting agent applied in hematopoietic stem cell transplantation (HSCT) to prevent rejection and Graft-vs.-Host Disease (GvHD). In this study, we compared two rabbit ATG products, ATG-Genzyme (ATG-GENZ), and ATG-Fresenius (ATG-FRES), with respect to dosing, clearance of the active lymphocyte binding component, post-HSCT immune reconstitution and clinical outcome. Fifty-eigth pediatric acute leukemia patients (n = 42 ATG-GENZ, n = 16 ATG-FRES), who received a non-depleted bone marrow or peripheral blood stem cell graft from an unrelated donor were included. ATG-GENZ was given at a dosage of 6–10 mg/kg; ATG-FRES at 45–60 mg/kg. The active component of ATG from both products was cleared at different rates. Within the ATG-FRES dose range no differences were found in clearance of active ATG or T-cell re-appearance. However, the high dosage of ATG-GENZ (10 mg/kg), in contrast to the low dosage (6–8 mg/kg), correlated with prolonged persistence of active ATG and delayed T-cell reconstitution. Occurrence of serious acute GvHD (grade III–IV) was highest in the ATG-GENZ-low dosage group. These results imply that dosing of ATG-GENZ is more critical than dosing of ATG-FRES due to the difference in clearance of active ATG. This should be taken into account when designing clinical protocols.

Highlights

Serotherapy with lymphocyte depleting antibodies, anti-thymocyte globulin (ATG) and alemtuzumab, is frequently applied as part of the conditioning regimen in allogeneic hematopoietic stem cell transplantation (HSCT)
In this study we aimed to compare clearance of the two brands of rabbit ATG, ATG-GENZ and ATG-FRES, given at different dosages and analyze the consecutive immune reconstitution in a homogeneous cohort of pediatric stem cell transplant recipients transplanted in two HSCT Centers (Table 1)
3 weeks post-HSCT, the active ATG concentration in patients receiving ATG-FRES had decreased by a factor 164 (27.9 to 0.17 arbitrary units (AU)/mL), while in patients receiving ATG-GENZ active ATG had decreased by a factor 16 (10.6 to 0.65 AU/mL (Figure 2B)

Summary

Introduction

Serotherapy with lymphocyte depleting antibodies, anti-thymocyte globulin (ATG) and alemtuzumab, is frequently applied as part of the conditioning regimen in allogeneic hematopoietic stem cell transplantation (HSCT). ATG products are polyclonal IgG antibodies, raised in Importance of Lymphodepleting ATG Levels horses or rabbits by immunization with human thymocytes (horse: ATGAM R , Pfizer, New York, NY, USA; rabbit ATGGenzyme, ATG-GENZ, Thymoglobulin R , Sanofi Genzyme, Cambridge, MA, USA), or with a Jurkat T-cell line (rabbit ATG-Fresenius, ATG-FRES, recently re-named as anti-human T-lymphocyte immunoglobulin ATLG, Grafalon R , Neovii Biotech, Rapperswil, Switzerland). Both ATG-GENZ and ATG-FRES target T-cells and, amongst others, neutrophils, monocytes, NK-, B-cells and non-immune cells like endothelial cells [5]. The optimal approach for monitoring ATG is regular measurement of active ATG levels, rather than total ATG (rabbit IgG)

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