Impact of Antithymocyte Globulins on Patient Outcome after Myeloablative Bone Marrow Stem Cell Transplantation from HLA 10/10-Matched Unrelated Donor: A Report from the French Society of Bone Marrow Transplantation and Cell Therapies (SFGM-TC)
Authors: Ravinet Aurélie , Cabrespine Aurélie , Socie Gerard , Yakoub-Agha Ibrahim , Vigouroux Stephane , Michallet Mauricette , Nguyen Stephanie , Huyn Anne , Mohty Mohamad , Suarez Felipe , Bay Jacques-Olivier , Peffault de Latour Regis 
Published: October 2019

Abstract
Background: A recent prospective study (Socie & al Blood 2011) demonstrated that the addition of antithymocyte globulins (ATG) to prophylaxis for graft versus host disease (GVHD) in the setting of standard myeloablative conditioning (MAC) regimen matched unrelated donor (UD) allogeneic stem cell transplantation (HSCT) resulted in a decrease in incidence of chronic GVHD without an increase of relapse or non-relapse mortality. However, stem cell source was mostly peripheral blood stem cells (PBSC) and patients (pts) were compatible at HLA-A, HLA-B, HLA-DRB1 and HLA-DQB1 (eight out of eight alleles). A retrospective study using the same setting (Mohty & al Leukemia 2012) found very similar results with donor/recipient pairs matched at 10 loci (ten out of ten alleles). However, one third of the pts received PBSC as stem cells source and 20% of the pts were transplanted with a mismatch donor (9 out of 10 alleles). We thus conducted this study to assess the impact of ATG in pts with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) transplanted with MAC using bone marrow only (BM) from matched 10/10 UD.
Patients and methods: We includedall consecutive pts older than 18 years who received a first HSCT in France for AML or MDS with BM from a matched 10/10 UD after a standard conditioning regimen (fractionated total body irradiation (TBI)-Cyclophosphamide(Cy), n=106 or Endoxan-Cy, n=91) between June 2000 and June 2012. Clinical data were prospectively collected using ProMISe (Project Manager Internet Server), an internet-based data registry system shared by all centers of the French Society of Bone Marrow Transplantation and Cell Therapies (SFGM-TC). This study was approved by the scientific committee of the SFGM-TC.
Results: A total of 197 adult pts met the criteria and were analyzed (165 AML (84%) and 35 MDS). 54 (27%) pts received ATG in the conditioning regimen whereas 143 (73%) did not. Median follow up was of 20.3 months [0.4-156]. Both groups (with or without ATG) were well balanced except for the number of CD34+ cells infused (higher in the ATG group: 3.07x106/kg [0.7-13] vs 2.71x106/kg [0.6-89] for none ATG group (p=0.03)) and GvHD prophylaxis (more likely cyclosporine plus methotrexate with ATG (94%) vs 84% without, p=0.05).
The probability of acute GvHD grade II-IV was similar between both groups: 41.3% with ATG vs 49.6% without, p=0.2. Incidence rate of severe acute GVHD grade III-IV at day 100 tended to be lower in the ATG group as compared with the none ATG group (20.3% vs 9.5%, respectively, p=0.052). The cumulative incidence (CI) of chronic GVHD at 2 years was 42% in the ATG group vs 28% in the none ATG group and 37% vs 44% at 4 years, respectively (p=0.18). The probability of extensive chronic GVHD at 2 years was identical between both groups (12% with ATG vs 16% without, p=0.95).
CI of non-relapse related mortality (NRM), relapse as well as disease free survival (DFS) and overall survival (OS) were similar between the 2 groups (Table 1). In multivariate analysis, advanced disease status was the only parameter associated with decreased DFS (HR 0.37, 95% CI [0.19-0.70], p=0 .02) and OS (HR 0,41, 95% CI [0,24;0,71], p<0.01). During the study, 106 pts died (28 pts (52%) in the ATG group and 78 in the none ATG group (53%)). No difference was observed in terms of cause of death (detailed in Table 2) between the two groups, relapse accounting for half the causes of in both groups (47%).
Conclusion:The addition of ATG to MAC regimen in pts with AML or MDS transplanted with BM from matched 10/10 resulted in similar outcomes in terms of NRM, relapse as well as DFS and OS. Despite the limitation due to the retrospective setting of our study, we did not find any obvious benefit for adding ATG to the conditioning regimen in this setting. Prospective studies are needed to firmly answer to this question and notably to better assess a possible benefit in terms of quality of life in the ATG group.
Table 1: 2-years cumulative incidence of NRM, relapse, DFS and OS Outcomes ATG group % [95% CI] Non ATG group % [95% CI] p value NRM 21 [15-27] 23 [19-27] 0.90 Relapse 32 [25-39] 31 [27-35] 0.83 DFS 46.9 [39.9-53.9] 46.7[39.7-53.7] 0.98 OS 57.1 [50.2-64] 53[46-60] 0.62
Table 2: main causes of death Causes of death ATG group n,(%) Non ATG group n,(%) Relapse 13 (46.3) 36 (46) GvHD 3 (10.7) 9 (11.5) Infection 2 (7) 12 (15.5) Organ toxicity 5 (18) 11 (14) Secondary neoplasia 1 (3.6) 1 (1.5) Rejection 0 2 (2.5) Unknown 4 (14.4) 7 (9)

Disclosures
No relevant conflicts of interest to declare.