Antithymocyte Globulins (ATG) as Part of the Myeloablative Conditioning (MAC) Regimen Can Reduce the Risk of Severe Graft-Vs.-Host Disease (GVHD) after Allogeneic Stem Cell Transplantation (allo-SCT) from Matched-Unrelated Donors (MUD)

The use of ATG in the setting of standard MAC allo-SCT is still controversial. Some studies, however, suggested a beneficial effect of ATG in preventing acute GVHD. Here, we report the results of a large multicenter retrospective study analyzing the effect of ATG, incorporated within the MAC regimen for MUD-transplants in leukemic patients compared to patients not receiving ATG. The purpose of the study was to compare the incidence and severity of acute and chronic GVHD as well as non-relapse mortality (NRM), leukemia-free and overall survivals (LFS, OS). The study included 171 adult patients with acute leukemia and MDS (73% standard risk and 27% more advanced disease) reported to the registry of the SFGM-TC between 1998 and 2004, and for whom detailed allelic HLA typing (4 digits) for the recipient and the donor was available. Patients’ characteristics were as follow: median age: 33 (range, 15-67), 57% male recipients, 35% female donors, 44% AML, 43% ALL, 11% MDS and 2% unclassified leukemia. The stem cell source was bone marrow in 72.5% of patients, while PBSCs were used in 27.5% of cases. 81% of patients were transplanted from 10/10 allelic MUD, and 19% from a MUD with at least one allelic difference. A high dose TBI-based MAC regimen was used in 84% of cases, while 16% received a high-dose chemotherapy containing MAC regimen. 85% of the patients received the classical CsA and short course methotrexate GVHD prophylaxis regimen. In this series, 120 patients (70%) did not receive ATG (“no-ATG” group), while 51 patients received ATG (“ATG” group; Thymoglobuline*-Genzyme in all cases; total ATG dose: ≤5 mg/Kg, n=13; >5 and <10 mg/Kg, n=17; ≥10 mg/Kg, n=21) as part of the MAC regimen. Except for a significantly higher number of allelic differences between recipient and donor (33% vs. 13%; P=0.002), the “no-ATG” and “ATG” groups were strictly comparable as for patients, disease and transplant characteristics.
95% of patients had a sustained engraftment at a median of 20 (range, 9-41) days after allo-SCT with no significant differences between the 2 groups. With a median follow-up of 30.3 (range, 2.6-68.1) months after allo-SCT, grade 0-1 and 2-4 acute GVHD occurred in 74 (46%) and 88 patients (54%) respectively, with grade 3-4 acute GVHD being significantly lower in the “ATG” group as compared to the “no-ATG” group (18% vs. 32%; P=0.04). In this series, 142 patients (83%) were evaluable for chronic GVHD. Limited and extensive chronic GVHD were observed in 22 and 25% of assessable patients respectively, with extensive chronic GVHD being significantly lower in the “ATG” group as compared to the “no-ATG” group (5% vs. 33%; P=0.001). Interestingly, patients from the “ATG” group had a higher incidence of limited chronic GVHD (33% vs. 18%; P=0.06). The use of ATG was not associated with a higher risk of infections: infection-related mortality was comparable between both groups (23% vs. 27%, P=NS). Also, NRM was comparable between both groups (30% vs. 29%; P=NS). In multivariate analysis including all relevant risk factors tested in the univariate analysis, we found that an HLA allelic mismatch and the non-use of ATG were associated with an increased risk of severe grade 3-4 acute GVHD (RR=2.80, 95%CI, 1.5-5.3), P=0.001; and RR=2.4, 95%CI, 1.1-5.0, P=0.02 respectively). Similarly, multivariate analysis showed that the absence of use of ATG was the unique and strongest parameter associated with an increased risk of extensive chronic GVHD (RR=6.9; 95%CI, 1.7-29.0, P=0.008). Finally, LFS and OS at 2 years were not significantly different between the “no-ATG” and “ATG” group (48.8% vs. 41.3%, P=NS; and 53.6% vs.          54.3%, P=NS; respectively)
Despite its retrospective nature, these results strongly indicate a global long-term beneficial effect of ATG when used as part of the MAC regimen prior to allo-SCT from MUD (especially in the HLA mismatch setting). Though prospective studies are needed to assess the optimal ATG dosing and administration schedule, such protective effect of ATG against severe acute and chronic GVHD, can be likely achieved without an increased risk of infections or leukemia recurrence.