A Phase 3 Trial of Thymoglobuline for Prevention of Chronic Gvhd in Transplantation from an HLA-Matched Sibling

Antihuman T-lymphocyte immune globulin (ATG) was shown to lower the incidence of chronic graft-versus-host disease (cGVHD) after allogeneic hematopoietic stem cell transplantation (allo-HSCT) from an unrelated donor. The type, dose, and duration of ATG treatment is a matter of ongoing controversy in allo-HSCT. Furthermore, there has been no phase 3 study to explore the role of ATG-thymoglobulin for the prevention of cGVHD in allo-HSCT from matched siblings, whereas results from a recent randomized trial of ATG-Fresenius was reported (NEJM 2016).

We performed a prospective, single-center, open-label, randomized trial of ATG-thymoglobulin as a part of the conditioning regimen. The primary endpoint was the cumulative incidence (CI) of cGVHD at a 2-year evaluation. A total of 126 patients with acute leukemia were planned to be enrolled and assigned randomly at a 1:1 ratio to receive ATG-thymoglobulin (1.25 mg/kg at three and two days before allo-HSCT) or receive no ATG-thymoglobulin stratified according to the refined Disease Risk Index and conditioning intensity. Both groups were well balanced for NCCN risk, disease type, disease status, and MRD status at HSCT.

The current study finally enrolled 120 patients with a median of 560 days of follow-up (range 52 – 1257). The CI of cGVHD in the ATG group (n=60) and non-ATG (n=60) group at 2 years after allo-HSCT was 37.2% and 82.7%, respectively (p<0.001). Moderate-to-severe cGVHD occurred in 11.7% of the ATG group and 47.2% of the non-ATG group (p<0.001). In multivariate analysis, non-AGT group, NCCN favorable to intermediate risk, and reduced intensity conditioning remained significant risk factors for the CI of chronic GVHD. There were no significant between-group differences in the CI of infectious complications, acute GVHD, or other allo-HSCT-related adverse events. In contrast, the ATG group had a significantly increased CI of relapse (CIR) compared with the non-ATG-group (28.8% vs 11.7%, p=0.010), which remained significant in the multivariate analysis. Disease-free survival, overall survival, and GVHD and relapse free survival were similar between the ATG and non-ATG groups.

In conclusion, the current study revealed that the use of ATG-thymoglobulin, even at a relatively low dose (2.5 mg/kg), decreases the occurrence of cGVHD at a cost of an increased risk for relapse in the setting of allo-HSCT from matched sibling donors for acute leukemia. The optimal dose, timing, and duration of ATG-thymoglobulin should be investigated further.