The Use of Anti-Thymocyte Globulin Is Associated with Decreased Risk of Chronic Graft-Versus-Host Disease without Impact on Survival after Allogeneic Peripheral Blood Stem Cell Transplantation for Adults with Philadelphia-Positive Acute Lymphoblastic Leukemia: An Analysis By the Acute Leukemia Working Party of the EBMT

BACKGROUND: Allogeneic hematopoietic stem cell transplantation (allo-SCT) is the standard of care for adults with Philadelphia-positive acute lymphoblastic leukemia (Ph-pos ALL). During the last decade mobilized peripheral blood stem cells (PBSCT) have become predominant source of graft for allo-SCT. However, as compared to bone marrow, PBSCT is associated with increased risk of chronic graft-versus-host disease (cGVHD). Attempts to reduce the cGVHD rate include the addition of anti-thymocyte globulin (ATG) to the conditioning regimen. The goal of this registry-based, retrospective study was to analyze the effect of ATG on results of allo-PBSCT in adults with Ph-pos ALL.

PATIENTS AND METHODS: 1055 patients, aged 18-76 years, with Ph-pos ALL, treated with unmanipulated allo-PBSCT in first complete remission between 1997-2014 were included in the analysis. Conditioning regimen was myeloablative in 769 (72%) cases and based on total body irradiation in 608 (58%) cases. Among 590 transplantations from matched sibling donors, ATG was used in 95 (16%) patients. While, in the 8/8 HLA-matched unrelated setting 304/465 (65%) patients were treated with ATG.

RESULTS: In a univariate analysis the use of ATG was associated with decreased incidence of the overall cGVHD (32% vs. 48%, p<0.001) and extensive cGVHD (14% vs. 22%, p=0.002) as well as a tendency to increased probability of survival free from grade III-IV acute GVHD, cGVHD and relapse (GRFS, 43% vs 36%, p=0.07). No significant difference could be demonstrated with regard to the incidence of grade II-IV acute GVHD (34% vs. 33%, p=0.59), grade III-IV acute GVHD (12.5% vs. 13%, p=0.68), relapse (25.5% vs. 27%, p=0.86) and non-relapse mortality (NRM, 19% vs. 18.5%, p=0.21), as well as probability of leukemia-free survival (LFS, 55% vs. 54.5%, p=0.95) and overall survival (OS, 68% vs. 67%, p=0.57). Among patients treated with ATG, original disease was the most frequent cause of death (40%) followed by infections (24%) and GvHD (21%). Respective proportions among those not treated with ATG were 36%, 23%, and 28%.

In a multivariate model adjusted for other potential risk factors, the use of ATG was associated with reduced risk of the overall cGVHD (HR=0.53, p<0.001) and extensive cGVHD (HR=0.53, p<0.001) while increased risk of relapse (HR=1.34, p=0.03). No significant effect was found with regard to the risk of NRM (HR=0.78, p=0.15), a chance of LFS (HR=1.01, p=0.49) and OS (HR=0.87, p=0.27).

CONCLUSIONS: Patients with Ph-pos ALL treated with allo-PBSCT benefit from the use of ATG in terms of reduced risk of cGVHD without impact on survival. Increased risk of relapse, as shown in a multivariate model implicates the need for strict monitoring of minimal residual disease and either prophylactic or pre-emptive use of tyrosine kinase inhibitors after transplantation. Further studies are needed to explore potential role of the ATG brand and dose.