Anti-Thymocyte Globulin (ATG) for Prophylaxis of Severe Graft Vs. Host Disease after Hematopoietic Stem Cell Transplant: A Systematic Review and Meta-Analysis

Introduction:

Hematopoietic stem cell transplantation (HSCT) is used for the treatment of multiple hematologic diseases. The donor cells kill the host malignant cells, but unfortunately, the immune response can cause graft vs. host disease (GvHD). Anti-thymocyte globulin (ATG) is an antibody derived from rabbits or horses. It targets antigens expressed on T-cells, B-cells, macrophages, natural killer cells, and dendritic cells, and used for the prevention of GvHD. We conducted a meta-analysis to assess the efficacy of ATG in preventing high-grade GvHD after hematopoietic stem cell transplant.

Methods:

A search was performed on PubMed, Cochrane, Embase, and Web of Science. We used the following mesh terms and Emtree terms, “antilymphocyte globulin” OR “antithymocyte globulin” AND “graft vs. host disease” from the inception of literature till 06/01/2020. We screened 5767 articles and included 10 randomized clinical trials (N=1,227) and 31 observational studies (N=14,895) in this meta-analysis. We extracted data for severe acute GvHD (grade III-IV or grade II-IV) and severe chronic GvHD (an extensive disease by Seattle criteria or moderate to severe disease according to NIH criteria). We excluded case reports, case series, preclinical trials, single-arm studies, review articles, meta-analysis, and controlled studies not providing any information about high-grade GvHD. We used the R programming language (version 4.0.2) to conduct a meta-analysis.

Results:

In 41 included studies (N=16,122), the median age was ≥40 years in 22 studies (N=12,099), ≤40 years in 16 studies (N=3536), and ≤18 years in 3 studies (N=487). 2986 patients had at least one HLA allele mismatch. Out of 41 studies, data for high-grade acute GvHD was available in 40 studies (N=16,047), and data for high-grade chronic GvHD was available in 33 studies (N=14,206), see Figure 1, 2.

For high-grade acute GvHD, risk ratio (RR) was 0.68 (I²=24%, 95% CI=0.61-0.75) in favor of the use of ATG vs. no use of ATG in the prophylaxis of GvHD with HSCT. In 9 RCTs (N=1,152), RR was 0.59 (I²=38%, CI=0.42-0.82) in favor of ATG use. High-grade acute GvHD significantly improved in all subgroups, i-e., peripheral blood (PB) /bone marrow (BM) HSCT from related donors (RR=0.73; 95% CI=0.61-0.88), PB/BM transplant from unrelated donors (RR=0.62; CI=0.52-0.72) and umbilical cord blood (UC) HSCT (RR=0.61; CI=0.43-0.88).

For high-grade chronic GvHD, RR was 0.47 (I²=49%, 95% CI=0.40-0.55) in favor of the use of ATG vs. no use of ATG in the prophylaxis of GvHD with HSCT. In 6 RCTs (N=714), RR was 0.40 (I²=58%, 95% CI=0.27-0.61) in favor of ATG use. High-grade chronic GvHD significantly improved with the use of ATG in both related donors (RR=0.44; 95% CI=0.34-0.58) and unrelated donors (RR=0.46; 95% CI=0.38-0.55) subgroups for BM / PB HSCT. However, there was no significant improvement in the risk of high-grade chronic GvHD with the use of ATG with cord blood HSCT (RR=0.98; 95% CI=0.73-1.31).

Conclusion:

ATG is effective in the prophylaxis of severe acute GvHD irrespective of donor relationship or type of HSCT. ATG is also effective in the prophylaxis of severe chronic GvHD with bone marrow or peripheral blood HSCT except for cord blood HSCT. Additional multicenter randomized double-blinded clinical trials are needed to confirm these results.