Differential Clinical and Immunological Impacts of Anti–T‐Lymphocyte Globulin (<scp>ATLG</scp>) vs. Anti‐Thymocyte Globulin (<scp>ATG</scp>) in Preventing Graft‐Versus‐Host Disease Post‐Allogeneic Hematopoietic Stem Cell Transplantation: A Comparativ

Both anti-T-lymphocyte globulin (ATLG-Grafalon) and anti-thymocyte globulin (ATG-Thymoglobulin) prevent acute and chronic graft-versus-host disease (GvHD) after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Despite distinct manufacturing and biological characteristics, the two brands of rabbit anti-lymphocyte globulins have never been compared in a prospective way. In this monocentric study, 114 adult patients transplanted with a matched related or unrelated donor after receiving either ATG (n = 50) or ATLG (n = 64) were included to compare their clinical outcomes and broad immune reconstitution parameters. The use of ATLG, compared with ATG, was associated with a 2-fold reduction in Grade II-IV acute GvHD incidence (Cox HR = 0.29; 95% CI 0.14-0.62, p = 0.006), similar relapse incidence, and improved severe GvHD and relapse-free survival (GRFS) (Cox HR = 0.51; 95% CI 0.29-0.91, p = 0.027). Biologically, reduced IL-15 but increased IL-21 serum concentrations and a significant reduction of PD1+ T cells, mainly across all differentiated stages of CD8+ T cells, were observed in the ATLG group. Immunosequencing of vβ T cell receptor (TCR) repertoires showed similar quantitative characteristics in terms of clonality and diversity across the two groups but different qualitative features, with reduced hyper-expanded T cell clones and higher variability in the distribution of complementarity-determining region 3 (CDR3) lengths in the ATLG group. Altogether, these results suggest that ATLG more effectively regulates alloreactive T cell activation, leading to better prevention of acute GvHD while preserving the graft-versus-leukemia response. These findings led us to initiate a multicentric Phase III randomized trial comparing the two anti-lymphocyte globulins. Trial Registration: The biological REAL GREFFE study was registered in clinicaltrial.gov under the number: NCT03357172.