Optimizing anti-T-lymphocyte globulin dosing to improve long-term outcome after unrelated hematopoietic cell transplantation for hematologic malignancies.

Abstract

Prophylaxis of graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation (HCT) remains challenging. Because prospective randomized trials of in-vivo T cell depletion using anti-T-lymphocyte globulin (ATLG) in addition to a calcineurin inhibitor and methotrexate (MTX) led to conflicting outcome results, we evaluated the impact of ATLG on clinical outcome, lymphocyte- and immune reconstitution survival models. In total, 1500 consecutive patients with hematologic malignancies received matched unrelated donor (MUD) HCT with cyclosporin and MTX (N=723, 48%) or with additional ATLG (N=777, 52%). In the ATLG cohort, grades III-IV acute (12% vs 23%) and extensive chronic GVHD (18% vs 34%) incidences were significantly reduced (P<.0001). Nonrelapse mortality (27% vs 45%) and relapse (30% vs 22%) differed also significantly. Event-free and overall survival estimates at 10years were 44% and 51% with ATLG and 33% and 35% without ATLG (P<.002 and <.0001). A dose-dependent ATLG effect on lymphocyte- and neutrophil reconstitution was observed. At ATLG exposure, lymphocyte counts and survival associated through a logarithmically increasing function. In this survival model, the lymphocyte count optimum range at exposure was between 0.4 and 1.45/nL (P=.001). This study supports additional ATLG immune prophylaxis and is the first study to associate optimal lymphocyte counts with survival after MUD-HCT.