Influence of ATLG Serum Levels on CD3/CD19-depleted Hematopoietic Grafts and on Immune Recovery in Pediatric Haplo-HSCT.

Anti-T lymphocyte globulin (ATLG) significantly reduces the risk of engraftment failure in allogeneic hematopoietic stem cell transplantation (HSCT), but hampers post-transplant immune reconstitution. We hypothesized that in patients receiving haploidentical CD3/CD19-depleted grafts these double-edged effects could be better balanced by attaining high ATLG serum concentrations before transplant, but as low as possible on the day of transplant. Therefore, we moved the start of ATLG application to day -12 and determined serum concentrations of T cell specific ATLG in pediatric patients treated with three established dosing regimens (15, 30, or 60 mg/kg). Corresponding mean T cell specific ATLG serum concentrations at day 0 were 1.14, 2.99, or 12.10 µg/ml, respectively. Higher ATLG doses correlated with higher peak levels at days -8 and -7 and reduced graft rejection, while lower ATLG doses correlated with significantly faster post-transplant recovery of T and NK cells. The rate of graft-versus-host disease (GvHD) remained low independent from ATLG doses. Moreover, in vitro assays showed that ATLG concentrations of 2.0 µg/ml and lower only slightly reduced the activity of NK cells and, therefore, the function of such effector cells might be preserved in the grafts. Pharmacokinetic analysis, compatible with linear first order kinetics, revealed similar half-life values independent of ATLG doses. Hence, the day on which a desired ATLG serum level is reached can be calculated prior to HSCT. Our retrospective study demonstrates the relevance of dosing and time of administration of ATLG on engraftment and immune recovery in ex vivo CD3/CD19-depleted haploidentical HSCT.