Anti-Thymocyte Globulin (ATG) is widely used during conditioning as GvHD prophylaxis in children and adults. Numerous studies have demonstrated a significant reduction in acute and chronic GvHD and improved relapse-free-GvHD-free survival (GFRS) with ATG, especially in the unrelated donor setting. (1, 2, 3). Nevertheless, there has yet to be a consensus on the best formulation, dosing, and schedule of ATG prior to transplant (4, 5, 6, 7). Pharmacokinetic studies have demonstrated wide variations among pediatric patients with slow clearance resulting in delayed immune reconstitution, increased risk of infections and transplant-related mortality, or fast clearance resulting in more GvHD (8, 9, 10). Using a validated pharmacokinetic model, Admiraal et al. concluded that a fixed 10 mg/kg dose resulted in excessive exposure for children with higher body weight and low lymphocyte count, setting the stage for individualized dosing based on these two parameters (11, 12). Children's body weight varies widely with age, and lymphocyte counts can vary from < 100/µL in patients with acute leukemia and severe combined immune deficiencies to normal levels (> 2500 /µL) in congenital anemias and inborn errors of metabolism. In the PARACHUTE phase II trial, ATG was dosed accordingly to body weight and pre-transplant absolute lymphocyte count (ALC) and administered for three or four days starting on day − 9 (13). This schedule resulted in a high rate of immune reconstitution in children, defined as a CD4 count ≥ 50/µl at day 100 post-transplant (CD4 IR), reported at 80% (95% CI 67–90) (14, 15, 16, 17). The dosing schedule proposed by the PARACHUTE trial provides a simple way to individualize ATG dosing for children in all hospital settings without the need for ATG pharmacokinetics.
The use of pre-transplant ALC to guide ATG dosing has been a topic of debate. Two recent reports found that an ALC < 500/µL conferred significantly worse survival outcomes to adults transplanted for hematologic malignancies, mainly due to an increased incidence of severe infections and non-relapse mortality (18, 19). Conversely, a study by Heelan et al. in adult patients using a fixed small dose of ATG starting on day − 3 found no correlation between ALC measured before the first dose of ATG and outcomes (20). As previously reported, the PARACHUTE schedule may compensate for wide ALC variations, allowing patients to get a similar exposure at different weights and ALC.
Since 2015 we started the administration of individualized ATG doses according to the PARACHUTE trial in children transplanted for malignant and non-malignant diseases. The primary endpoint was to reach 80% CD4 IR+. Other endpoints of interest included a severe cGvHD incidence of < 5% and a Grade III-IV GFRS ≥ 70%. We report on outcomes, including engraftment, CD4 IR, aGvHD, cGVHD, CMV reactivation, non-relapse mortality, relapse-free GVHD-free survival (GFRS), and overall survival.