Population Pharmacokinetic Model Demonstrates Poor Outcomes with ATG Overexposure in Adults Undergoing Ex Vivo CD34-Selected Allogeneic Hematopoietic Cell

Abstract

<h3>Background</h3> We recently showed that empiric weight-based ATG dosing in heavier patients (pts) prior to <i>ex vivo</i> CD34-selected allogeneic hematopoietic cell transplantation (allo-HCT) is associated with high non-relapse mortality (NRM) and poor survival. A more precise method is to assess the relationship between ATG pharmacokinetic (PK) exposure and outcomes. Therefore, we estimated ATG exposure using a population PK model and hypothesized that peri-HCT ATG overexposure would similarly result in unfavorable outcomes secondary to poorer immune reconstitution (IR). <h3>Methods</h3> We studied 415 consecutive adult pts who underwent first myeloablative <i>ex vivo</i> CD34-selected allo-HCT with ATG (Thymoglobulin) between 2006 and 2017. We estimated pre-/post-HCT and total ATG area under the curve (AUC, in mg*d/L) for all pts using an established PK model (Admiraal et al., Lancet Hematol 2017). We evaluated the association between ATG exposure and outcomes using a nonparametric estimate of median relapse-free survival (RFS) by ATG exposure to define an optimal ATG AUC cut point (highest RFS) that was used to estimate RFS and NRM. We also evaluated how CD4+ T cell IR related to NRM in a subgroup of 232 pts with sufficient data. IR was defined according to prior studies as absolute CD4+ ≥ 50 at ≥ 2 time points before day +100 and 1 subsequent time point within 60 days. <h3>Results</h3> Among all pts, median age was 55 (range, 19-73), 228 (55%) were male, 204 (49%) had AML, 105 (25%) MDS, 50 (12%) ALL, and 56 (14%) other hematologic diseases. HCT-CI was 0 in 85 (20%), 1-2 in 146 (35%), and ≥ 3 in 184 (45%) of pts. Allografts were HLA matched related in 150 (36%), matched unrelated in 202 (49), and mismatched in 63 (15%). CMV serostatus was positive in 251 (60%). Conditioning regimens were chemotherapy based in 279 (67%) and TBI based in 136 (33%). All but 2 pts, who were inevaluable given early deaths, engrafted. All pts received 1-3 doses of ATG 2.5 mg/kg between days -4 and -1: 361 (87%) received 2 doses, 47 (11%) 3 doses, and 7 (2%) 1 dose. Among all pts, median estimated ATG AUC values were: pre-HCT 19 (range, 9-36), post-HCT 48 (range, 17-101), and total 66 (29-125). Median follow-up among survivors was 3.9 years (range, 0.7-12). A post-HCT ATG AUC of >60 was associated with poorer median predicted RFS (Figure 1). Pts with an estimated post-HCT ATG AUC of >60 and <60, respectively, had 5-year RFS of 31% and 55%, p=0.008 and higher 5-year NRM of 51% and 22%, p<0.001 (Figure 2). Pts who did not have or had IR, respectively, by day +100 post-HCT had higher 5-year NRM, 34% versus 8%, p<0.001 (Figure 3). <h3>Conclusions</h3> Population PK modeling confirms that post-HCT ATG overexposure in certain pts undergoing <i>ex vivo</i> CD34-selected allo-HCT leads to inferior RFS and markedly higher NRM possibly due to poor IR. Identifying the optimal ATG exposure and individualizing ATG dosing may improve early CD4+ IR and ultimately improve survival in these pts.