Phase II Study of Pharmacokinetic Model-Based ATG Dosing to Improve Survival through Enhanced Immune Reconstitution in Pediatric and Adult Patients Undergoing Ex Vivo CD34-Selected Allogeneic HCT (PRAISE-IR)

Background Ex vivo CD34-selected allo-HCT is associated with favorable CRFS but limited by delayed immune reconstitution (IR) and in some trials higher non-relapse mortality (NRM) (BMT CTN 1301, JCO 2023). We recently reported that the use of traditional weight-based ATG dosing in this setting led to high post-HCT ATG pharmacokinetic (PK) exposure that was associated with delayed CD4+ T cell IR (CD4+IR) and increased NRM risk (Lakkaraja et al., Blood Adv 2022). Methods Between 5/2021-12/2023, we conducted an investigator-initiated, single-center, phase II study of population PK model-based ATG dosing targeting a low post-HCT exposure with the aim of improving CD4+IR (NCT04872595). Pediatric and adult patients with hematologic malignancies undergoing their 1st allo-HCT received model-based ATG to target a post-HCT exposure of <20 AU*d/mL beginning on day -12 followed by a myeloablative conditioning regimen (Table 1) and a PBSC ex vivo CD34-selected allograft (CliniMACS CD34 Reagent System [Miltenyi Biotec, Gladbach, GER]) from a HLA 7-8/8 matched donor.The primary endpoint was the proportion of patients who reached CD4+IR, defined as CD4+ T cell values >50/µL at 2 consecutive timepoints by day +100. The trial size of N=56 was based on an optimal Simon 2-stage design that had 90% power to detect a 20% increase from a historical rate of 32% to ≥52%, with 5% 1-sided α. Successful CD4+IR was required in ≥24 of 56 evaluable patients to reject the null hypothesis. We defined time-to-CD4+IR as the time from HCT to CD4+IR. For this endpoint, we censored patients without CD4+IR by day +100 and considered death before CD4+IR by day +100 a competing risk. Other endpoints included the incidences of NRM and relapse, and rates of relapse-free (RFS) and overall survival (OS). Results To date, data were available for 59 patients: 3 were not evaluable and 2 are still within the 100-day period, leaving 54 evaluable patients. Among evaluable patients, the median age was 55 (range, 4-70), 32 (59%) were male, most (N=30; 56%) were treated for AML, and most (N=42; 78%) received regimen B. Median estimated pre- and post-ATG exposures were 52 (35.3-73.8) and 9.9 (4.3-16.1) AU*d/mL, respectively (Table 1).The median follow-up was 17 months (1-28). A total of 37 patients reached CD4+IR by day +100. Cumulative incidence of CD4+IR was 69% (95% CI, 56-81%). The 2-year incidences of NRM and relapse were 9% (0-17%) and 13% (3-24%), respectively. The 2-year RFS and OS rates were 78% (66-91%) and 86% (76-97%), respectively (Figures 1A-D). Conclusions The use of model-based ATG dosing to achieve optimal post-HCT exposure led to high rates of CD4+ IR, thereby exceeding our primary objective. These CD4+IR rates came with low NRM resulting in highly favorable survival, suggesting that the NRM rates for ex vivo CD34-selected allo-HCT observed in trials such as BMT CTN 1301 were driven by high ATG exposure and may be offset by model-based dosing.