Rabbit Anti-Thymocyte Globulin Exposure (rATG) in CD34+ Selected Hematopoietic Cell Transplantation and Its Impact on Immune Reconstitution and Outcomes in Children and Adults

Background: Rabbit anti-thymocyte globulin (rATG) is used in allogeneic hematopoietic cell transplantation (alloHCT) to prevent graft versus host-disease (GVHD) and graft rejection. In the T-cell replete setting, post-HCT rATG exposure is variable with high exposures resulting in delayed CD4+immune reconstitution (CD4+IR) and higher mortality. The goal of this study was to estimate the rATG exposure in pediatric and adult recipients of ex vivo T-cell depleted CD34+ selected alloHCT and correlate it with outcomes to determine the optimal exposure.

Methods: We performed a retrospective analysis of patients who underwent their first myeloablative-conditioned ex vivo CD34+ selected alloHCT between 2008 and 2018. Post-HCT rATG exposure was estimated as area under the curve (AUC) (mg*d/L) using a validated population pharmacokinetic (PK) model (Admiraal et al.,Lancet Hematology 2017). Outcomes of interest were CD4+IR, defined as CD4+>50/uL at two consecutive measures within 100 days of HCT, non-relapse mortality (NRM), overall survival (OS), GVHD, and relapse. We evaluated the association between post-HCT rATG exposures and CD4+IR using a smoothed effect to define the optimal post-HCT rATG exposure. We subsequently analyzed outcomes in 3 post-HCT rATG exposure groups, <30 mg*d/L, 30-55 mg*d/L, and >=55 mg*d/L. Cox proportional hazard models and multi-state competing risk models were used for analyses.

Results: Of 554 patients included, 239 (43%) were female, median age at HCT was 49 (range 0.2 to 73) years and 425 (76.7%) received matched donor transplant, while 129 (23.3%) patients received mismatched donor HCT. In this cohort of patients, 515 (93%) underwent alloHCT for hematologic malignancies - leukemia: 356 (64.3%), myelodysplastic syndrome: 122 (22%), and other hematological malignancies: 37 (6.7%) while 39 (7%) underwent alloHCT for non-malignant indications. Total Body Irradiation based conditioning regimen was administered in 177 (32%) patients. Among all 554 patients, 540 (97%) attained engraftment. Median post-HCT rATG exposure was 47mg*d/L (range 0 - 101 mg*d/L).

A decreasing post-HCT AUC (optimum <30 mg*d/L) was associated with higher probability of CD4+IR (p< 0.0001, Figure 1a); lower NRM (p=0.03, Figure 1b) and improved OS (p=0.05, Figure 1c). Patients who attained CD4+IR earlier had lower rates of NRM (p<0.0001, Figure 1d).

On further assessing rATG exposure post allo-HCT by three cut -off levels (<30mg*d/L, 30-55 mg*d/L and >=55 mg*d/L), time to CD4+IR varied depending on the ATG exposure (Figure 1e). In multivariable cox models, post-HCT rATG exposure >=55 mg*d/L was associated with an increased risk of NRM as compared to the lower exposure of <30 mg*d/L (HR: 4.11, CI: 1.52, 11.2, Figure 1f), and inferior OS (HR: 2.03, CI: 1.03,4.00, Figure 1g). In addition, post-HCT rATG exposure >=55 mg*d/L was associated with a higher risk of acute GVHD (HR: 2.28, CI: 1.01, 5.16, Figure 1h). In patients with hematologic malignancies, post-HCT rATG exposure was not associated with relapse (HR: 0.73, CI: 0.31,1.7). In the entire cohort of 554 patients, 9 (1.6%) patients had graft rejection: 1 primary rejection in the post-HCT ATG exposure <30mg*d/L group, 6 secondary rejections in the post-HCT ATG exposure of 30-55 mg*d/L group and 2 secondary rejections in the post-HCT ATG exposure >=55mg*d/L group. Among all patients, 204 (37%) died secondary to reasons such as relapse of disease: 73 (36%), infection: 51 (25%), GVHD: 40 (20%), toxicity/organ failure: 29 (14%) and other causes: 11 (5%).

Conclusions: In a large cohort of patients who underwent ex vivo CD34+ selected alloHCT, higher post-HCT rATG exposure led to higher NRM, a paradoxical increase in GVHD, and lower OS driven by poorer CD4+ IR. The increased rates of GVHD with higher post-HCT exposure may be related to increased infections in these cohorts, though this needs to be explored further. Individualizing rATG dosing by PK targeting to a low post-HCT rATG exposure may improve outcomes. We intend to validate these results in a forthcoming prospective clinical trial.

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