Exposure of Thymoglobulin Is Associated with Overall Survival in Children Receiving Allogeneic-Hematopoietic Cell Transplantation (HCT): Towards Individualized Dosing to Improve Survival

Background: To prevent graft versus host disease (GvHD) and rejection in unrelated hematopoietic cell transplantation (HCT), children receive anti-thymocyte globulin (ATG), in the conditioning regimen. The therapeutic window is critical as over-exposure results in delayed immune reconstitution (IR) and under-exposure GvHD:  both causing significant morbidity and mortality. As the optimal exposure is unknown we studied the association between active ATG (Thymoglobulin) exposure and outcomes as a step towards an evidence based dosing regimen of Thymoglobulin.

Methods: All pediatric patients transplanted between 2004 - 2012 receiving Thymoglobulin in the two study centers were included. Only first HCTs were included and patients mounting IgG anti-ATG antibodies were excluded. Serum active Thymoglobulin concentrations were quantified by flow cytometry investigating the binding to a T-cell line. Different exposure related variables such as AUC (area under the curve: fig 1) were tested for their association with the endpoints: event-free survival (EFS), overall survival (OS), acute GvHD and T-cell reconstitution. AUC's were calculated using a validated population PK model. EFS was defined as being alive with engraftment without relapse of disease. T-cell reconstitution was defined as a CD3+ T-cell count > 100 x10⁶/L in two consecutive occasions within 100 days after HCT. aGvHD was classified using the Glucksberg criteria. Cox proportional hazard and regression models were used.

Results: Pharmacokinetic and -dynamic data were available from 196 pediatric HCT's (Table 1); 28 were excluded due to 2^nd/3^rd HCT (13) or antibodies (15).

	Total
Number of patients (n)	168
Male sex (%)	58
Age (years)	6.1 (0.2-22.7)
Starting day ATG (days before transplantation)	5 (1-19)
Diagnosis  (%)
Malignancy	48
Immune deficiency	21
Bone marrow failure	8
Metabolic disease	13
Benign hematology	8
Stem cell source  (%)
Bone marrow	39
Peripheral blood stem cells	10
Cordblood	47
Cordblood with haplo or cordblood	4
Event Free Survival (%)	57
Overall Survival (%)	67
Follow up (weeks)	130 (1-440)

Table 1:

Post-HCT exposures correlates best with the endpoints. 5-year probability of OS and EFS were higher in patients with a low (<20 AU*days/L) post-HCT AUC (p<0.01: OS according to AUC in Fig 2). Multivariate predictors for lower OS were high (>20 AU*days/L) post-HCT AUC (p=0.024), mismatch donor (p=0,01) and malignancy (p=0,007). In addition, low post-HCT AUC of Thymoglobulin was associated successful T-cell reconstitution (p<0.005) while incidence of aGvHD increased (p=0.01), although the absolute increase of probability of aGvHD is less relevant (fig 3).

Conclusion:  High (>20 AU*days/L) post-HCT exposure of Thymoglobulin is associated with a lower OS and a lower probability of successful IR. These results may contribute to individualized dosing guidelines of Thymoglobulin in children, aiming to improved survival.