Thymoglobulin® Exposure Is Influencing CD4+ Immune Reconstitution As a Predictor for Improved Overall Survival in Paediatric Haematopoietic Cell Transplantation: Towards Individualised Dosing

Thymoglobulin^¨ is introduced to the conditioning regimen in hematopoietic cell transplantation (HCT) to prevent graft-versus-host-disease (GvHD) and graft failure (GF). Side effects of Thymoglobulin^¨ include delayed immune reconstitution (IR) of donor T-cells. We determine the therapeutic window by studying the relationship between Thymoglobulin exposure and clinical outcome.

All first HCT's in paediatric patients between 2004-2012 receiving Thymoglobulin^¨ in the two Dutch pediatric HCT centres were included. Thymoglobulin^¨ exposure measures were determined using a validated population pharmacokinetic model. Primary endpoint was IR (defined as CD4+ T-cells >50×10⁶/L in two consecutive measurements within 100 days); secondary endpoints were overall survival (OS), event free survival, acute and chronic GvHD and GF. Cox proportional hazard and logistic regression models were used.

In a cohort of 251 patients (Table 1), low post-HCT area under the curve (AUC) of active Thymoglobulin^¨ was the best predictor for successful IR (P<0.0001; Fig 1a). Incidence of GvHD was not significantly influenced by post-HCT AUC. Successful IR is associated with OS in multivariate analyses (MV) (HR 0.49, P=0.005; fig 1b) through reducing relapse- and non-relapse mortality. Subgroup analyses showed a direct association between post-HCT AUC and OS in cord blood recipients with a benign disease (< > 20 AU*day/mL) and matched bone marrow/PBSC sources (< > 50 AU*day/mL) (Fig 2). Incidence of acute grade 2-4 and chronic GvHD and GF was most influenced by pre-HCT Thymoglobulin^¨ exposure in all patients (< > median of 40 AU*day/mL; P<0.01, P=0.03 and P=0.03 in MV, respectively; fig 3).

	Leiden	Utrecht	Total
Number of patients (n)	142	109	251
Male sex [n (%)]	96 (68)	61 (56)	157 (63)
Age (years)	6á2 (0á4-19)	5á9 (0á2-23)	6á2 (0á2-23)
Cumulative Thymoglobulin¨ dose [n (%)]
<9 mg/kg	4 (3)	5 (5)	9 (4)
9-11 mg/kg	136 (96)	97 (89)	233 (92)
>11 mg/kg	2 (1)	7 (6)	9 (4)
Diagnosis [n (%)]
Malignancy	69 (49)	47 (43)	116 (46)
Immune deficiency	23 (16)	28 (26)	51 (20)
Bone marrow failure	6 (4)	9 (8)	15 (6)
Benign disorders	44 (31)	25 (23)	69 (28)
Stem cell source [n (%)]
Bone marrow	89 (63)	29 (27)	118 (47)
Peripheral blood stem cells	30 (21)	12 (11)	42 (17)
Cordblood	23 (16)	68 (62)	91 (37)
Conditioning regimen [n (%)]
Reduced intensity	0 (0)	6 (5)	6 (2)
Chemotherapy-based	103 (73)	88 (81)	191 (76)
TBI-based	39 (27)	15 (14)	54 (22)
Positive CMV status of recipient [n (%)]	70 (49)	56 (51)	126 (50)
Positive CMV status of donor [n (%)]	57 (40)	19 (17)	76 (30)
Follow up (weeks)	126 (3-427)	84 (1-382)	111 (1-427)
Shown as median (range) unless otherwise specified

Thymoglobulin exposure is a predictor for IR, GvHD and GF, and in subgroups for OS. IR is a predictor for OS and EFS. Individualised dosing of Thymoglobulin^¨ targeting to optimal Thymoglobulin^¨ exposures may improve the outcomes after (paediatric) HCT.