TABLE 4.
Reported associations of pharmacokinetic parameters of ATG and clinical outcomes.
| First author, year | n | Age, median (range) | Diagnosis | Regimen | Dose ATG | Major findings |
|---|---|---|---|---|---|---|
| Call et al. (2009) | 13 | 10 (2–16) | AML: 4 (31%) | TBI/Thio/CY | Thymoglobulin | Weight-based dosing regimen (total dose 10 mg/kg) of Thymoglobulin was effective and well tolerated by all patients. None of the patients developed grade III-IV aGvHD. |
| ALL: 3 (23%) | 10 mg/kg, administered as 1 mg/kg on day -4 and 3 mg/kg/day on days -3 to −1 | |||||
| CML: 3 (23%) | ||||||
| JCML: 2 (15%) | ||||||
| MDS: 1 (8%) | ||||||
| Admiraal et al. (2015a) | 251 | 6.2 (0.2–22.7) | Malignancy: 116 (46%) | RIC | Thymoglobulin | Individualized dosing of ATG could result in improved outcomes. For the CB group, AUC ≥20 AU × day/mL decreased immune reconstitution in CB, but decreased immune reconstitution was noted only if AUC ≥100 AU × day/mL in BM and PB. Successful immune reconstitution by day 100 was associated with increased OS. An AUC before HSCT of ≥40 AU × day/mL resulted in a lower incidence of aGvHD, cGvHD and graft failure compared with an AUC <40 AU × day/mL. |
| IEI: 51 (20%) | MAC – chemo | <9 mg/kg 4% | ||||
| BMF:15 (6%) | MAC - TBI | 9–11 mg/kg 94% | ||||
| Non-malignant: 69 (27%) | >11 mg/kg 2% | |||||
| Day start ATG -5, dose divided over 4 days | ||||||
| Admiraal et al. (2016) a | 137 | 7.4 (0.2–22.7) | ALL: 22 (16%) | Bu-Flu | Thymoglobulin | Low ATG exposure (AUC <16 AU a day/mL) was the best predictor for CD + T cell recovery in CB transplant. Patients with a high AUC had a significantly lower EFS compared to low exposure or without ATG. Every 10-point increase in ATG exposure resulted in 5% lower survival probability. Patients receiving ATG had a significantly lower incidence of aGvHD (III-IV) compared with those not receiving ATG (HR, 0.27; 95% CI, 0.08–0.86; p = 0.027). |
| AML: 30 (22%) | Bu-Flu-Clo | Before 2010 | ||||
| Lymphoma: 4 (3%) | TBI based | 10 mg/kg | ||||
| IEI: 33 (24%) | Cy-Flu | Day start ATG -5, dose divided over 4 days | ||||
| BMF: 7 (5%) | After 2010 | |||||
| Benign non-IEI (41 (30%) | <40 kg: 10 mg/kg | |||||
| >40 kg: 7.5 mg/kg | ||||||
| Day start ATG -9, dose divided over 4 days | ||||||
| Oostenbrink et al. (2019) | 58 | 9 (1–18) | ALL: 33 (57%) | Chemo + TBI | Thymoglobulin | Active ATG of both ATG products was cleared at different rates, more variability in the Thymoglobulin treated group. Patients treated with Grafalon had a median level of 27.9 AU/mL and with Thymoglobulin 10.6 AU/mL at day 0. Three weeks after HSCT, 15/16 Grafalon patients had an active ATG level <1 AU/mL while 17/42 Thymoglobulin patients had still active ATG levels above this threshold. For Thymoglobulin, exposure to ATG was significantly higher with 10 mg/kg compared to 6–8 mg/kg and was associated with delayed immune recovery. Occurrence of aGvHD (grade III–IV) was highest in the Thymoglobulin low dosage group. |
| 42 Thymoglobulin | 6 (1–17) | AML: 25 (43%) | Chemo | 8.7 (6.0–10.5) mg/kg | ||
| 16 Grafalon | Grafalon | |||||
| 53 (45–60) mg/kg | ||||||
| Vogelsang et al. (2020) | 32 | 5.3 (0.1–17.3) | Non-malignant: 22 (69%) | TreoFluThio | Thymoglobulin | Grafalon and Thymoglobulin show different pharmacological and immunological impact in children. Active plasma levels for Grafalon were less variable compared to Thymoglobulin. Median active peak plasma levels were 77.9 μg/ml for Grafalon and 8.11 μg/ml for Thymoglobulin. Incidence of GvHD was similar for patients with high (above the median) or low (below the median) exposure. Immune recovery of total leucocytes and T cells was delayed in patients with high ATG exposure. No significant difference was found for overall survival. |
| 22 Thymoglobulin | 13.7 (1.5–17.2) | Malignant: 10 (31%) | NMA | 4.5–10 mg/kg | ||
| 10 Grafalon | TBI/VP-16 | Grafalon | ||||
| 30–60 mg/kg |
a
66 patients (48%) were included in the previous analysis of 2015. (J)CML: (juvenile) chronic myeloid leukemia, RIC, reduced intensity conditioning; MAC, myeloablative conditioning.