TABLE 2.
Reported associations of pharmacokinetic parameters of treosulfan and clinical outcomes.
| First author, year | n | Age, median (range) | Diagnosis | Regimen | Dose | Major findings |
|---|---|---|---|---|---|---|
| van der Stoep et al. (2017) | 77 | 4.8 (0.2–18.3) | HBP: 31 (40.3%) | TreoFlu: 25 (35.5%) | 3 × 10 g/m2: 12 (15.6%) | High Treo AUC0-∞ (>1,650 mg*h/L per day) was associated with a higher risk of ≥ grade 2 mucositis (OR 7.03; 95%CI 1.60–30.86, p = 0.01). There is also an increased risk of skin toxicity (OR 9.96; 95%CI 1.85–53.46, p = 0.007). |
| Hem. malig: 12 (15.6%) | TreoFluThio: 52 (67.5%) | 3 × 14 g/m2: 65 (84.4%) | ||||
| IEI: 22 (28.5%) | ||||||
| BMF: 11 (14.3%) | ||||||
| Other: 1 (1.3%) | ||||||
| Mohanan et al. (2018) | 87 | 9.0 (1.5–25) | TM: 87 | TreoFluThio | 3 × 14 g/m2: 87 (100%) | In a post-hoc analysis, lower Treo clearance (<7.97 L/h/m2) was associated with poor overall survival (HR 2.7; 95%CI 1.09–6.76, p = 0.03) and event free survival (HR 2.4; 95%CI 0.98–5.73, p = 0.055). No association with toxicity. |
| Chiesa et al. (2020) | 87 | 1.6 (0.2–16.7) | IEI: 79 (91%) | TreoFlu | 3 × 10 g/m2: 4 (5%) | Higher cumulative Treo AUC0-∞ showed higher risk of mortality in multivariable analysis (HR 1.32; 95%CI 1.07–1.64, p = 0.0093), a trend was seen for low AUC0-∞ associated with poor engraftment (HR 0.61; 95%CI 0.36–1.04, p = 0.072) in univariable analysis. TRM was higher in patients with AUC>6,000 mg*h/L than <6,000 mg*h/L (39% vs. 3%, p = 0.00001). A cumulative AUC0-∞ of 4,800 mg*h/L is proposed as target. |
| IBD: 5 (5%) | 3 × 12 g/m2: 23 (26%) | |||||
| JMML: 2 (2%) | 3 × 14 g/m2: 60 (69%) | |||||
| IEM: 1 (1%) | ||||||
| van der Stoep et al. (2021) | 110 | 5.2 (0.2–18.8) | IEI: 38 (35%) | TreoFlu: 37 (32%) | 3 × 10 g/m2: 18 (16%) | All grade mucositis was associated with high Treo AUC0-∞ (OR 4.43; 95%CI 1.43–15.50, p = 0.01), but not mucositis ≥2 or higher (OR 1.51; 95%CI 0.52–4.58, p = 0.46). Skin toxicity ≥ grade 2 was associated with high AUC0-∞ (OR 3.97; 95%CI 1.26–13.67, p = 0.02). No association with 1-year donor chimerism, 2-years OS and EFS. |
| HBP: 55 (50%) | TreoFluThio: 77 (68%) | 3 × 14 g/m2: 92 (84%) | ||||
| BMF: 17 (15%) |
HPB, hemoglobinopathies; hem. malig, hematological malignancies; IEI, inborn errors of immunity; BMF, bone marrow failure; TM, thalassemia major; IBD, inflammatory bowel disorder; JMML, juvenile myelomonocytic leukemia; IEM, inborn errors of metabolism.