TABLE 1.
Reported associations of pharmacokinetic parameters of busulfan and clinical outcomes.
| First author, year | n | Age, median (range) | Diagnosis | Regimen | Dose interval | Major findings |
|---|---|---|---|---|---|---|
| Bartelink et al. (2009) | 102 | 3.1 (0.2–21.0) | Malignant: 46 (45%) | BuCyMel: 43 (42%) | Once daily: 64 (63%) | Bu exposure of 72–80 mg*h/L was associated with the highest OS and EFS (p = 0.021 and p = 0.028). Increased AUC was associated with less graft failure and relapse (HR 0.047; p = 0.004), but more aGVHD (HR 1.56; p = 0.019). |
| Non-malignant: 56 (55%) | Other: 59 (58%) | 4 times daily: 38 (37%) | ||||
| Ansari et al. (2014) | 75 | 6.2 (0.1–20.0) | Malignant (ALL/AML/MDS): 48 (64%) | BuCy: 67 (89%) | 4 times daily | Css,day1 > 600 ng/ml (daily AUC of 14.4 mg*h/L or cumulative AUC of 57.6 mg*h/L) was associated with lower EFS (HR 5.14; 95%CI 2.19–12.07; p < 0.001) and lower OS (HR 7.55; 95%CI 2.20–25.99; p = 0.001). |
| Non-malignant: 27 (36%) | BuCyVP16: 6 (8%) | |||||
| BuMel: 2 (3%) | ||||||
| Bartelink et al. (2016) | 674 | 4.5 (0.1–30.4) | Malignant: 274 (41%) | BuCy: 352 (52%) | Once daily: 267 (40%) | Optimum cAUC of 78–101 mg*h/L decreased the probability of graft failure or relapse (HR 0.57; 95%CI 0.39–0.84, p = 0.0041). High cAUC increased the risk of TRM (HR 2.99; 95%CI 1.82–4.92, p < 0.0001) and toxicities (HR 1.69; 95%CI 1.12–2.57; p = 0.013). |
| Non-malignant: 400 (59%) | BuFlu: 252 (37%) | 4 times daily: 324 (48%) | ||||
| BuCyMel: 70 (10%) | Other: 83 (12%) | |||||
| Benadiba et al. (2018) | 36 | 5.9 (0.6–19.3) | AML: 23 (63.9%) | BuCy: 33 (91.7%) | 4 times daily | Css,day1 > 600 ng/ml (daily AUC of 14.4 mg*h/L or cumulative AUC of 57.6 mg*h/L) was a significant risk factor for OS (HR 5.2; 95%CI 1.26–21.5, p = 0.02) and EFS (HR 3.83; 95%CI 1.33–11.05, p = 0.01). |
| MDS: 13 (36.1%) | BuMel: 2 (6%) | |||||
| BuCyVP16: 1 (2.3%) | ||||||
| Philippe et al. (2019) | 293 | 6.2 (0.2–21.0) | Malignant: 170 (58%) | Not clearly specified | 4 times daily: 282 (96%) | The incidence of VOD was 25.6%. Patients with Cmax of ≥1.88 ng/ml were 6 times more likely to develop VOD (63.3 vs. 21.3%, RR 6.0 p < 0.001). |
| Non-malignant: 123 (42%) | Once daily: 10 (3.4%0 | |||||
| Twice daily: 1 (0.6%) |
ALL, acute lymphoblastic anemia; AML, acute myeloid leukemia; MDS, myelodysplastic syndrome; Mel, melphalan; Cy, cyclophosphamide; VP16, etoposide.