Table 1.
Summary of studies assessing exposure response to busulfan.
| References | Population | Conditioning regimen | TDM dose adjustment? | Tested outcome | Exposure-response result | Other covariates influencing the outcome |
|---|---|---|---|---|---|---|
| Bartelink et al. (36) |
N = 674 Age range: – 30.4 (median 4.5) Haematological malignancies: 41% |
IV Q6 h and Q24 h BuCy (52%) BuFlu (38%) BuCyMel (10%) |
Yes, target defined by the treatment centres | EFS | AUCcum < 78 mg.h/L: 66.1% EFS at 2 years vs. AUCcum < 78 mg.h/L: AUCcum 78−101 mg.h/L: 81% EFS at 2 years HR = 0.64, p =0.004 AUCcum >101 mg.h/L: 49.5% EFS at 2 years, HR = 1.21, NS |
Immunodeficiency diagnoses vs. other non-malignant diseases |
| OS | Vs. AUCcum < 78 mg.h/L: AUCcum 78−101 mg.h/L: HR = 0.53, p = 0.016 AUCcum >101 mg.h/L: HR = 1.03, NS |
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| Graft failure/relapse | Vs. AUCcum < 78 mg.h/L: AUCcum 78−101 mg.h/L: HR = 0.57, p = 0.004 AUCcum >101 mg.h/L: HR = 0.41, p = 0.094 |
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| TRM | Vs. AUCcum < 78 mg.h/L: AUCcum 78−101 mg.h/L: HR = 1.07, NS AUCcum >101 mg.h/L: HR = 2.99, p < 0.001 |
Use of three alkylating agents | ||||
| Acute toxicity: SOS grade II–IV and aGvHD grade II–IV | Vs. AUCcum < 78mg.h/L: AUCcum 78−101 mg.h/L: HR = 1.14, p = NS AUCcum >101 mg.h/L: HR = 1.69, p = 0.013 |
Use of three alkylating agents, transplant after 2006 |
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| cGvHD | AUCcum < 78 mg.h/L: 4.3% cGvHD AUCcum >78 mg.h/L: HR = 1.3, NS |
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| cGvHD-free, event-free survival | Vs. AUCcum < 78 mg.h/L: AUCcum 78−101 mg.h/L: HR = 0.57, p < 0.001 AUCcum >101 mg.h/L: HR = 1.38, NS |
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| Bartelink et al. (37) |
N = 102 Age range: 0.1–21.0 years (median 3.1) Haematological malignancies: 46% |
IV q6h and q24h BuCyMel (43%) Others (57%): Bu combined with Cy, Flu or/and VP16 |
Yes, three different AUCcum targets: 78.8 mg.h/L 62.4 mg.h/L 70.0 mg.h/L |
EFS | AUCcum 72–80 mg.h/L: highest EFS (p = 0.028) Optimal AUCcum: 74–82 mg.h/L |
HLA disparity, age |
| OS | AUCcum 72–80 mg.h/L: highest OS (p = 0.021) | HLA disparity, age | ||||
| Graft failure/relapse | AUCcum >72.5 mg.h/L: HR = 0.47, p = 0.004 vs. AUCcum < 72.5 mg.h/L | |||||
| SOS (grade II–IV) | In patients given BuCyMel: AUCcum >74 mg.h/L: HR = 4.1, p = 0.012 vs. AUCcum < 74mg.h/L |
Mel-containing regimens | ||||
| aGvHD (grade II–IV) | AUCcum is a significant predictor of aGvHD (HR = 1.56; p = 0.019) In patients given BuCyMel: AUCcum >74 mg.h/L: HR = 4.5, p = 0.016 vs. AUCcum < 74 mg.h/L |
Mel-containing regimens | ||||
| Mucositis | NS | Mel-containing regimens | ||||
| Acute lung toxicity | NS | |||||
| Ansari et al. (38) |
N = 75 Age range: 0.1–20 years (median 6.2) Haematological malignancies: 64% |
IV q6 h BuCy (89%) BuCyVP16 (8%) BuMel (3%) |
Yes, from the 5th dose for a target Css of 600–900 ng/mL (AUCcum 57.6–86.4 mg.h/L) | EFS | First dose Css >600 ng/mL (AUC6h >3.6 mg.h/L): higher event incidence, HR=5.14, p < 0.001 vs. Css <600 ng/ml | |
| OS | First dose Css >600 ng/mL (AUC6h >3.6 mg.h/L): higher mortality, HR = 7.55, p = 0.001 vs. Css <600 ng/ml | |||||
| NRM | First dose Css >600 ng/mL (AUC6h >3.6 mg.h/L): higher NRM, HR = 7.55, p = 0.001 vs. Css <600 ng/ml | |||||
| Relapse | First dose Css >600 ng/mL (AUC6h >3.6 mg.h/L): tendency of higher incidence of relapse (41 vs. 23%, p = 0.13) vs. Css <600 ng/ml | |||||
| aGvHD (grade II–IV) | First dose Css >600 ng/mL (AUC6h >3.6 mg.h/L): higher incidence of aGVHD (21 vs. 5%, p = 0.04) vs. Css <600 ng/ml | |||||
| SOS | First dose Css >600 ng/mL (AUC6h >3.6 mg.h/L): tendency of higher incidence of SOS (p = 0.12) vs. Css <600 ng/ml | |||||
| Lung toxicity | First dose Css >600 ng/mL (AUC6h >3.6 mg.h/L): tendency of higher incidence of lung toxicity (p = 0.06) vs. Css <600 ng/ml | |||||
| Haemorrhagic cystitis | First dose Css >600 ng/mL (AUC6h >3.6 mg.h/L): tendency of higher incidence of HC (p = 0.07) vs. Css <600 ng/ml | |||||
| Ansari et al. (39) |
N = 108 Age range: 0.1–19.9 years (median 5.8) Haematological malignancies: 64% |
IV q6 h BuCy (76.8%) BuCyVP16 (10.9%) BuMel (1.4%) BuCyMel (10.9%) |
Yes, target defined by the treatment centres | EFS | First dose Css <600 ng/mL (AUC6h < 3.6 mg.h/L): event incidence of 17% First dose Css 600–900 ng/mL (AUC6h 3.6–5.4 mg.h/L): event incidence of 50% First dose Css >900 ng/mL (AUC6h > 5.4 mg.h/L): event incidence of 65% p < 0.001 |
|
| OS | First dose Css <600 ng/mL (AUC6h < 3.6 mg.h/L): event incidence of 7% First dose Css 600–900 ng/mL (AUC6h 3.6–5.4 mg.h/L): event incidence of 38% First dose Css >900 ng/mL (AUC6h > 5.4 mg.h/L): event incidence of 60% p < 0.001 |
GSTA1 polymorphisms | ||||
| TRT | First dose Css <600 ng/mL (AUC6h < 3.6 mg.h/L): event incidence of 40% First dose Css 600–900 ng/mL (AUC6h 3.6–5.4 mg.h/L): event incidence of 48% First dose Css >900 ng/mL (AUC6h >5.4 mg.h/L): event incidence of 85% p < 0.001 First dose Css >900 ng/mL: significantly higher TRT in GSTA1-slow-metabolising patients (88 vs. 37%, p < 0.0005) |
GSTA1 polymorphisms | ||||
| Baker et al. (40) |
N = 52 Age range: 0.1–53 years (median 9.2) Haematological malignancies: 100% (AML) |
Oral q6h Bu with Cy | No | Relapse | NS | |
| OS | First dose Css <578 ng/mL (AUC6h < 3.5 mg.h/L): trend of improved OS (69 vs. 49% at 3 years, p = 0.07) vs. Css >578 ng/ml | |||||
| DFS | First dose Css <578 ng/mL (AUC6h < 3.5 mg.h/L): improved DFS (63 vs. 42% at 3 years, p = 0.05) vs. Css >578 ng/ml | |||||
| NRM | First dose Css >578 ng/mL (AUC6h >3.5 mg.h/L): higher risk of NRM (30 vs. 8% at 3 years, p = 0.06) vs. Css >578 ng/ml | |||||
| aGvHD | NS | |||||
| Bartelink et al. (41) |
N = 674 Age range: 0.1–30.4 years (median 4.5) Haematological malignancies: 41% |
IV q6 h and q24 h BuCy (52%) BuFlu (38%) BuCyMel (10%) |
Yes, target defined by the treatment centres | EFS | AUCcum 78–101 mg.h/L vs. AUCcum 59–99 mg.h/L (EMA): HR = 0.91, p = NS AUCcum 78–101 mg.h/L vs. AUCcum 59–89 mg.h/L (FDA): HR = 0.66, p = 0.024 AUCcum 78–101 mg.h/L vs. AUCcum 59–78 mg.h/L: HR = 0.78, p = 0.035 |
|
| Benadiba et al. (42) |
N = 36 cord blood transplanted patients Age range: 0.6–19.3 years (median 5.9) Haematological malignancies: 100% (AML or MDS) |
IV q6 h BuCy (91.7%) BuCyVP16 (5.6%) BuMel (2.8%)HC |
Yes, from the 5th dose for a target Css of 600–900 ng/mL (AUCcum 57.6–86.4 mg.h/L) | EFS | First dose Css >600 ng/mL (AUC6h >3.7 mg.h/L): higher incidence of event, HR = 3.83, p = 0.01 vs. Css <600 ng/ml | |
| OS | First dose Css >600 ng/mL (AUC6h >3.7 mg.h/L): higher mortality, HR = 5.2, p = 0.02 vs. Css <600 ng/ml | |||||
| NRM | First dose Css >600 ng/mL (AUC6h >3.7 mg.h/L): higher NRM (28.6 vs. 0%, p = 0.009) vs. Css <600 ng/ml | |||||
| Neutrophil recovery | First dose Css >600 ng/mL (AUC6h >3.7 mg.h/L): lower neutrophil recovery incidence (95.5 vs. 75.5%, p = 0.01) vs. Css <600 ng/ml | |||||
| Platelet recovery | First dose Css >600 ng/mL (AUC6h >3.7 mg.h/L): lower platelet recovery incidence (67.9 vs. 100%, p = 0.04) vs. Css <600 ng/ml | |||||
| SOS | NS | |||||
| aGvHD grade II–IV | NS | |||||
| Lung-toxicity | NS | |||||
| Hemorrhagic cystitis | First dose Css >600 ng/mL (AUC6h >3.7 mg.h/L): higher HC incidence (50.0 vs. 18%, p = 0.04) vs. Css <600 ng/ml | |||||
| Relapse | NS | MDS, cord blood compatibility (trends) | ||||
| Bolinger et al. (43) |
N = 38 Age range: 0.6–18 years Haematological malignancies: 37% (AML) |
Oral q6 h Bu followed by Cy | No | Graft rejection TRT |
First dose Css >600 ng/mL (daily AUC <14.4 mg.h/L): lower incidence of graft rejection (0 vs. 35%, p = 0.018) vs. Css <600 ng/ml NS |
|
| Bolinger et al. (44) |
N = 39 Age range: 0.6–18.5 years Haematological malignancies: 41% (23% AML) |
Oral q6 h Bu followed by Cy | Yes, following a test dose, and at dose 5, 9, and/or 13 if necessary to a Css range of 600–900 ng/ml ± 10% (AUCcum 57.6 – 86.4 mg.h/L ± 10%) | Graft rejection | Overall Css 600–900 ng/mL (daily AUC 14.4 – 21.6 mg.h/L): higher rate of engraftment (94 vs. 74%, p = 0.043) vs. Css <600 ng/ml | |
| TRT | Trend of increased grade III–IV TRT with increasing Bu overall CSS | |||||
| Copelan et al. (45) |
N = 28 Age range: 4–54 years (6 patients < 18 years) Haematological malignancies: 100% |
Oral q6 h Bu followed by Cy | No | Early TRM (6 months post transplantation) SOS |
Trend of early TRM associated with high first dose AUC6h (p = 0.06) SOS significantly associated with high first dose AUC6h (p = 0.03) |
|
| Relapse | NS | |||||
| Late NRM | NS | |||||
| EFS | NS | |||||
| cGVHD | NS | |||||
| Obstructive bronchiolitis | NS | |||||
| Esteves et al. (46) |
N = 202 Age: 31% < 18 years Haematological malignancies: 81% (10% ALL) |
IV q24 h Bu with other agents (Cy, Flu, Mel, and/or Thio) Oral q6h Bu followed by Cy |
Yes, according to test dose PK. Three defined AUCcum targets: 49.3 mg.h/L 65.7 mg.h/L 82.1 mg.h/L Historical control group: no TDM |
SOS Oral mucositis Relapse EFS OS |
Increased SOS with AUC24h >5,000 μM.min (AUC24h >20.5 mg.h/L (HR = 3.39, p = 0.034) vs. AUC24h <5,000 μM.min NS NS NS NS |
|
| Grochow et al. (47) |
N = 30 Age range: NR Included paediatric patients and haematological malignancies. |
Oral q6 h Bu followed by Cy | No | SOS | The incidence of SOS correlated with first dose AUC6h >3,200 μM.min (AUC6h >13.1 mg.h/L): (χ2 =18; p < 0.0001) vs. AUC6h <3,200 μM.min | |
| Kerl et al. (48) |
N = 59 Age range: 0.2–18.7 years Diagnoses non-reported |
IV q6 h or q24 h Bu followed by Cy | Only in q24 h patients | SOS | The incidence of SOS correlated with higher first dose AUC only in q6h patients (p < 0.05) | |
| Ljungman et al. (49) |
N = 172 Age range: 1.2–65 years (median 36) Haematological malignancies: 100% |
Oral q6 h Bu followed by Cy | No | TRM | Bu concentration ≥721 ng/mL: increased TRM during the 1st year after transplantation (29 vs. 14%, p = 0.01) vs. Css <721 ng/ml | |
| OS | Bu concentration ≥721 ng/mL: decreased OS (56 vs. 40%, p = 0.05) vs. Css <721 ng/ml Autologous HSCT only: NS |
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| DFS | Bu concentration ≥721 ng/mL: decreased DFS(51 vs. 37%, p = 0.03) vs. Css <721 ng/ml Autologous HSCT only: NS |
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| Relapse | NS | |||||
| Philippe et al. (50) |
N = 293 Age range: 0.2–21 years (mean 6.5) Haematological malignancies: 42.7% (1 ALL patient) |
IV q6h, q12h, and q24h Bu with Cy, Flu, Mel, Thio, or/and VP16 | Yes, to target an AUC6h of 900–1,500 μM.min (3.7–6.1 mg h/L) | SOS | Univariate analysis: first dose AUC, Cmax, percentage of time above 1,300 ng/mL associated with SOS. Multivariate analysis: highest Cmax associated with SOS |
Age <3 years, weight <9 kg, severe combined immunodeficiency or a lymphohistiocytosis, VP16 |
| Engraftment | AUCcum associated with engraftment | Weight, age, haematological malignant disease, Cy co-administration associated with engraftment Flu co-administration associated with rejection |
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| Zwaveling et al. (51) |
N = 31 Age range: 0.22–14 (median 5.0) Haematological malignancies: 58% |
IV q6h Bu BuCy (35%) BuCyMel (48%) BuCyVP16 (6%) FluBuCy (10%) |
Yes, from the 2nd day of treatment | SOS OS Engraftment Relapse |
No association between AUCcum and SOS No association between AUCcum and OS No association between AUCcum and engraftment No association between AUCcum and relapse |
|
| McCune et al. (52) |
N = 53 Age range: 1.2 - 65 (median 36) Haematological malignancies: 55% (1 ALL patient) |
Oral q6 h Bu followed by Cy | From the 2nd day of treatment | Graft rejection TRT |
Risk of rejection decreasing with increased Css (P = 0.0024) Severe TRT were not related to Css |
|
| Philippe et al. (53) |
N = 138 Age range: 0.17 – 21 (median 5) Haematological malignancies: 50.7% (13 ALL patients) |
IV q6h Bu with Cy, Flu, Mel, Thio, or/and VP16 | Yes, to target an AUC6h of 980–1,250 μM.min (4.0 – 5.1 mg.h/L) | SOS-free survival at 1 month post HSCT SOS |
No difference between patients within a local AUC range (AUC6h 4.0 – 5.1 mg.h/L) and the EMA AUC range (AUC6h 3.7 – 6.2 mg.h/L) No correlation between first dose AUC and cumulative AUC with SOS. No difference between patients within a local AUC range (AUC6 h 4.0 – 5.1 mg.h/L) and the EMA AUC range (AUC6 h 3.7 – 6.2 mg.h/L) |
Patients < 9 kg |
| Engraftment | No correlation between first dose AUC and cumulative AUC with SOS. | Non-malignancies | ||||
| OS | No difference between patients within a local AUC range (AUC6h 4.0 – 5.1 mg.h/L) and the EMA AUC range (AUC6h 3.7 – 6.2 mg.h/L) | |||||
| Relapse | higher probability with AUCcum <3.7 mg.h/L, 42.9%) than in patients within EMA target range (AUC6h 3.7 – 6.2 mg.h/L) | |||||
| Schechter et al. (54) |
N = 47 Age range: 0.25 – 16.2 (median 5.1) Haematological malignancies: 29.7% (No ALL patients) |
IV q6 h Bu with Cy, Mel, Thio or/and VP16 | Yes, to target an AUC6h of 900–1,500 μM.min (3.7–6.1 mg h/L) | SOS | Higher Cmax in patients who developed SOS (4.2 ± 0.68 vs. 4.8 ± 0.73 μM; P = 0.035) | |
| Bouligand et al. (55) |
N = 45 Age range: 1.2 – 20 (median 5.1) 1 Lymphoma patient. Mainly neuroblastoma, medulloblastoma or Ewing sarcoma diagnoses |
Oral q6 h Bu with either Mel or Thio | No | SOS | BuThio patients with SOS had a significantly higher AUC6h after the 13th dose (6.201 ± 0.607 mg.h/L) than those who did not (5.024 ± 0.978 mg.h/L) (P < 0.05) This difference was not observed in patients that received BuMel |
Second alkylating agent: Mel or Thio |
aGvHD, acute graft-versus-host disease; AML, acute lymphoblastic leukaemia; AUC, area under the curve; Bu, busulfan; cGvHD, chronic graft-versus-host disease; Css, steady state concentration; Cy, cyclophosphamide; DFS, disease-free survival; EFS, event-free-survival; EMA, European Medicines Agency; FDA, US Food and Drug Administration; Flu, fludarabine; GSTA1, glutathione S-transferase A1; HC, haemorrhagic cystitis; HLA, human leukocyte antigen; HR, hazard ratio; IV, intravenous; MDS, myelodysplastic syndrome; Mel, melphalan; NRM, Non-relapse mortality; NS, not significant; OS, overall survival; q24h, every 24 hours; q6h, every 6 hours; SOS, sinusoidal obstruction syndrome; TDM, therapeutic drug monitoring; Thio, thiotepa; TRM, treatment-related mortality; TRT, treatment-related toxicity; VP16, etoposide.