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High-dose chemotherapy (HDC) was investigated in high-risk neuroblastoma (HR-NBL) to reduce the risk of relapse. We report the results of the 30-year experience of a cohort of patients with HR-NBL treated with high-dose (HD) busulfan (Bu)-containing regimens. From 1980 to 2009, 215 patients aged >1 year with stage 4 NBL were treated with HD Bu-containing regimens at Gustave Roussy. These data were prospectively recorded in the Pediatric Transplantation Database. The median age at diagnosis was 40 months (12-218 months). All patients had a stage 4 neuroblastoma. NMYC amplification was displayed in 24% of the tumors. The hematopoietic support consisted of bone marrow or PBSCs in 46% and 49% of patients, respectively. The 5-year event-free survival and overall survival rates of the whole cohort were 35.1% and 40%, respectively. Age at diagnosis, bone marrow involvement and tumor response after induction chemotherapy were significant prognostic factors. Toxicity was manageable and decreased over time, owing to both PBSC administration and better supportive care. Based on this experience, HD Bu-melphalan (Mel) has been implemented in Europe and compared with Carboplatin-Etoposide-Mel in the European SIOP Neuroblastoma (SIOPEN)/HR-NBL randomized protocol. It has now become the standard HDC in the SIOPEN HR strategy.

Purpose: Busulfan-melphalan high-dose chemotherapy followed by autologous stem cell transplantation is an essential consolidation treatment of high-risk neuroblastoma in children. Main treatment limitation is hepatic veno-occlusive disease, the most severe and frequent extra-hematological toxicity. This life threatening toxicity has been related to a drug interaction between busulfan and melphalan which might be increased by prior disturbance of iron homeostasis, i.e. an increased plasma ferritin level., Methods: We performed an experimental study of busulfan and melphalan pharmacodynamic and pharmacokinetics in iron overloaded mice., Results: Iron excess dramatically increased the toxicity of melphalan or busulfan melphalan combination in mice but it did not modify the clearance of either busulfan or melphalan. We show that prior busulfan treatment impairs the clearance of melphalan. This clearance alteration was exacerbated in iron overloaded mice demonstrating a pharmacokinetic interaction. Additionally, iron overload increased melphalan toxicity without altering its pharmacokinetics, suggesting a pharmacodynamic interaction between iron and melphalan. Based on iron homeostasis disturbance, we postulated that prior induction of ferritin, through Nrf2 activation after oxidative stress, may be associated with the alteration of melphalan metabolism., Conclusion: Iron overload increases melphalan and busulfan-melphalan toxicity through a pharmacodynamic interaction and reveals a pharmacokinetic drug interaction between busulfan and melphalan.

Introduction: Busulfan is widely used in a neuroblastoma setting, with several studies reporting marked inter-patient variability in busulfan pharmacokinetics and pharmacodynamics. The current study reports on the pharmacokinetics of oral versus intravenous (IV) busulfan in high-risk neuroblastoma patients treated on the European HR-NBL-1/SIOPEN study., Methods: Busulfan was administered four times daily for 4 days to children aged 0.7-13.1 years, either orally (1.45-1.55 mg/kg) or by the IV route (0.8-1.2mg/kg according to body weight strata). Blood samples were obtained prior to administration, 2, 4, and 6h after the start of administration on dose 1. Busulfan analysis was carried out by gas chromatography-mass spectrometry and data analysed using a NONMEM population pharmacokinetic approach., Results: Busulfan plasma concentrations obtained from 38 patients receiving IV busulfan and 25 patients receiving oral busulfan, were fitted simultaneously using a one-compartment pharmacokinetic model. Lower variability in drug exposure was observed following IV administration, with a mean busulfan area under the plasma concentration versus time curve (AUC) of 1146 ± 187 μM.min (range 838-1622), as compared to 953 ± 290 μM.min (range 434-1427) following oral busulfan. A total of 87% of children treated with IV busulfan achieved AUC values within the target of 900-1500 μM.min versus 56% of patients following oral busulfan. Busulfan AUC values were significantly higher in HR-NBL-1/SIOPEN trial patients who experienced hepatic toxicity or veno-occlusive disease (VOD) (1177 ± 189 μM.min versus 913 ± 256 μM.min; p=0.0086). Further stratification based on route of administration suggested that the incidence of hepatic toxicity was related to both high busulfan AUC and oral drug administration., Conclusion: The reduced pharmacokinetic variability and improved control of busulfan AUC observed following IV administration support its utility within the ongoing HR-NBL-1/SIOPEN trial., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Background: A prospective clinical trial was performed in order to validate the pharmacokinetic (PK) and clinical benefits of a new dosing schedule of intravenous busulfan (IV Bu) in children., Procedure: IV Bu was administered as a 2-hr infusion every 6 hr for 4 days. Five dose levels were given according to body-weight strata., Results: The 67 children aged from 4 months to 17.2 years were followed up over 50 months after autologous or allogeneic stem-cell transplantation. Reduced PK variability was seen after IV Bu administration enabling efficient targeting with 78% of patients within the 900-1,500 µM · min therapeutic window and reproducible exposures across administrations. No neurological complications occurred. The low incidence of hepatic veno-occlusive disease (VOD) recorded was not correlated with high area under the curve (AUC). Only stomatitis was correlated with high AUC in the autologous group. The 4-year overall survival was 59% in the autologous group and 82% in the allogeneic group., Conclusion: The new dosing schedule using IV Bu provides adequate therapeutic targeting from the first administration, with low toxicity and good disease control in high-risk children. The choice of this formulation of Bu should be considered because of its low morbidity and good outcome., (Copyright © 2011 Wiley Periodicals, Inc.)

Introduction: Oral busulfan clearance is age-dependent and children experience a wide variability in plasma exposure. BSA- or age-based dosing is used with therapeutic drug monitoring (TDM) to reduce this variability., Purpose: A new intravenous (IV) dosing of busulfan (Bu) based on body weight, designed to improve AUC targeting without TDM and dose-adjustment, was prospectively evaluated., Method: Bu was administered as a 2 h IV infusion every 6 h over 4 days (16 administrations). Five dose levels were defined on body weight as follows: 1.0 mg/kg for <9 kg; 1.2 mg/kg for 9 to <16 kg; 1.1 mg/kg for 16-23 kg; 0.95 mg/kg for >23-34 kg; 0.80 mg/kg for >34 kg. Bu treatment was followed by Cyclophosphamide or Melphalan prior to allogeneic or autologous transplantation in 55 children aged 0.3-17.2 years (median 5.6 years)., Results: No difference in AUC values was observed between weight strata (mean +/- SD 1248 +/- 205 micromol.min), whereas a significant difference in Bu clearance was demonstrated. This new dosing enabled to achieve a mean exposure comparable to that in adults. At dose 1, 91% of patients achieved the targeted AUC range (900-1500 micromol.min) while no patients were underexposed. At doses 9 and 13, over 75% of patients remained within that target whilst most of the others were slightly above. Successful engraftment was achieved in all patients. In conclusion, from infants to adults this new dosing enabled, without TDM and dose adjustment, to successfully target a therapeutic AUC window.

We previously demonstrated that Busulfan-Thiotepa (Bu-Thio) and ASCT effectively treated patients with locally relapsed medulloblastoma after surgery and conventional chemotherapy. We thus evaluated the administration of Bu-Thio in patients relapsing after conventional CNS irradiation. Patients were scheduled to receive Busulfan (600 mg/m(2)) and Thiotepa (900 mg/m(2)) and ASCT. Resection of residual tumour and additional irradiation were performed if necessary and feasible after Bu-Thio. Toxicity was compared to that observed in 35 patients treated without previous CNS irradiation. From 5/88 to 3/02, 15 patients were treated according to this strategy. Toxicity was significantly higher than that observed in unirradiated patients: thrombocytopenia <50,000/mm(3) lasting 56 days (13-732) (P=0.02) and 30 days (4-124), respectively, HVOD (10/15 and 12/35 patients, respectively) (P=0.06), neurological toxicity (8/15 vs 3/35 patients) (P=0.01). Tumour response was assessable in seven patients and consisted in two CR, three PR and two NR. Currently, two of 15 patients are alive with no evidence of disease. In conclusion, the toxicity of Bu-Thio was significantly more severe in previously irradiated patients. In spite of a high response rate, this strategy failed to improve the prognosis of previously irradiated patients with a relapse from a medulloblastoma.

A strong relationship has been demonstrated between high systemic exposure to busulfan and the occurrence of hepatic veno-occlusive disease (HVOD) after a busulfan-cyclophosphamide regimen (BU CY). We report a prospective study aimed at exploring the pharmacodynamics of high-dose busulfan combined with either melphalan (BU MEL) or thiotepa (BU TTP) followed by autologous stem cell transplantation in children and adolescents with a malignant solid tumor. Busulfan was given orally at a total dose of 600 mg m(-2). In all, 45 patients with a median age of 6.3 years were included in the study: 25 received BU MEL and 20 received BU TTP. The incidence of HVOD was 44% (CI 95% [23-65%]) in the BU MEL group and 25% (CI95% [9-49%]) in the BU TTP group. In the BU TTP group, patients who developed HVOD had a significantly higher AUC 0-6 h after the 13th dose (6201+/-607 h ng ml(-1)) than those who did not (5024+/-978 h ng ml(-1)) (P<0.05). In the BU MEL group, there was no difference in terms of systemic exposure to busulfan between patients who developed HVOD and those who did not. In conclusion, the guidelines established for monitoring BU CY cannot be extrapolated when busulfan is combined with another drug.

Although infants with stage 4 neuroblastoma (NB) usually have a good prognosis, metastatic relapses after 1 year of age and amplification of the N-myc oncogene are established poor prognostic factors. In order to improve the survival of patients with such high-risk factors, we performed consolidation with a busulfan (600 mg/m2)-melphalan (140 mg/m2)-containing regimen followed by autologous stem cell transplantation (SCT). From 1986 to 1998, 12 patients were treated according to this strategy. Their median age at diagnosis was 9 months (1-11). Consolidation was performed after a metastatic relapse in five children, because of persistent bone metastases in one and as first-line consolidation in six patients whose tumor exhibited N-myc amplification. The 5-year EFS rate is 64. 5% (36-85%) with a median follow-up of 92 months (20-126). One toxicity-related death occurred in a very heavily pretreated patient. Hepatic veno-occlusive disease was the major side-effect that occurred in nine of 12 children. This busulfan-melphalan combination appears to dramatically improve the prognosis of these high-risk infants with metastatic NB. Given its high toxicity, indications for this consolidation must be restricted to high-risk infants and a lower dose of busulfan (480 mg/m2) is recommended in children weighing less than 10 kg. Bone Marrow Transplantation (2000) 25, 937-942.

High-dose busulphan-containing chemotherapy regimens have shown high response rates in children with relapsed or refractory neuroblastoma, Ewing's sarcoma and medulloblastoma. However, the anti-tumour activity of busulfan as a single agent remains to be defined, and this was evaluated in athymic mice bearing advanced stage subcutaneous paediatric solid tumour xenografts. Because busulphan is highly insoluble in water, the use of several vehicles for enteral and parenteral administration was first investigated in terms of pharmacokinetics and toxicity. The highest bioavailability was obtained with busulphan in DMSO administered i.p. When busulphan was suspended in carboxymethylcellulose and given orally or i.p., the bioavailability was poor. Then, in the therapeutic experiments, busulphan in DMSO was administered i.p. on days 0 and 4. At the maximum tolerated total dose (50 mg kg(-1)), busulphan induced a significant tumour growth delay, ranging from 12 to 34 days in the three neuroblastomas evaluated and in one out of three medulloblastomas. At a dose level above the maximum tolerated dose, busulphan induced complete and partial tumour regressions. Busulphan was inactive in a peripheral primitive neuroectodermal tumour (PNET) xenograft. When busulphan pharmacokinetics in mice and humans were considered, the estimated systemic exposure at the therapeutically active dose in mice (113 microg h ml(-1)) was close to the mean total systemic exposure in children receiving high-dose busulphan (102.4 microg h ml(-1)). In conclusion, busulphan displayed a significant anti-tumour activity in neuroblastoma and medulloblastoma xenografts at plasma drug concentrations which can be achieved clinically in children receiving high-dose busulphan-containing regimens.

We studied pubertal status and ovarian function in 21 girls aged 11-21 years who had earlier received 1.2-13 years (median 7 years) high-dose chemotherapy and autologous BMT without TBI for malignant tumors. Ten of them were given busulfan (600 mg/m2) and melphalan (140 mg/m2) with or without cyclophosphamide (3.6 g/m2). Eleven others did not receive busulfan. Twelve girls (57%) had clinical and hormonal evidence of ovarian failure. Among nine others who had completed normal puberty, six had normal gonadotropin levels, one had elevated gonadotropin levels and two had gonadotropin levels at the upper limit of normal. The 10 girls who received busulfan all developed severe and persistent ovarian failure. High-dose busulfan is therefore a major cause of ovarian failure even when given in the prepubertal period. These findings emphasize the need for long-term endocrine follow-up of these patients in order to initiate estrogen replacement therapy.

Hepatic veno-occlusive disease (HVOD) is a frequent life-threatening toxicity in patients undergoing bone marrow transplantation (BMT) after the administration of a high-dose busulfan-containing regimen. Recent studies have shown that the morbidity and mortality of HVOD may be reduced in adults by pharmacologically guided dose adjustment of busulfan. We analyzed the pharmacodynamic relationship between busulfan disposition and HVOD in 61 children (median age, 5.9 years) with malignant disease. Busulfan, given at a dose ranging from 16 mg/kg to 600 mg/m2, was combined with one or two other alkylating agents (cyclophosphamide, melphalan, thiotepa). Only 3 patients received the standard busulfan/cyclophosphamide (BUCY) regimen. A total of 24 patients (40%) developed HVOD, which resolved in all cases. A pharmacokinetics study confirmed the previously reported wide interpatient variability in busulfan disposition but did not reveal any significant alteration in children with HVOD. The mean area under the concentration-time curve (AUC) after the first dose of busulfan was higher in patients with HVOD (6,811 +/- 2,943 ng h ml-1) than in patients without HVOD (5,760 +/- 1,891 ng h ml-1., P = 0.10). This difference reflects the higher dose of busulfan given to patients with HVOD. No toxic level could be defined and, moreover, none of the toxic levels identified in adults were relevant. The high incidence of HVOD in children given 600 mg/m2 busulfan may be linked to the use of more intensive than usual high-dose chemotherapy regimens and/or drug interactions. Before the prospective evaluation of busulfan dose adjustment in children, further studies are required to demonstrate firmly the existence of a pharmacodynamic relationship in terms of toxicity and allogeneic engraftment, especially when busulfan is combined with cyclophosphamide. The maximal tolerated and minimal effective AUCs in children undergoing BMT are likely to depend mainly upon the disease, the nature of the combined high-dose regimen, and the type of bone marrow transplant.

In bone marrow transplantation, high-dose busulfan is given p.o., usually every 6 h over 4 consecutive days. Since this repeated administration might alter busulfan disposition, fluctuations in busulfan plasma levels were studied over the 4-day treatment period in 21 children (median age, 5 years) with malignant solid tumors. In addition, urinary excretion of unchanged busulfan was measured every 6 h in 4 patients. Busulfan (37.5 mg/m2 for 16 doses) was given on an empty stomach at 12 p.m., 6 p.m., midnight, and 6 a.m. for 4 consecutive days, starting at 12 p.m. Trough plasma levels, i.e., concentration 6 h after each dose and just before the next one, and urinary excretion of busulfan were measured using a gas chromatography-mass spectrometry assay. Busulfan trough plasma levels exhibited a significant circadian rhythm with a higher mean level at 6 a.m. compared to that at 12 p.m., 6 p.m., and midnight. This rhythm was characterized by a double amplitude (mean +/- SD) of 42 +/- 14% and an acrophase (maximum) occurring at 5:48 a.m. +/- 115 min. In addition, once the steady state was reached, no decreasing trend was observed in any patient. Busulfan renal clearance proved to be low since only 5.4 +/- 1.2% of the given dose were excreted unchanged in urine. In the 4 patients studied, busulfan urinary excretion exhibited a significant circadian rhythm which was apparently linked to the physiological circadian rhythm in urinary output. Ten of 20 evaluable patients developed hepatic venoocclusive disease (HVOD). A significant circadian rhythm in the plasma level was found in both HVOD and non-HVOD patients with no difference between the two groups with regard to the 24-h mean, amplitude, or acrophase. Thus, the circadian changes in busulfan trough plasma levels observed at the steady state were not related to the occurrence of HVOD in these children with solid tumors. Moreover, since this rhythm was stable from day 2 to day 4, it should not compromise dose adjustment.

Risk factors for hepatic veno-occlusive disease (HVOD) were analysed in a population of 136 autografted children who received high-dose busulfan (BU) as part of a conditioning regimen. HVOD was diagnosed according to McDonald's clinical criteria. The incidence of HVOD was particularly high in this series (22%) compared with series with other conditioning regimens but the outcome was favorable in 26 patients (87%). Four deaths occurred (13%), one of which was HVOD related. The clinical presentation of HVOD was similar to that described in previous reports. Although statistical analysis failed to demonstrate any factors predictive of outcome, it did identify risk factors for the occurrence of HVOD: these were (1) a total dose of BU exceeding the standard 16 mg/kg dose; (2) the use of three as opposed to two alkylating agents; (3) the sequence of BU administration when given in the conditioning regimen containing three alkylating agents; and (4) concomitant ketoconazole therapy.

Recent studies have reported that the pharmacokinetics of high-dose busulfan in bone marrow transplantation (BMT) are age-dependent: with the usual dosage of 16 mg/kg over 4 days, systemic exposure is two to four times lower in children than in adults. Data suggested that the dose of busulfan should rather be calculated on the basis of the body surface area (BSA). We measured plasma pharmacokinetics of busulfan in 27 children (mean age, 5.4 years) who were administered a new dosage of 600 mg/m2 over 4 days, ie, 17.8 to 29.2 mg/kg (mean, 24.8 mg/kg), using a gas chromatography-mass spectrometry assay. Our results demonstrate that, with this new dosage, systemic exposure is significantly increased in children compared with that achieved with the usual dosage of 16 mg/kg (6,404 +/- 2,378 v 3,918 +/- 1,170 ng.h/mL; P = .003). Moreover, there is no longer a significant difference in systemic exposure between children treated with this new dosage and adults given a dose of 16 mg/kg of busulfan. However, despite the use of a dosage normalized to the BSA, there is still a wide interindividual variation in systemic exposure, ranging from 3,566 to 13,129 ng.h/mL, which may account for the high incidence of venoocclusive disease (VOD) of the liver that we have already reported. The optimal dosage and schedule of busulfan in children requires a more individual approach that could be based on dose adjustment and plasma level monitoring.

Busulfan is known to be neurotoxic in animals and humans, but its acute neurotoxicity remains poorly characterized in children. We report here a retrospective study of 123 children (median age, 6.5 years) receiving high-dose busulfan in combined chemotherapy before bone marrow transplantation for malignant solid tumors, brain tumors excluded. Busulfan was given p.o., every 6 hours for 16 doses over 4 days. Two total doses were consecutively used: 16 mg/kg, then 600 mg/m2. The dose calculation on the basis of body surface area results in higher doses in young children than in older patients (16 to 28 mg/kg). Ninety-six patients were not given anticonvulsive prophylaxis; 7 (7.5%) developed seizures during the 4 days of the busulfan course or within 24 h after the last dosing. When the total busulfan dose was taken into account, there was a significant difference in terms of neurotoxicity incidence among patients under 16 mg/kg (1 of 57, 1.7%) and patients under 600 mg/m2 (6 of 39, 15.4%) (P less than 0.02). Twenty-seven patients were given a 600-mg/m2 busulfan total dose with continuous i.v. infusion of clonazepam; none had any neurological symptoms. Busulfan levels were measured by a gas chromatographic-mass spectrometry assay in the plasma and cerebrospinal fluid of 9 children without central nervous system disease under 600 mg/m2 busulfan with clonazepam:busulfan cerebrospinal fluid:plasma ratio was 1.39. This was significantly different (P less than 0.02) from the cerebrospinal fluid:plasma ratio previously defined in children receiving a 16-mg/kg total dose of busulfan. This study shows that busulfan neurotoxicity is dose-dependent in children and efficiently prevented by clonazepam. A busulfan dose calculated on the basis of body surface area, resulting in higher doses in young children, was followed by increased neurotoxicity, close to neurotoxicity incidence observed in adults. Since plasma pharmacokinetic studies showed a faster busulfan clearance in children than in adults, this new dose may approximate more closely the adult systemic exposure obtained after the usual 16-mg/kg total dose, with potential inferences in terms of anticancer or myeloablative effects. The busulfan dose in children and infants undergoing bone marrow transplantation should be reconsidered on the basis of pharmacokinetic studies.