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Pharmacodynamics of tandem high-dose melphalan with peripheral blood stem cell transplantation in children with neuroblastoma and medulloblastoma

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Abstract

Repeated high-dose (HD) chemotherapy with peripheral blood stem cell (PBSC) transplantation is a new modality aimed at increasing both the dose and its intensity in the treatment of chemosensitive tumours. The aim of this study was to evaluate the tolerance, pharmacokinetics (PK) and pharmacodynamics (PD) of HD single-agent melphalan administered over two consecutive courses (C1 and C2) in children. Twenty-one patients (10 girls) with a median age of 4.1 years (range 8 months–14 years) were entered into this study. Five had metastatic neuroblastoma (NB) and 16 a cerebral primitive neuroectodermal tumour (PNET). Melphalan was given at a dose of 100 mg/m2 every 21 days. PBSCs were infused at a median number of 2.98 × 106 CD34+cells/kg. Forty courses, ie 21 C1 and 19 C2, were administered. Both courses were well tolerated. The median duration of ANC <500/μl was 7 and 6 days after C1 and C2, respectively. Platelet recovery (not mandatory to continue the HD strategy) was achieved in 52% of courses. GI toxicity was mild to moderate. The melphalan AUC ranged from 177 to 475 μg·min/ml (no difference between C1 and C2). Prolonged neutropenia was associated with a young age (P < 0.001) and a low amount of CFU-GM (P = 0.002). A long time to platelet recovery was associated with a high AUC (P = 0.004) and a young age (P = 0.02). Grade 1 or 2 GI toxicity was associated with a high AUC (P = 0.015). Partial remission was observed in 11/14 patients with measurable cerebral PNET. In conclusion, tandem HD melphalan is feasible and safe in children, and achieved a high response rate in cerebral PNET. The observed PK–PD relationships may help us design PK-guided outpatient treatment. Bone Marrow Transplantation (2001) 27, 471–477.

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Acknowledgements

We thank all the nursing staff of the bone marrow transplantation unit ‘La Mer’, Department of Paediatric Oncology, Institut Gustave Roussy. We are grateful to Mrs Lorna Saint-Ange for editing the manuscript.

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Authors and Affiliations

  1. Department of Paediatric Oncology, Institut Gustave-Roussy, Villejuif, France

    G Vassal, D Valteau-Couanet, C Schoeppfer, J Grill, C Kalifa, C Ardiet & O Hartmann

  2. Laboratory of Pharmacogenetics and Pharmacotoxicology (CNRS UMR 8532), Institut Gustave-Roussy, Villejuif, France

    G Vassal

  3. Laboratory of Pharmacokinetics, Centre Léon-Bérard, Lyon, France

    B Tranchand & C Hill

  4. Department of Biostatistics, Institut Gustave-Roussy, Villejuif, France

    C Mahé & C Hill

  5. Department of Radiology, Institut Gustave-Roussy, Villejuif, France

    D Couanet

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  1. G Vassal
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  10. C Ardiet
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Vassal, G., Tranchand, B., Valteau-Couanet, D. et al. Pharmacodynamics of tandem high-dose melphalan with peripheral blood stem cell transplantation in children with neuroblastoma and medulloblastoma. Bone Marrow Transplant 27, 471–477 (2001). https://doi.org/10.1038/sj.bmt.1702806

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