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

Repeated high-dose (HD) chemotherapy with peripheral blood stem cell (PBSC) transplantation is a new modality aimed at increasing both the dose and it s intensity in the treatment of chemosensitive tumours, The aim of this stu dy was to evaluate the tolerance, pharmacokinetics (PK) and pharmacodynamic s (PD) of HD single-agent melphalan administered over two consecutive cours es (C1 and C2) in children. Twenty-one patients (10 girls) with a median ag e of 4.1 years (range 8 months-14 years) were entered into this study. Five had metastatic neuroblastoma (NB) and 16 a cerebral primitive neuroectoder mal tumour (PNET), Melphalan was given at a dose of 100 mg/m(2) every 21 da ys. PBSCs were infused at a median number of 2.98 x 10(6) CD34(+) cells/kg, Forty courses, ie 21 C1 and 19 C2, were administered. Both courses were we ll tolerated. The median duration of ANC <500/<mu>\l 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 modera te. The melphalan AUC ranged from 177 to 475 mug . min/ml (no difference be tween 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 recove ry 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 remis sion was observed in 11/14 patients with measurable cerebral PNET. In concl usion, 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.