Associatie tussen blootstelling aan busulfan en behandel- Resultaten bij kinderen die beenmergtransplantatie ondergaan

Objective The optimal dose, target AUC and dosing schedule of intravenous busulfan in children undergoing heterologous stem cell transplantation is unclear. We retrospectively analyzed the association between busulfan exposure expressed as AUC and clinical outcomes in two Dutch paediatric stem cell transplantation centres. Design and methods All children, transplanted between 2001-2006, receiving intravenous busulfan as part of a myeloablative regimen, were included. The association between busulfan AUC and the endpoints overall survival and event-free survival (EFS), as well as association with toxicity [acute-graft-versus-host disease grade 2-4 (aGvHD), veno-occlusive disease and mucositis grade 3-4], were tested using univariable and multivariable Cox regression analysis. Results 102 patients were included, 46 with malignant and 56 with non-malignant indications (AUC range 30-110 mg-l ^-1 h). EFS and overall survival after median of 2 years follow-up time were 68% and 72%, respectively. EFS was optimal when the exposure of busulfan (AUC) was 78 mg-l ^-1 h (CI95 74-82 mg-l ^-1 h). EFS was negatively influenced by graft-failure/relapse below the lower limit of busulfan exposure and by toxicity above the upper limit. aGvHD grade 2-4 occurred more frequently with higher busulfan exposure. Addition of melphalan was an independent risk factor: melphalan use combined with a high busulfan exposure (AUC >74 mg-l ^-1 h) was associated with high incidences of aGvHD (58%), veno-occlusive disease (66%) and mucositis grade 3-4 (26%). Conclusions Dose targeting of busulfan to a narrow therapeutic range increases EFS in children. Adding melphalan to optimal busulfan exposure is associated with severe toxicity.