Individualization of drug exposure in pediatric hematopoietic stem cell transplantation

Summary

Allogeneic haematopoeitic stem cell transplantation is a potentially curative treatment for a variety of diseases. Its use is limited by 1) the risk of graft failures and relapse of malignant diseases, 2) transplantation-associated complications, and 3) late effects. There is a large and largely unpredictable variability in outcomes of allogeneic haematopoeitic stem cell transplantation between children. Within a complex setting with a lot of variables, individualisation of the drug therapy in the conditioning regimen may improve the benefit - harm balance of pediatric allogeneic haematopoeitic stem cell transplantation. Busulfan is an alkalating antineoplastic agent which forms the backbone of most chemotherapy-based conditioning regimens and there is a large variability between children in exposures, in efficacy and toxicity of busulfan based-conditioning. The studies performed in this thesis focused on three items: 1) the association between exposure to busulfan (area under the concentration-time curve or route of administration) and clinical outcomes, 2) the relationship between dose and exposure to busulfan in neonates, infants, children and adolescents, 3) the association between biomarkers of immune reconstitution and clinical outcomes in sibling bone marrow, unrelated bone marrow, and unrelated cord blood transplantation.Our studies showed that therapeutic drug monitoring based dose-targeting of intravenous busulfan resulted in higher event-free survival and overall survival compared to un-targeted oral busulfan, but also to a higher incidence of toxicity (veno-occlusive disease). Intravenous busulfan exposure of a narrow window between 74 and 82 mg*h/L was optimal for the outcome parameter event-free survival. The pharmacokinetics of intravenous busulfan in neonates, children, adolescents and young adults, based on data from multiple international transplant centers, with body weights ranging between 3 and 100 kilograms, were best described on the basis of a 2-compartment model. A non-linear function was found to best describe the relationship between bodyweight and clearance, thereby explaining 65% of the observed variability in clearance between patients. The external validation showed that the model predicted busulfan concentrations in pediatric and young adult patients ranging between 3 and 86 kg without bias and with good precision, regardless of transplant center, underlying disease, ethnicity, body weight age or body mass index. This model forms the basis for individualized busulfan dosing. A study of biomarker – outcome relationship showed that the speed of immune reconstitution early after allogeneic haematopoeitic stem cell transplantation, and hence mortality, differed among recipients of matched sibling bone marrow, unrelated bone marrow and unrelated cord blood. Longitudinal biomarkers related to immune reconstitution, namely: the area under the CD4+ cell curve in the first 90 days and the occurrence of an early peak in CD4+ cell counts, were identified as early predictors of overall survival. The PK-related biomarkers (busulfan-exposure) and PD-related biomarkers (biomarkers of immune reconstitution) defined in this thesis can be implemented in clinical practice and form the basis of future PK-PD studies of other drugs in pediatric allo-HSCT such as ATG, fludarabine and new agents.

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