Tailored busulfan and fludarabine conditioning in allogeneic hematopoietic cell transplantation patients

Allogeneic hematopoietic cell transplantation (HCT) is a life-saving treatment for various blood disorders, immune deficiencies, and certain types of cancer. Prior to transplantation, patients undergo so-called conditioning, often with chemotherapy such as busulfan and fludarabine. Conditioning with these drugs is essential both to treat the underlying disease and to allow engraftment of new stem cells. Because the efficacy and toxicity of these drugs may be strongly related to the amount of drug in the body (the exposure, expressed as the area under the curve; AUC), therapeutic drug monitoring (TDM) can be used to adjust dosages based on blood concentrations.

This thesis investigated how treatment with busulfan and fludarabine can be further personalized and optimized. The occurrence of veno-occlusive disease, a side effect of busulfan, is associated with the degree of busulfan exposure (the AUC). However, when patients receive multiple similarly acting drugs, the risk is inherently increased, and the exposure did not further increase the risk. In addition, the optimal busulfan exposure was estimated in children with inborn immune disorders. Previously, there was no consensus on this, and each SCT center pursued a different exposure target. For fludarabine, a randomized double-blind study found no clear association between exposure and treatment outcomes.

Our results demonstrate that simple mathematic models are sufficient to accurately estimate busulfan exposure and that TDM is essential to achieve the correct exposure. In addition, different TDM schedules were compared. In children, it was sufficient to perform TDM on the first day, with additional measurements only in the case of major dose adjustments. In adults, however, it was preferable to perform TDM on the first two days.

In summary, it is important that conditioning is tailored to the individual patient, taking into account factors such as the underlying disease, patient characteristics, and concomitant medication, which may all influence treatment. Further research is needed to identify these factors and translate them into clinical practice.