Blood cancers

Researchers close in on optimal busulfan exposure target for children


Optimising the target for cumulative busulfan exposure has a significant effect on survival chances in children or young adults after allogeneic haemopoietic cell transplantation, researchers have found.

The multicentre, retrospective cohort analysis has been published in The Lancet Haematology, and revealed a cumulative busulfan exposure of between 78 mg × h/L and 101 mg × h/L, combined with the non-alkylating drug fludarabine, predicted the highest event-free survival in children or young adults independent of indication and cell source.

But co-author, Professor Peter Shaw, Clinical Professor of Paediatrics and Child Health at the Children’s Hospital, Westmead, said it was important for clinicians to understand that this exposure range was reached using a computer program not widely used, and this would need to be considered when using different programs.

“There may need to be some individual fine-tuning,” he said. “Different software will give different readings.”

Professor Shaw said the results were exciting but there was still more research to be done to optimise the efficacy of the drug while minimising toxicity risk, particularly when it is used in conjunction with other drugs.

“We have been using this drug for 30 years and we’re only just getting it right with this drug,” he told the limbic.

“We give this drug once, we give it for four or five days and we have to get it right. There’s no going back.”

The researchers identified 14 studies, 13 retrospective and one randomised prospective study of intravenous busulfan in children and adults, which showed that higher exposure (expressed as cumulative area under the curve [AUC]) was associated with an increased risk of toxicity, including mucositis, graft-versus-host disease, veno-occlusive disease, and transplantation-related mortality, and a low busulfan AUC was associated with a higher probability of graft rejection or disease relapse.

“Findings from our study showed that the way of calculating the AUC affects the optimum AUC,” they wrote.

“Validated population pharmacokinetic methods seem to be the most reliable way to calculate the AUC, allow for comparisons of busulfan AUCs between institutions, and help to facilitate prospective studies of individualised busulfan dosing strategies.”

Professor said the study also highlighted the need of a more standardised approach to AUC estimation among transplant centres, which would in turn help researchers analyse data.

“The use of a new, harmonised, and validated approach to measuring busulfan exposure can be used to target a new, optimum cumulative busulfan exposure in children or young adults undergoing allogeneic HCT,” the authors concluded.

“If this new approach is adopted, we expect higher survival chances with lower toxicity in these patients.”

 

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