Busulfan AUC Thresholds Linked to Pediatric HSCT Event-Free Survival

Key Takeaways

• Chinese pediatric allogeneic HSCT recipients receiving busulfan-based conditioning were observed to have higher 2-year EFS when first-dose busulfan AUC reached at least 4.5 mg×h/L.
• For Bu3 regimens, cumulative busulfan AUC at or above 54 mg×h/L was associated with higher 2-year EFS than lower exposure. For Bu4 regimens, cumulative busulfan AUC of 70-90 mg×h/L was associated with the most favorable 2-year EFS relative to both lower and higher exposure.
• Cumulative busulfan exposure was not significantly associated with acute graft-versus-host disease or oral mucositis, and veno-occlusive disease events were too few for a meaningful exposure analysis.

Busulfan remains central to myeloablative conditioning for children undergoing allogeneic hematopoietic stem cell transplantation (HSCT), but its narrow therapeutic window and marked pharmacokinetic variability make exposure targeting difficult. Whether children receiving 3-day and 4-day conditioning should share the same exposure targets remains unresolved.

In a multicenter prospective cohort study in China, investigators enrolled patients younger than 18 years undergoing first allogeneic HSCT with intravenous busulfan-based 3-day or 4-day myeloablative conditioning at 5 pediatric HSCT centers from January 2018 through January 2023. The final outcomes cohort included 455 patients after exclusion of 2 with follow-up shorter than 3 months, and the study was registered as NCT04786002. Busulfan exposure was defined as first-dose and cumulative area under the concentration-time curve (AUC), estimated with a one-compartment population pharmacokinetic (PopPK) model using first-order elimination and Bayesian individual clearance estimates after postinfusion sampling and liquid chromatography-tandem mass spectrometry measurement. Event-free survival (EFS) was defined as graft failure, relapse, or nonrelapse-related mortality (NRM), and secondary endpoints included veno-occlusive disease (VOD), acute graft-versus-host disease (aGVHD), hemorrhagic cystitis, and oral mucositis, with models adjusted for clinical covariates including anti-thymocyte globulin (ATG) use.

Overall 2-year EFS was 80.5%, and lower busulfan exposure tracked with poorer transplantation outcomes. Across the full cohort, first-dose AUC below 4.5 mg×h/L was independently associated with inferior EFS, with HR 1.63, 95% CI 1.06-2.50, and 2-year EFS 76.4% versus 84.6% when exposure reached at least 4.5 mg×h/L. In Bu3 recipients, cumulative AUC below 54 mg×h/L was associated with poorer EFS, with HR 1.73, 95% CI 1.01-2.94, and 2-year EFS 77.7% versus 86.4%; in Bu4 recipients, the 70-90 mg×h/L range was the most favorable exposure window, with 2-year EFS 88.9% versus 71% below 70 mg×h/L and 66.1% above 90 mg×h/L, and both outer strata had inferior adjusted EFS.

The exposure-outcome relationships came from an observational cohort and should not be framed as causal effects of busulfan dosing. The authors noted that potential confounders affecting survival were not fully included, disease heterogeneity was not stratified, several multivariable findings were borderline, and bronchiolitis obliterans syndrome was not predefined for exposure analysis. Safety interpretation also remained cautious because VOD occurred in 5 patients, cumulative exposure was not significantly associated with aGVHD or oral mucositis, and the Bu3 grade 3-4 hemorrhagic cystitis signal was borderline rather than definitive.

Busulfan exposure tracked with EFS in Chinese pediatric HSCT recipients, with a first-dose threshold of at least 4.5 mg×h/L across the cohort and regimen-specific cumulative exposure ranges associated with more favorable 2-year outcomes in Bu3 and Bu4. The observed pattern suggests that regimen intensity may matter when interpreting busulfan exposure rather than assuming a single cumulative target for all schedules. The authors cautioned that both the PopPK model and the proposed exposure targets require validation in independent external cohorts.

Clinician Questions

How was busulfan exposure measured in Chinese pediatric allogeneic HSCT recipients in this cohort?

Busulfan exposure in Chinese pediatric patients undergoing first allogeneic HSCT was defined as first-dose AUC and cumulative AUC, estimated with a one-compartment PopPK model using first-order elimination and Bayesian individual clearance estimates. Blood samples were collected after the first infusion, and busulfan concentrations were measured by liquid chromatography-tandem mass spectrometry across participating centers.

What counted as event-free survival in this busulfan exposure study after pediatric HSCT?

In this Chinese pediatric allogeneic HSCT cohort, event-free survival meant time from transplantation to the first occurrence of graft failure, disease relapse, or nonrelapse-related mortality. The main exposure comparisons were interpreted at the 2-year EFS timepoint.

Which pediatric HSCT patients were included in the busulfan exposure analysis, and how broadly do the findings apply?

The cohort included children undergoing first allogeneic HSCT with intravenous busulfan-based 3-day or 4-day myeloablative conditioning in Chinese pediatric transplant practice. The findings are most directly applicable to similar settings, and the authors said the PopPK model and proposed exposure targets need independent external validation before broader generalization.