Intravenous Busulfan Pharmacokinetics in Conditioning Regimens for Allogeneic Hematopoietic Stem Cell Transplantation: Impact of Dosing Weight

Introduction:  The area-under-the curve (AUC) for busulfan has been linked to clinical outcomes such as veno-occlusive disease (VOD) and cancer relapse.  The choice of body weight (actual versus adjusted weight) to calculate the dose of busulfan may be critical in attaining goal AUC based on pharmacokinetic (PK) analysis, especially for overweight patients.

Objective: Determine a correlation between weight chosen for dosing of busulfan and outcomes.

Methods: An IRB-approved retrospective analysis was performed on hematopoietic stem cell transplant (HSCT) recipients who had received either Q6H IV busulfan with cyclophosphamide (Bu/Cy) or once-daily IV busulfan with fludarabine (Flu/Bu) as conditioning regimens. All patients underwent prospective monitoring of serum PKs at a specialized therapeutic drug monitoring central laboratory. Data was analyzed using Systat ver 13.  

Results:  Of the 31 patients with evaluable PK results, mean age was 53 years; 48% were male; 77% were Caucasian and 58% had AML/MDS. GVHD prophylaxis consisted of tacrolimus/methotrexate in 58% and tacrolimus/mini-methotrexate in 42% of patients; 35% of the patients also received anti-thymocyte globulin. With regards to conditioning regimen, 58% received Flu/Bu (50% dosed on actual weight, 50% dosed on adjusted) and 42% received Bu/Cy (23% = actual weight, 77% = adjusted). Only two patients did not require a dose adjustment based on AUC results. Overall, patients dosed by adjusted body weight were more likely to under-shoot the goal AUC (-12.8 % vs. +19.5 %, p=0.018), and require busulfan dose increases (+20% vs. -19.9%, p=0.012) compared to those dosed on actual body weight. A subgroup analysis confirmed this result for patients receiving Bu/Cy (-23.6 % vs. +2.2%, p=<0.001 for goal AUC and +36.2% vs. -4.5 %, p=0.008 for busulfan dose changes in adjusted vs. actual body weight groups, respectively), but not Flu/Bu conditioning regimens (-0.8 % vs. +25.3%, p=0.123 for goal AUC and +3.4% vs. -25.1 %, p=0.174 for busulfan dose changes in adjusted vs. actual body weight groups, respectively).  Notably, two patients dosed by actual body weight in the Flu/Bu group experienced an AUC of > 9000 µmol*min. Time to neutrophil or platelet engraftment, progression-free survival and overall survival were not significantly different between those dosed on actual versus adjusted body weight (p>0.05). No neurologic adverse events or VOD incidents were observed in any group.

Conclusions:

Our prospective analysis of IV busulfan PK data in various myeloablative and non-myeloablative busulfan based conditioning regimens for HSCT provides important insight into the choice of appropriate busulfan dosing weight. Further studies are warranted to elucidate which weight is most likely to achieve goal area-under-the curve and subsequent optimal patient outcomes.