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Toxicity Analysis of Busulfan Pharmacokinetic Guided Therapeutic Dose Monitoring for Myeloablative Conditioning Regimens with Allogeneic Transplantation

https://doi.org/10.1016/j.bbmt.2019.12.313Get rights and content
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Background

Busulfan (Bu) based conditioning regimens are associated with serious toxicities including myelosuppression, hepatotoxicity, and sinusoidal obstructive syndrome (SOS).  Previous literature reports increased risk of toxicities when the daily AUC concentrations exceed 6000 uM-minute. Bu TDM has also been associated with improved overall and progression free survival in allogeneic hematopoietic stem cell transplantation (allo-HSCT) recipients. We implemented real time pharmacokinetic (PK)-guided therapeutic dose monitoring (TDM) of Bu for myeloablative conditioning (MAC) regimens.

Objectives

Compare toxicity of IV Bu before and after implementation of TDM. The primary endpoint was incidence of hepatotoxicity, defined as days of elevation of AST or ALT > 3 times the upper limit of normal (ULN) or total bilirubin >1.5 times ULN. Secondary outcomes included time to neutrophil and platelet engraftment, duration of IV opioid administration, breakthrough antiemetic use, incidence of SOS, hospital length of stay (LOS), incidence of Bu dose adjustment, and repeat Bu PK.

Methods

A Bu PK-guided TDM program was implemented in April 2018 for patients receiving busulfan/ cyclophosphamide (BuCy) MAC regimens for allo-HSCT.  Medical records were retrospectively reviewed with weight-based dose (WBD) BuCy conditioning from August 2017 through March 2018 (N=14) and TDM from April 2018 through December 2018 (N=22).  Bu was given at a fixed dose of 0.8 mg/kg/dose every 6 hours for 16 doses on days -8 to -4 for WBD patients.  For TDM patients, after a WBD of 3.2 mg/kg/dose on day -7 (Bu1), serial plasma Bu concentrations were used to calculate Bu area under the curve (AUC) for subsequent dose adjustment on days -6 to -4 to target a daily AUC of 5000 μM-minute. If the AUCactual/AUCtarget exceeded 1.2 or was less than 0.8, the second dose of Bu (Bu2) was changed by no more than ± 20%, repeat PK samples were drawn, and the process was repeated for TDM for the third dose of Bu.

Results

Recipients of Bu TDM were younger than those receiving WBD (median 45 vs. 58 years, p=0.008). No other baseline differences were observed. There was no difference in hepatotoxicity between TDM and WBD (median 1 vs. 0 days, p=0.40), time to neutrophil (median 17 vs. 17 days, P=0.18) or platelet engraftment (median 29 vs. 25 days, p=0.75), IV opioid administration (median 4 vs. 4 days, p=0.83), breakthrough antiemetic use (median 59 vs. 58 doses, p=0.99), SOS (4.5 vs. 7.1%, p=1.0), or LOS (median 28 vs. 27 days, p=0.95). In the TDM group, 45% of patients had increases and 41% had decreases in Bu dose after Bu1.  32% of patients required repeat PK after Bu2.

Conclusions

A PK dose monitoring program for MAC IV Bu regimens may be considered a safe practice in allo-HSCT recipients.  The majority of patients receiving PK-guided TDM required dose changes, and TDM patients had no significant difference in toxicity compared to those receiving WBD.

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