Intravenous (IV) Busulfan (BU) Pharmacokinetics Using Busulfan and Fludarabine (Flu) Conditioning in Institutions Where the Capability of Doing Pharmacokinetics Is Not Present

BACKGROUND:   IV BU overcomes the wide variation in achieving steady state drug concentration associated with its oral administration. Many institutions are limited in using IV BU because of an inability to perform PK analysis at an institutional level.  At Markey Cancer Center we utilized a unique strategy for administering IV BU in order to facilitate PK analysis at an off-site laboratory.

METHODS:  This is a retrospective, chart review of 14 patients admitted for allogeneic stem cell transplant between November 2012 - September 2013 who received a conditioning regimen of IV BU and IV flu. Flu (30 mg/m2) was administered daily on days T-7 through T-3. BU dosing (desired area under the curve (AUC)) was determined based on patient age and performance status based per physician discretion. BU PK calculations were performed by the Seattle Cancer Care Alliance Pharmacokinetics Laboratory, Seattle, WA. Growth factors were not used. Patients received a once-daily BU dose (based on BSA) on days T-7 and T-5. On day T-7, BU levels were collected at the end of the infusion, 15 minutes after completion of the infusion, and at 4, 5 ,6, and 8 hours after the start of infusion. Patients did not receive BU on day T-6 in order to facilitate the ability to use PK analysis to adjust the last two BU doses on T-4 and T-3.

RESULTS: Patient characteristics are described in Table 1. The median BU AUC achieved for the myeloabalative group was 5380.5 (4821 - 5978) uMol/min and reduced intensity group was 4004 (3732 - 4155) uMol/min. Acute GVHD was observed in six and chronic in two patients. Two patients also developed cytomegalovirus related disease. One patient relapsed at day 88 with 4% blasts on bone marrow biopsy. After a median follow up 176 days all patients are alive.

CONCLUSIONS:  Our results demonstrate that PK-guided IV BU-based conditioning regimens could be used in institutions where the ability to perform institutional PK is not present. More patients and longer follow-up time would be required to conclusively determine the effectiveness of this approach.

 

Patient Characteristics
	(Numbers)
Diagnosis AML HLH MDS ALL	8 1 3 2
Disease Status CR N/A	11 3
Regimen IV BU/ IV Flu IV BU/ IV Flu + Thymoglobulin(1.5 mg/kg  (T-3 to T-1)	9 5
Regimen Intensity AUC 6000 AUC 4500 AUC 4000	8 1 5
Donors Related Unrelated	5 9
HLA Match 9/10 10/10	2 12
	Median (Range)
CD34 Cells Infused (cells/kg)	7 (2.7-15)
Age at the time of transplant (years)	48.5 (23-61)
Body Surface Area (m2)	1.825 (1.5 – 2.1)
AUC Achieved prior to PK adjustment  (micromole/min) 6000 4000	4482.5 (3652 - 5771) 3221 (2556 - 4579)
Overall AUC Achieved (micromole/min) 6000 4000	5380.5 (4821 - 5978) 4004 (3732 - 4155)
Dose Adjustment 6000 4000	339 (252 - 460) 240 (150 - 273)
Time to Achieve Engraftment (days) ANC > 500 k/uL	15 (11-20)

Table1:AML- Acute myeloid leukemia; HLH - Hemophagocytic lymphohistiocytosis;  ALL- Acute lymphocytic leukemia; CR – Complete remission; N/A – Not applicable.