a study on Leukemia
Busulfan and etoposide have been used as preparative therapy for autoSCT (stem cell transplant) in adults with acute myeloid leukemia (AML) at UCSF for the past 10 years. Over this period and together with collaborative transplant centers, over 200 patients have received this treatment. By intent-to-treat analysis, and with median follow-up of 7.0 years, the 5-year DFS is 55%. The current protocol will utilize the combination of IV Busulfan (BU) and etoposide. The busulfan dose will be escalated amongst 3 targeted dose levels. All targeted dose levels represent higher busulfan dosing than standard myeloablative dosing, with the lowest dose being approximately 14% higher than standard. Busulfan levels will be monitored after the first, fourth and twelfth doses. Dose adjustments will be made "in real time" based on AUC levels determined from the first and fourth doses. This strategy of busulfan monitoring and dose adjustment has improved the therapeutic widow of BU in previous clinical trials. The current protocol will utilize the combination of intravenous busulfan and etoposide. The busulfan dose will be escalated amongst 3 targeted dose levels (area under the curve (AUC) levels at time 6 hours of 1250 uMol*min, 1400 uMol*min and 1550 uMol*min). All targeted dose levels represent higher busulfan dosing than standard myeloablative dosing with the lowest dose (1250 uMol*min) being approximately 14% higher than standard. In the absence of dose-limiting toxicity, cohorts of 4-6 patients will be treated at each dose level and 10 additional patients will be treated at the maximum tolerated dose (MTD) to confirm safety. The busulfan dosing will begin at 1 mg/kg based on historical plasma levels obtained from patients receiving BU at a starting dose of 0.8 mg/kg at UCSF Medical Center. The highest dose level proposed for this study will exceed the reported toxic level for busulfan in the alloSCT setting. Patients will be followed closely for toxicity and strict stopping rules have been included. Eligibility criteria will exclude patients with prior history of hepatotoxicity or viral hepatitis. Potential hepatotoxic agents will not be allowed just prior to and during the busulfan dosing period. In addition, patients who experience hepatotoxicty during pre-transplant mobilization therapy may be excluded from receiving dose-escalated busulfan therapy. Every attempt will be made to prevent or avoid hepatotoxicity.
A Phase I Study of Targeted, Dose-Escalated Intravenous Busulfan and Bolus Etoposide as Preparative Therapy for Patients With Acute Myeloid Leukemia Undergoing Autologous Stem Cell Transplantation
TREATMENT: STEP 1 - CONSOLIDATION CHEMOTHERAPY
To prevent neurotoxicity from high-dose cytarabine (HDAC), cytarabine doses will be adjusted according to renal function. The dose of cytarabine will be reduced to 1000 mg/m2/dose if creatinine is 1.5-1.9 mg/dL or if there is an increase from baseline creatinine at start of cytarabine of 0.6-1.1 mg/dL (example: baseline creatinine 0.8 mg/dL increase to 1.4 mg/dL (difference of 0.6 mg/dL)), decrease cytarabine to 1000 mg/m2/dose.The dose of cytarabine will be reduced to 100 mg/m2/dose if creatinine> 2.0 mg/dL or if there is an increase from baseline> 1.2 mg/dL.Cytarabine will be discontinued immediately for any clinical evidence of cerebellar neurotoxicity (dysarthria, dysmetria, gait disturbance).
Supportive Care Measures:
a. Salt and soda swish tid
PERIPHERAL BLOOD STEM CELL (PBSC) COLLECTION
TREATMENT: STEP 2 - AUTOLOGOUS STEM CELL TRANSPLANT
Dose adjustments and busulfan laboratory values will also be reviewed regularly by Jeanine McCune Ph D., at the University of Washington, in Seattle, WA. Dr. McCune is a collaborator on this trial and manages the Busulfan pharmacokinetics laboratory in Seattle. She is a leader in the field of Busulfan metabolism, pharmacokinetics and administration.
Acute Myeloid Leukemia AML autologous transplant Etoposide Busulfan
For people ages 18 years to 69 years
Before Consolidation Chemotherapy
Signed informed consent.
Eligibility to be Re-assessed Before Autologous SCT
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