Targeted, Dose-Escalated Intravenous Busulfan and Bolus Etoposide as Preparative Therapy for Patients With Acute Myeloid Leukemia Undergoing Autologous Stem Cell Transplantation

Busulfan and etoposide have been used as preparative therapy for autoSCT (stem cell
transplant) in adults with 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 hepatotoxicity during pre-transplant mobilization therapy may be excluded from
receiving dose-escalated busulfan therapy. Every attempt will be made to prevent or avoid
hepatotoxicity.

Inclusion Criteria:

- Age 18-69 years inclusive

- Diagnosis

- AML in 1st CR or 2nd CR or

- AML evolved from MDS or

- APL 2nd CR

- CR achieved with 2 courses of therapy

- Patient in hematologic CR for greater than or equal 30 days

- ECOG PS 0,1,or 2

- Cr less than 2.0

- Total bilirubin less than 2.0

- Transaminases (AST/ALT) less than 3x ULN

- Alkaline phosphatase less than 3x ULN

- DLCO greater than 40

- LVEF greater than 40

- If liver disease, liver biopsy shows less than grade 2 inflammation

- Patient has been out of hospital since discharge from induction for 28

- Recent Bone marrow biopsy (2 weeks from study entry demonstrating remission, ANC
greater than 1000, Plat greater than 100,000, nl cytogenetics)

Exclusion Criteria:

- No active infection

- No evidence of active Hep B or prior C

- No HIV disease

- No pregnancy and nursing (neg hcg)

- No extramedullary leukemia or active CNS disease

- No prior myeloproliferative disease