Allogeneic Transplantation Using Timed Sequential Busulfan, Cladribine, and Fludarabine Conditioning in Patients With Acute Myelogenous Leukemia (AML) and Myelodysplastic Syndrome (MDS)

Central Venous Catheter:

If you choose to take part in this study, the chemotherapy, some of the other drugs in this
study, and the stem cell transplant will be given by vein through a central venous catheter
(CVC). A CVC is a sterile flexible tube and needle that will be placed into a large vein
while you are under local anesthesia. Blood samples will also be drawn through your CVC. The
CVC will remain in your body during treatment. Your doctor will explain this procedure to you
in more detail, and you will be required to sign a separate consent form.

For a stem cell transplant, the days before you receive your stem cells are called minus
days. The day you receive the stem cells is called Day 0. The days after you receive the stem
cells are called plus days.

Study Groups:

You will be randomly assigned (as in the flip of a coin) to 1 of 2 study groups:

- Group 1 will receive busulfan on Days -13 and -12, and busulfan, fludarabine, and
cladribine on Days -6 through -3.

- Group 2 will receive will receive busulfan on Days -20 and -13, and busulfan,
fludarabine, and cladribine on Days -6 through -3.

You will have a 50/50 chance of being assigned to either group. Both groups will then have a
stem cell transplant.

Study Drug Administration:

If you are in Group 1, you will receive busulfan by vein over about 3 hours on Day -13 and
Day -12. You will receive this as either an outpatient in the clinic or as an inpatient in
the hospital.

If you are in Group 2, you will receive a dose of busulfan by vein over about 3 hours on Day
-20 and Day -13. You will receive this as either an outpatient in the clinic or as an
inpatient in the hospital.

For both arms, about 11 samples of blood (about 1-2 teaspoons each time) will be drawn for
pharmacokinetic (PK) testing at time points before and after you receive your first dose of
busulfan. For Group 1, this will be on Day -13. For Group 2, this will be on Days -20 and
-13. The study staff will tell you the blood testing schedule. PK testing measures the amount
of study drug in the body at different time points and will help the doctor decide your dose
of busulfan for Days -6 through -3. If the doctor thinks it is needed, PK blood testing may
also be done on Day -6 during your dose of busulfan.

A heparin lock line will be placed in your vein to lower the number of needle sticks needed
for these draws. If it is not possible for the PK tests to be performed for technical
reasons, you will be taken off study and receive the standard fixed dose of busulfan.

On Days -11 through -8, you will not receive anything.

On Day -7, you will be admitted to the hospital and will receive fluids by vein.

On Days -6 through -3, you will receive busulfan by vein over 3 hours, fludarabine by vein
over 1 hour, then cladribine by vein over 2 hours each day.

On Day 0, you will receive the stem cell transplant by vein.

On Days 3 and 4, if the stem cells are from a related or matched unrelated donor, you will
receive cyclophosphamide over 3 hours each day by vein to help lower the risk of GVHD.

Starting on Day +5, you will receive Tacrolimus nonstop by vein until you are able to take it
by mouth to help lower the risk of graft-versus-host disease (GVHD). You will then take
Tacrolimus by mouth 2 times a day for about 3 months. After that, your Tacrolimus dose may be
lowered if you do not have GVHD. Your doctor will discuss this with you.

Starting 1 week after the transplant, you will receive filgrastim as an injection under the
skin 1 time a day until your blood cell levels return to normal. Filgrastim is designed to
help with the growth of white blood cells.

Study Testing:

While you are in the hospital, you will be checked for any side effects as part of standard
care. Blood (about 2 teaspoons) will be drawn every day to check for side effects, for
routine tests, to check your blood counts, to check your kidney and liver function, and to
check for infections.

As part of standard care, you will remain in the hospital for about 3-4 weeks after the
transplant. After you are sent home from the hospital, you must remain in the Houston area to
be checked for infections and other transplant side effects until about 3 months after
transplant. During this time, you will return to the clinic at least 1 time each week. At
each visit, blood (about 2 teaspoons) will be drawn for routine tests.

About 1, 3, 6, and 12 months after the transplant:

- You will have a physical exam.

- Blood (about 5 teaspoons) will be drawn to see how the body has reacted to the
transplant.

- If your doctor thinks it is needed, you will have a bone marrow aspiration to check the
status of the disease. To collect a bone marrow aspiration, an area of the hip or other
site is numbed with anesthetic, and a small amount of bone marrow is withdrawn through a
large needle.

Length of Study:

You will be on study for up to 1 year after the transplant. You may be taken off study early
if the disease gets worse, if you have any intolerable side effects, of if you are unable to
follow study directions.

You should talk to the study doctor if you want to leave the study early. If you are taken
off study early, you still may need to return for routine follow-up visits after the
transplant, if your doctor thinks it is needed. It may be life-threatening to leave the study
after you have begun to receive the study drugs but before you receive the stem cells.

Inclusion Criteria:

1. Patients with biopsy-proven acute myeloid leukemia or myelodysplastic syndrome with
persistent disease or in remission.

2. HLA-identical sibling or 8/8 matched unrelated donor transplant.

3. Patients age 18 to 70 years old. Eligibility for pediatric patients will be determined
in conjunction with an MDACC pediatrician. Patients age 2-17 years old may be enrolled
after at least 10 adults (ages 18-70 years old) have been assessed for safety at Day
30, as defined in the Statistical Considerations section.

4. Direct Bilirubin < 1 mg/dl and ALT < 3 times upper limit of normal.

5. Creatinine clearance > 50 ml/min (calculated creatinine clearance is permitted).

6. Adequate pulmonary function with FEV1, FVC and DLCO >/=50% of expected corrected for
hemoglobin and/or volume. Children unable to perform pulmonary function tests (e.g.,
less than 7 years old) pulse oximetry of >/= 92% on room air.

7. LVEF >/= 40%.

8. Patient, LAR, or parent able to sign informed consent. Able to give assent for
patients age 7-17.

9. Negative Beta HCG test in a woman with child bearing potential, defined as not
post-menopausal for 12 months or no previous surgical sterilization. Women of child
bearing potential must be willing to use an effective contraceptive measure while on
study.

10. Performance score of >/= 70 by Karnofsky/Lansky or PS 0 to 1 (ECOG
Exclusion Criteria:

1. Prior allogeneic or autologous transplantation.

2. Uncontrolled infections.

3. HIV seropositivity.

4. HCT Co-morbidity Index score >3. The principal investigator is the final arbiter of
eligibility for comorbidity score >3.