The goal of this clinical research study is to learn if combining busulfan with clofarabine
and fludarabine can help control the disease better than the previous standard method (using
busulfan and fludarabine alone) in patients with AML or MDS. The safety of this combination
therapy will also be studied.
Busulfan is designed to kill cancer cells by binding to DNA (the genetic material of cells),
which may cause cancer cells to die. Busulfan is commonly used in stem cell transplantation.
Clofarabine is designed to interfere with the growth and development of cancer cells.
Fludarabine is designed to interfere with the DNA of cancer cells, which may cause the cancer
cells to die.
You will be randomly assigned (as in the toss of a coin) to 1 of 2 study groups.
- Group 1 will receive busulfan, fludarabine, and clofarabine.
- Group 2 will receive busulfan and fludarabine.
Both groups will have a stem cell transplant. The stem cells will be given by vein. The cells
will travel to your bone marrow where they are designed to make healthy, new blood cells
after several weeks.
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 Drug Administration and Procedures:
Both groups will receive a "test" dose of busulfan by vein over about 45 minutes to 1 hour.
This low-level test dose of busulfan is to check how fast busulfan is processed by your body
and cleared from your blood. This information will determine the amount of busulfan you will
receive. You may receive the busulfan test dose as an outpatient during the week before you
are admitted to the hospital or as an inpatient 8 days before your stem cell transplant.
About 11 samples of blood (about 1 teaspoon each time) will be drawn for pharmacokinetic (PK)
testing. PK testing measures the amount of study drug in the body at different time points
and will also help determine your dose of busulfan. These blood samples will be drawn at
various times before you receive busulfan and over the next 11 hours. These blood draws will
be repeated again on the first day of high-dose busulfan treatment (Day -6, which is 6 days
before the transplant).
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 or
scheduling reasons, you will receive the standard fixed dose of busulfan.
On Days -6 through -3, you will receive fludarabine by vein over 1 hour, then clofarabine (if
you are in Group 1) by vein over 1 hour, then busulfan by vein over 3 hours.
After the transplant, you will receive tacrolimus, methotrexate, or other immunosuppressive
(lowering the immune system) drugs in the standard manner to lower the risk of graft-vs-host
disease (GvHD), a reaction of the donor's immune cells against the recipient's body.
If you are going to be receiving a transplant from an HLA-nonidentical or unrelated donor,
you will also receive antithymocyte globulin (ATG) by vein over 4 hours on the 3 days before
the transplant. This drug is designed to further weaken your immune system to reduce the risk
of rejecting of the transplant.
You will receive filgrastim as an injection under the skin 1 time a day, starting 1 week
after the transplant, until your blood cell levels return to normal. Filgrastim is designed
to help with the growth of white blood cells.
While you are in the hospital, you will be checked for any side effects as part of your
standard of care. Blood (about 2 teaspoons) will be drawn every day to check for side
effects, for routine tests, to check your blood counts, 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
transplant. After you are released from the hospital, you must remain in the Houston area to
be monitored 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. The
following tests and procedures will be performed:
- You will be asked about how you are feeling and about any side effects you may be
- Blood (about 2 teaspoons) will be drawn for routine tests.
Around 14-30 days after the transplant (when the transplant "engrafts", or "takes"), you will
have a bone marrow aspirate to check the status of the disease.
Around Day 30, and about 3, 6, and 12 months after the transplant, the following tests and
procedures will be performed:
- You will have a physical exam, including measurement of your vital signs (blood
pressure, heart rate, temperature, and breathing rate).
- You will be asked about how you are feeling and about any side effects you may be
- Blood (about 2 teaspoons) will be drawn to see how well the transplant has taken.
- 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 taken off study 5 years after the end of treatment. 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 post-transplant follow-up visits,
if your transplant doctor decides 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.
This is an investigational study. Busulfan and fludarabine are both FDA approved and
commercially available for the treatment of AML and MDS. Clofarabine is FDA approved for
treating other types of cancer, but is being used in AML and MDS for research only. The use
of these study drugs together at the dose level used in this study is investigational.
Up to 250 patients will take part in this study. All will be enrolled at MD Anderson.
1. Patients must have one of the following hematologic malignancies: a) Acute myeloid
leukemia (AML) any stage and cytogenetic risk-group with the only exception being that
patients with AML and favorable cytogenetics (t(8;21, inv 16, or t(15;17) who achieve
complete remission with one course of induction chemotherapy are not eligible .
Patients with treatment related AML are eligible. b) Myelodysplastic syndromes (MDS)
with intermediate or high risk International Prognostic Scoring System score (IPSS
scores) or treatment related MDS. Patients with low risk MDS are eligible if they fail
to respond to hypomethylating agent therapy such as azacitidine or decitabine.
2. Age 3-70 years old. Eligibility for pediatric patients will be determined in
conjunction with an MDACC pediatrician.
3. Performance score of >/= 60 by Karnofsky or PS 0 to 2 (ECOG) (age > 12 years), or
Lansky Play-Performance Scale >/= 60 or greater (age <12 years).
4. 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
5. Adequate major organ system function as demonstrated by: Left ventricular ejection
fraction of at least 40%.
6. Pulmonary function test (PFT) demonstrating a diffusion capacity of least 50%
predicted. For children </=7 years of age who are unable to perform PFT, oxygen
saturation >/=92% on room air by pulse oximetry.
7. Creatinine < 1.5 mg/dL. If question about renal function discuss with study chairman
and do 24 hour creatinine clearance (clearance should be >50 ml/min).
8. Bilirubin < to 2.0 x normal (except Gilbert's Syndrome). SGPT (ALT) < 200. No evidence
of chronic active hepatitis or cirrhosis.
9. Histocompatible stem cell donor: Patients must have an HLA matched related or
unrelated donor (HLA A, B, C and DR) willing to donate for allogeneic hematopoietic
transplantation. High resolution allele level typing is required for donors other than
genotypically identical siblings.
10. No uncontrolled infection. Protocol PI or designé will be final arbiter if there is
uncertainty regarding whether a previous infection is controlled on appropriate
11. Patient or patient's legal representative, parent(s) or guardian able to sign informed
1. Positive for HIV, HBsAg, HCV or other viral hepatitis or cirrhosis from any cause.
2. Prior allogeneic or autologous stem cell transplant using a myeloablative busulfan or
total body radiation containing conditioning regimen defined as busulfan-based using a
total dose of >/=12 mg/kg given by mouth or >/=10 mg/kg given IV; or a total-body
irradiation (> 4 Gy).
3. Active or prior CNS leukemia, unless in complete remission for at least 3 months.
4. Previous therapeutic XRT to the liver as part of involved-field radiation.
5. History of serious chronic mental disorder or drug-abuse accompanied by documented
problems of compliance with therapeutic programs.
6. Lack of care-giver for the early (100-day) post-transplant period.