Clinical trial NCT00469144: IV Busulfan With Allo-BMT: Study for Patients With Acute Myelogenous Leukemia and Myelodysplastic Syndrome
Official title: A Randomized Study of Once Daily IV Busulfan With Fludarabine With Hemopoietic Stem Cell Transplantation for Acute Myelogenous Leukemia (AML) and Myelodysplastic Syndrome (MDS)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Myelodysplastic Syndrome
Leukemia
Acute Myeloid Leukemia
Keywords: Stem Cell Transplantation
Leukemia
Busulfan
Fludarabine
MDS
AML
Lead sponsor: M.D. Anderson Cancer Center
Sponsor class: OTHER
Collaborators: name: National Cancer Institute (NCI)
First posted: 2007-05-04
Enrollment: 233
Sex: ALL
Maximum age (years): 65
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The goal of this clinical research study is to learn if giving busulfan in a dose based on blood levels, along with a fixed (unchanging) dose of fludarabine, is more effective and causes fewer side effects for AML or myelodysplastic syndrome patients than the standard method of giving a fixed busulfan dose based on body size, along with a fixed dose of fludarabine. The safety of dosing based on blood levels will also be studied.

Detailed description: Busulfan is a chemotherapy drug that kills cancer cells by binding to DNA, and is commonly used in stem cell transplantation. Fludarabine is an antimetabolite drug which has anti-leukemia and immunosuppressive effects.

If you are eligible to take part in this study, you will be randomly assigned (as in the toss of a coin) to 1 of 2 study groups. One group will receive a fixed dose of busulfan, while the other group will receive an adjusted dose of busulfan based on blood levels of the drug. Both groups will receive fludarabine treatment as well as a stem cell transplant.

Patients in the adjusted-dose group will first receive a low-level "test" dose of busulfan to check how their blood levels change over time; this information will be used to decide the next dose needed to reach the target blood level that matches your body size. Patients in the fixed-dose group will receive a fixed dose of busulfan without the test dose. If you are assigned to the fixed-dose group, this measurement will only affect your dose level if you have an unusually high or low drug level in your blood. Patients in both groups will have a total of about 20 teaspoons (less than 7 tablespoons) of blood drawn over time to check their busulfan blood levels following one or more of the busulfan treatments.

About 11 samples of blood will be drawn to check your blood levels of busulfan over time following the test dose and the first high-dose busulfan treatment; each sample is about 1 teaspoon of blood. A heparin lock will be placed in your vein to lower the number of needle sticks needed for these draws. If it is not possible for these blood level tests to be performed for technical or scheduling reasons, you will receive the standard fixed dose.

Both groups of patients receive fludarabine through a central venous catheter (CVC--a small tube inserted into one of your major veins, usually in the chest or shoulder blade) over 1 hour, once a day, for 4 days. After each dose of fludarabine, the high-dose Busulfan will be infused through the CVC over 3 hours. These drugs are given to try to kill malignant cells and suppress your immune system in order to reduce the risk of stem cell transplant rejection. If you are going to be receiving a transplant from an HLA-type-nonidentical or unrelated donor, you will also receive Thymoglobulin (ATG) over 4 hours on the 3 days prior to the transplant to further suppress your immune system.

After 2 days of rest, the allogeneic stem cells (bone marrow or peripheral blood stem cells) will then be given intravenously (IV--through a needle in your vein). You will receive the drug G-CSF (Neupogen) as an injection under the skin daily starting 1 week after the transplant until your blood cell levels return to normal.

Patients usually remain in the hospital for about 4 weeks after stem cell transplantation. After you are released from the hospital, you will continue as an outpatient in the hospital area to be monitored for infections and transplant-related complications for a minimum of 100 days after the transplant.

Patients who previously had leukemia involvement in the nervous system may need to receive spinal taps, with injection of cytosine arabinoside and hydrocortisone, several times over the year after transplantation to try to keep the leukemia from coming back.

You will undergo blood tests and bone marrow biopsies at 3, 6, and 12 months after the transplant, to check if the disease is in remission. Your health status will be followed along with their local physician to find out if the leukemia or myelodysplastic syndrome comes back, as well as to check the length of your survival.

This is an investigational study. All of the drugs used in this study are approved by the FDA for treatment of cancer. Up to 230 patients will take part in this study. All will be enrolled at MD Anderson.

Eligibility criteria: Inclusion Criteria:

1. Acute myeloid leukemia past first remission, in first or subsequent relapse, in first remission (cytogenetics other than t(8;21, inv 16, t(15;17)) or induction failures. Only myeloid leukemia but not biphenotypic leukemia is allowed on this study.
2. Myelodysplastic syndromes with intermediate or high risk International Prognostic Scoring System score
3. Patient has not been administered any other systemic chemotherapeutic drug (including Mylotarg) within 21 days prior to trial enrollment (BMT Day -7 or day -9 for the test-dose arm of the study). Hydroxyurea is permitted if indicated to control induction refractory disease, and IT chemotherapy is allowed if indicated as maintenance treatment for previously diagnosed leptomeningeal disease, that has been in remission for at least 3 months prior to enrollment on this study).
4. No active infection. Protocol PI will be final arbiter if there is uncertainty regarding whether a previous infection is resolved.
5. age \<=65
6. Patients must have a matched related or unrelated donor willing to donate. A donor who is HLA identical or mismatched in 1 locus on Class I \[HLA, A or B\], or molecularly mismatched in 1 locus on Class II \[HLA, DR or DQ\] is also acceptable.
7. ZUBROD performance status \<2
8. Life expectancy is not severely limited by concomitant illness and expected to be \>12 weeks.
9. Left ventricular ejection fraction \>45% No uncontrolled arrhythmias or symptomatic cardiac disease.
10. No symptomatic pulmonary disease. Forced expiratory volume at one second (FEV1), forced vital capacity (FVC) and diffusion capacity of lung for carbon monoxide (DLCO) \>/= 50% of expected corrected for hemoglobin. In patients \</= 7 years pulmonary function will be assessed per pediatric BMT routine
11. Serum creatinine \</= 1.5 mg%.
12. Serum glutamate pyruvate transaminase (SGPT) \</= 200 IU/ml, serum bilirubin and alkaline phosphatase within accepted laboratory standard normal limits or considered not clinically significant. No evidence of chronic active hepatitis or cirrhosis. If positive hepatitis serology, discuss with Study Chairman and consider liver biopsy.
13. No effusion or ascites \>1L prior to drainage.
14. HIV-negative.
15. Female patient is not pregnant (negative B-human chorionic gonadotropin (HCG) pregnancy test in all women of child-bearing-potential in accordance with departmental routine).
16. Patient or patient's legal representative, parent(s) or guardian able to sign informed consent.
17. No prior autologous stem cell transplants

Exclusion Criteria:

1) None.

Primary outcomes:
measure: Treatment-related Mortality (TRM)
timeFrame: From transplant at Day 0 to Day 100 and 1 year following transplant
measure: 3 Year Progression Free Survival
timeFrame: 3 years
Secondary outcomes:
Other outcomes:
Locations:
city: Houston
country: United States
facility: University of Texas MD Anderson Cancer Center
state: Texas
Study officials:
affiliation: M.D. Anderson Cancer Center
name: Richard E. Champlin, MD
role: PRINCIPAL_INVESTIGATOR
References: