Acute Myeloid Leukemia, Leukemia, Myelodysplastic Syndrome
Conditions
Keywords
Stem Cell Transplantation, Leukemia, Busulfan, Fludarabine, MDS, AML
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.
Interventions
DRUGBusulfan
Fixed Dose = 130 mg/m\^2 IV Daily Over Three Hours x 4 Days. Adjusted Dose = 32 mg/m\^2 IV Over 2 Hours Test Dose x 1 Day. Proceeding dosage level determined by pharmacokinetic studies to achieve a daily area under curve (AUC) of 6,000 microMol-min ± 10%.
DRUGFludarabine
40 mg/m\^2 IV Daily Over 1 Hour x 4 Days
Sponsors
National Cancer Institute (NCI)
M.D. Anderson Cancer Center
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
No minimum to 65 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Treatment-related Mortality (TRM) | From transplant at Day 0 to Day 100 and 1 year following transplant | Time to failure (TTF) defined as either disease recurrence or death, from the time of bone marrow transplant (BMT) and reported as TRM at 100 days and 1 year. Treatment period defined as BMT Day -9 for patients treated on the PK-guided treatment arm, and day -7 for patients receiving the fixed-dose busulfan treatment through BMT Day +28. The post study surveillance period is defined as BMT Day +29 through BMT Day +100. Bone marrow aspirate with cytogenetics at approximately one (1) month and three (3) months, or as clinically indicated. Response Criteria is measured by the bone marrow aspirate to determine it has leukemic blast. Bone marrow blast less than 5% is considered to be a complete response. |
| 3 Year Progression Free Survival | 3 years | PFS defined as length of time either due to disease recurrence or death, from the time of stem cell infusion (Bone marrow or PBPC) to 3 years. Response Criteria is measured by the bone marrow aspirate to determine it has leukemic blast. Bone marrow blast less than 5% is considered to be a complete response. |
Countries
United States
Participant flow
Recruitment details
Recruitment Period: June 28, 2005 to May 12, 2011. All recruitment done at The University of Texas MD Anderson Cancer Center.
Pre-assignment details
A total of 233 participants were enrolled, out of which 8 participants withdrew from study prior to treatment and are not evaluable on protocol.
Participants by arm
| Arm | Count |
|---|---|
| Fixed-Dose Busulfan + Fludarabine Busulfan Fixed Dose = 130 mg/m\^2 intravenous (IV) Daily Over Three Hours x 4 Days. Fludarabine 40 mg/m\^2 IV Daily Over 1 Hour x 4 Days. | 114 |
| Adjusted Dose Busulfan + Fludarabine Busulfan Adjusted Dose = 32 mg/m\^2 IV Over 2 Hours Test Dose x 1 Day. Fludarabine 40 mg/m\^2 IV Daily Over 1 Hour x 4 Days.
Adjusted Dose = 32 mg/m\^2 IV Over 2 Hours Test Dose x 1 Day; Proceeding dosage level determined by pharmacokinetic studies to achieve a daily area under curve (AUC) of 6,000 microMol-min ± 10%. | 111 |
| Total | 225 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 0 | 1 |
| Overall Study | No Response | 5 | 5 |
| Overall Study | Progressive Disease | 1 | 0 |
Baseline characteristics
| Characteristic | Fixed-Dose Busulfan + Fludarabine | Adjusted Dose Busulfan + Fludarabine | Total |
|---|---|---|---|
| Age, Continuous | 52 years | 50 years | 50 years |
| Region of Enrollment United States | 114 participants | 111 participants | 225 participants |
| Sex: Female, Male Female | 55 Participants | 56 Participants | 111 Participants |
| Sex: Female, Male Male | 59 Participants | 55 Participants | 114 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 29 / 114 | 26 / 111 |
| serious Total, serious adverse events | 2 / 114 | 3 / 111 |
Outcome results
Primary
3 Year Progression Free Survival
PFS defined as length of time either due to disease recurrence or death, from the time of stem cell infusion (Bone marrow or PBPC) to 3 years. Response Criteria is measured by the bone marrow aspirate to determine it has leukemic blast. Bone marrow blast less than 5% is considered to be a complete response.
Time frame: 3 years
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Fixed-Dose: Participants in CR | 3 Year Progression Free Survival | 42 Days |
| Adjusted Dose: Participants in CR | 3 Year Progression Free Survival | 56 Days |
Primary
Treatment-related Mortality (TRM)
Time to failure (TTF) defined as either disease recurrence or death, from the time of bone marrow transplant (BMT) and reported as TRM at 100 days and 1 year. Treatment period defined as BMT Day -9 for patients treated on the PK-guided treatment arm, and day -7 for patients receiving the fixed-dose busulfan treatment through BMT Day +28. The post study surveillance period is defined as BMT Day +29 through BMT Day +100. Bone marrow aspirate with cytogenetics at approximately one (1) month and three (3) months, or as clinically indicated. Response Criteria is measured by the bone marrow aspirate to determine it has leukemic blast. Bone marrow blast less than 5% is considered to be a complete response.
Time frame: From transplant at Day 0 to Day 100 and 1 year following transplant
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Fixed-Dose: Participants in CR | Treatment-related Mortality (TRM) | 100 Days | 3 Percentage of Participants |
| Fixed-Dose: Participants in CR | Treatment-related Mortality (TRM) | 1 Year | 19 Percentage of Participants |
| Adjusted Dose: Participants in CR | Treatment-related Mortality (TRM) | 1 Year | 17 Percentage of Participants |
| Adjusted Dose: Participants in CR | Treatment-related Mortality (TRM) | 100 Days | 3 Percentage of Participants |
| Fixed Dose: Participants Not in CR | Treatment-related Mortality (TRM) | 100 Days | 7 Percentage of Participants |
| Fixed Dose: Participants Not in CR | Treatment-related Mortality (TRM) | 1 Year | 18 Percentage of Participants |
| Adjusted Dose: Participants Not in CR | Treatment-related Mortality (TRM) | 100 Days | 3 Percentage of Participants |
| Adjusted Dose: Participants Not in CR | Treatment-related Mortality (TRM) | 1 Year | 3 Percentage of Participants |
Comparison: 100 Days, Between Arms: Participants in CRp-value: 0.9Wilcoxon (Mann-Whitney)
Comparison: 100 Days, Between Arms: Participants not in CRp-value: 0.4Wilcoxon (Mann-Whitney)
Comparison: 1 Year, Between Arms: Participants in CRp-value: 0.7Wilcoxon (Mann-Whitney)
Comparison: 1 Year, Between Arms: Participants not in CRp-value: 0.05Wilcoxon (Mann-Whitney)