Busulfan and Fludarabine in Patients With AML and MDS

Study Overview
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Brief Summary
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Primary Objectives: To administer multiple doses of an intravenous formulation of busulfan (Bu) at a dose adjusted to yield a blood drug level with a median daily area under the plasma concentration curve (AUC) of approximately 6,500 µMol-min. This dose will be given intravenously over three hours once daily for four (4) days, in combination with Fludarabine at a dose of 40 mg/m2 as preparation for bone marrow or peripheral stern cell transplantation in patients with acute myeloid leukemia or myelodysplastic syndromes. To determine the outcome of Acute Myeloid Leukemia (AML)/myelodysplastic syndromes (MDS) patients undergoing treatment with this regimen. Data regarding engraftment, toxicity, relapse rate, long-term (disease-free) outcome, and overall survival will be collected. To determine the safety profile of this regimen when utilized as preparation for allogeneic transplantation. To describe the plasma pharmacokinetics of busulfan when administered intravenously in this regimen.

Detailed Description
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Patients who agree to the optional pharmacology procedures #1 will initially receive a therapeutic test dose of busulfan to test the blood levels over time; this information will be used to determine the subsequent high-dose busulfan doses. Patients who do not agree to the optional pharmacology procedure will receive a fixed dose of busulfan as has previously been done for 3 years. Patients in this study will then receive fludarabine through a central venous catheter over one hour, once a day, for four days. High-dose Busulfan will be injected through the catheter over three hours, once a day, for four days, starting immediately after fludarabine. After two days of rest, the allogeneic bone marrow, peripheral blood stem cells or cord blood will then be given intravenously. Patients will receive the drug Granulocyte colony-stimulating factor (G-CSF - Neupogen) as an injection under the skin until their blood counts recover. Patients will remain in the hospital for about 4-6 weeks. After discharge, patients will continue as outpatients in the hospital area until they are able to safely leave the immediate hospital area or for a minimum of 100 days after the transplant. Some patients may need to receive spinal taps with instillation of cytosine arabinoside and hydrocortisone several times over the year after transplantation. This is only for patients with a previous clinical history of leukemic involvement of the brain. This is an investigational study. The FDA has approved the study drugs. Up to 200 patients will take part in this study. All will be enrolled at M. D. Anderson.

Official Title
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A Phase II Study of High-Dose Intravenous Busulfan and Fludarabine With Allogeneic Marrow and Peripheral Blood Progenitor Cell Transplantation for Acute Myeloid Leukemia and Myelodysplastic Syndromes

Conditions
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Leukemia

Intervention / Treatment
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* Drug: Busulfan
* Drug: Fludarabine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Acute leukemia past first remission, in first or subsequent relapse, in first remission (high-risk, i.e., cytogenetics other than t(8;21, inv 16, t(15;17)) or induction failures. Myelodysplastic syndromes in any clinical stage, excluding only patients who have isolated stable mono-cytopenia and who are clinically stable. Patient has not been administered any other systemic chemotherapeutic drug (including Mylotarg) within 21 days prior to trial enrollment (BMT Day -7 or BMT day -9). (Hydroxyurea and intrathecal chemotherapy is permitted). No uncontrolled infection. Patients up to age 65 will be eligible for this study. ALLOGENEIC TRANSPLANTATION: Patients should have an acceptable related or unrelated volunteer donor available for a bone marrow peripheral blood progenitor cell or cord blood transplant. Bone marrow and peripheral blood cell donors should be matched for at least 5 of 6 HLA A, B and DR loci. Cord blood donors should be matched for at least 4 of 6 A, B and DR loci. Life expectancy is not severely limited. Pulmonary, cardio, renal and liver function tests normal. In patients < 7 years pulmonary function will be assessed per pediatric BMT routine. No evidence of chronic active hepatitis or cirrhosis. HIV-negative. Female patient is not pregnant Signed informed consent. Patient admitted on Sunday, or Monday to allow for pharmacokinetic directed therapy. Exclusion Criteria: 1) Not fulfilling eligibility criteria above.

Ages Eligible for Study
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Maximum Age: 66 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Busulfan + Fludarabine<br>Once a day for four days, Busulfan 130 mg/m^2 through intravenous catheter over 3 hours immediately after Fludarabine 40 mg/m^2 over 1 hour. | Drug: Busulfan<br>* 130 mg/m^2 injected through the intravenous catheter over three hours, once a day, for four days, starting immediately after Fludarabine.<br>* Other names: Myleran;Drug: Fludarabine<br>* 40 mg/m^2 through a central venous catheter over one hour, once a day, for four days.<br>* Other names: Fludara;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Successful Engraftment | Successful Engraftment defined as first of 3 consecutive days with Absolute neutrophil count (ANC) equal to or more than 0.5 * 10^9/L. Failure to engraft by day +30 considered primary engraftment failure. Study period one week prior to transplant through post Day 28. | Study period one week prior to transplant through post Day 28 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Acute Myeloid Leukemia, Myelodysplastic Syndromes, Busulfan, Busulfex, Myleran, Fludarabine, Fludarabine Phosphate, Fludara