Allogeneic Transplantation Using Timed Sequential Busulfan and Fludarabine Conditioning
Condition: Leukemia; Acute Myeloid Leukemia; Acute Lymphocytic Leukemia; Chronic Myeloid Leukemia; Chronic Lymphocytic Leukemia; Myeloproliferative Diseases; Non-Hodgkins Lymphoma; Hodgkins Lymphoma; Multiple Myeloma; Myelodysplastic Syndrome
MeSH terms: Lymphoma; Leukemia; Leukemia, Myeloid; Multiple Myeloma; Leukemia, Myeloid, Acute; Lymphoma, Non-Hodgkin; Preleukemia; Leukemia, Lymphoid; Leukemia, Lymphocytic, Chronic, B-Cell; Hodgkin Disease; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Myelodysplastic Syndromes; Myeloproliferative Disorders
Intervention: Fludarabine monophosphate; Busulfan; Stem Cell Infusion; Tacrolimus; Methotrexate; G-CSF
Intervention description: 40 mg/m2 by vein on Days -6 through -3.; First two doses of Busulfan, 80 mg/m2 administered as an outpatient or as an inpatient to facilitate for this pharmacokinetically directed therapy. Busulfan is administered at the dose calculated to achieve a total (including first two doses delivered on day -13 and -12) systemic exposure of 20,000 ± 12% µMol-min based on the pharmacokinetic studies.; Fresh or cryopreserved bone marrow or peripheral blood progenitor cells infused on Day 0.; Starting dose of 0.015 mg/kg (ideal body weight) as 24 hour continuous infusion daily adjusted to achieve therapeutic level of 5-15 ng/ml. Tacrolimus changed to oral dosing when tolerated and can be tapered off after day +90 if no graft versus host disease (GVHD) present.; 5 mg/m2 by vein on Days 1, 3, 6 and 11 post transplant.; 5 mcg/kg/day subcutaneously beginning on Day +7, and continuing until absolute neutrophil count (ANC) is > 500 * 10/L for 3 consecutive days.
Intervention MeSH terms: Methotrexate; Fludarabine phosphate; Fludarabine; Busulfan; Tacrolimus
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 201.0
Sex: All
Minimum age: 5 Years
Maximum age: 75 Years
Healthy volunteers: No
Keywords: Leukemia; Acute myeloid leukemia; Acute lymphocytic leukemia; Chronic myeloid leukemia; Chronic lymphocytic leukemia; Myeloproliferative Diseases; Non-Hodgkins Lymphoma; Hodgkins lymphoma; Multiple myeloma; Myelodysplastic syndrome; MDS; Fludarabine monophosphate; Fludarabine phosphate; Fludara; Busulfan; Busulfex; Myleran; Tacrolimus; Prograf; Methotrexate; G-CSF; Filgrastim; Neupogen; Stem cell transplant; Allogeneic Transplantation

Summary:

      The goal of this clinical research study is to learn if giving busulfan and fludarabine
      before a stem cell transplant can help control the disease better than the standard method in
      patients with leukemia, lymphoma, multiple myeloma, MDS, or MPD. In this study, 2 doses of
      busulfan will be given 2 weeks before a stem cell transplant followed by 4 doses of busulfan
      and fludarabine during the week before the stem cell transplant, rather than the standard
      method of giving 4 doses of busulfan and fludarabine only during the week before the stem
      cell transplant.

      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 transplants.

      Fludarabine is designed to interfere with the DNA of cancer cells, which may cause the cancer
      cells to die.
    

Eligibility criteria:

        Inclusion Criteria:

          1. Patients with high-risk hematologic malignancies with anticipated poor prognosis with
             non transplant therapy, including those in remission or with induction failure and
             after treated or untreated relapse. Diagnoses to be included a) Acute myeloid
             leukemia; b) Acute lymphocytic leukemia; c) Chronic myeloid leukemia; d) Chronic
             lymphocytic leukemia; e) Myelodysplastic syndrome; f) Myeloproliferative syndromes; g)
             Non-Hodgkins lymphoma; h) Hodgkins Lymphoma; i) Multiple myeloma.

          2. Patients must have a histocompatible stem cell donor. An HLA-identical related donor
             or a 8/8 matched unrelated donor.

          3. Age 5 to 75 years old.

          4. Performance score of >/= 70 by Karnofsky/Lansky or PS 0 to 1 (ECOG </=1).

          5. Left ventricular ejection fraction at least 40%.

          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. Creatinine clearance (calculated creatinine clearance is permitted) should be >40
             ml/min.

          8. Bilirubin </= 2 x the upper limit of normal (except Gilbert's Syndrome). SGPT (ALT) <
             200.

          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. Patient or patient's legal representative, parent(s) or guardian able to sign informed
             consent.

        Exclusion Criteria:

          1. HIV seropositivity.

          2. Uncontrolled infections.