Thiotepa-Clofarabine-Busulfan With Allogeneic Stem Cell Transplant for High Risk Malignancies
Thiotepa-Clofarabine-Busulfan With Allogeneic Stem Cell Transplant for High Risk Malignancies
Any time the words "you," "your," "I," or "me" appear, it is meant to apply to the potential
 participant.

 The goal of this clinical research study is to learn if thiotepa, busulfan, and clofarabine,
 when given before an allogeneic (bone marrow , blood, or cord blood cells) or haploidentical
 (bone marrow) stem cell transplantation can help to control cancers of the bone marrow and
 lymph node system. The safety of this treatment will also be studied.

 This is an investigational study. Thiotepa and clofarabine are FDA approved and commercially
 available for the treatment of leukemia. Busulfan is FDA approved and commercially available
 for use in stem cell transplantation. The combination of thiotepa, clofarabine, and busulfan
 together with a stem cell transplant is investigational.

 Up to 60 participants will take part in this study. All will be enrolled at M. D. Anderson.
The Study Drugs:

 Thiotepa and busulfan are designed to bind to DNA (genetic material of cells), which may
 cause cancer cells to die. They are commonly used in stem cell transplants.

 Clofarabine is designed to interfere with the growth and development of cancer cells.

 Study Drug Administration:

 If you are found to be eligible to take part in this study, you will begin receiving the
 study drugs before you receive the stem cell transplant.

 The days before you receive your stem cells are called minus days, such as Day -2 and Day -1.
 The day you receive the stem cells is called Day 0. The days after you receive the stem cells
 are called plus days, such as Day +1 and Day +2.

 On Day -8 (8 days before you receive the stem cell transplant), you will receive thiotepa
 through a central venous catheter (CVC) over 2 hours. A CVC is a sterile, flexible tube that
 will be placed into a large vein while you are under local anesthesia. Your doctor will
 explain this procedure to you in more detail, and you will be required to sign a separate
 consent form for this procedure.

 On Day -7, you will receive busulfan through a CVC. This dose of busulfan is a low level
 "test" dose to check how your blood levels change over time. This information will be used to
 decide the next dose level of busulfan.

 Blood (about 1 teaspoon each time) will be drawn 6-11 times total over Days -7 and -5 for
 pharmacokinetic (PK) testing. PK testing measures the amount of busulfan in the body at
 different time points. This PK testing will be done to find the dose of busulfan needed for
 your body size on the other days that you receive busulfan. A heparin lock line will be
 placed in a vein to lower the number of needed sticks performed for draws. If you cannot have
 the blood level tests performed for any reason, you will receive the standard busulfan dose.

 On Days -6, -5, -4, and -3, you will receive clofarabine through a CVC over 1 hour.

 On Days -5, -4, and -3, you will receive busulfan through a CVC over 3 hours.

 If you will receive stem cells from a donor whose cells do not match your own cells closely,
 on Days -4 and -3 you will also receive antithymocyte globulin (ATG) by vein over 4 hours.
 This will help to reduce the risk of your body rejecting the transplant. If your transplant
 will involve haploidentical stem cells, you will not receive ATG on Days -4 and -3.

 On Days -2 and -1, you will "rest," which means you will not be given any drugs, but your CVC
 will remain in place.

 If thiotepa is not available:

 If thiotepa is not available, or if you doctor thinks it is in your best interest, you will
 receive the following study drugs and total body irradiation (TBI) before you receive the
 stem cell transplant. TBI involves the delivery of high doses of radiation designed to
 destroy cancer cells and/or lower the immune system in order to lower the risk of the body
 rejecting the new stem cells.

 Between Days -16 and -7, you will receive a low-level "test" dose of busulfan by vein over
 about 45 minutes to 1 hour. Test doses are used to study how your body breaks down busulfan
 and decide the dose of busulfan that you will receive. You may receive the test dose before
 Day -6 as an outpatient in the clinic, or on Day -6 as an inpatient in the hospital.

 Blood (about 1 teaspoon each time) will then be drawn for PK testing up to 11 times over the
 11 hours after the busulfan test dose and on Day -4. PK testing measures the amount of study
 drug in the body at different time points. The study staff will tell you more about the PK
 testing schedule.

 A heparin lock line will be placed in your vein before the PK testing to lower the number of
 needle sticks needed for these draws. If for any reason it is not possible for the PK tests
 to be performed, you will receive the standard dose of busulfan.

 On Day -7 or Day -6, you will be admitted to the hospital and given fluids through a CVC to
 hydrate you.

 On Days -5, -4, -3, and -2, you will receive clofarabine through a CVC over 1 hour.

 On Days -4, -3, and -2, you will receive busulfan through a CVC over 3 hours.

 If you will receive stem cells from a donor whose cells do not match your own cells closely,
 on Days -3 and -2 you will also receive antithymocyte globulin (ATG) by vein over 4 hours.
 This will help to reduce the risk of your body rejecting the transplant. If your transplant
 will involve haploidentical stem cells, you will not receive ATG on Days -3 and -2.

 On Day -1, you will receive TBI one time.

 Stem Cell Transplant:

 On Day 0, you will have an allogeneic or haploidentical stem cell transplant through the CVC.
 Allogeneic stem cells come from a donor whose cells closely match your own cells.
 Haploidentical stem cells come from a donor whose cells do not match your own cells as
 closely, but they are specially processed to help prevent graft versus host disease (GVHD).

 Receiving stem cells is similar to receiving a blood transfusion. The time required to
 receive the stem cells will depend on the type of cells you are receiving. Receiving cord
 blood stem cells can take several minutes. Receiving bone marrow and blood stem cells may
 take several hours.

 You will receive G-CSF (filgrastim) (which helps to produce white blood cells) as an
 injection under the skin once a day, starting 1 week after the transplant, until your blood
 cell levels return to normal.

 You will receive drugs (mycophenolate mofetil (MMF), tacrolimus and/or methotrexate) to help
 prevent side effects, such as GVHD. You will receive methylprednisolone if you develop GVHD.

 You will stay in the hospital for about 4 weeks after the stem cell transplantation.

 If you had a haploidentical stem cell transplant, on Days 3 and 4 after your stem cell
 transplant, you will receive cyclophosphamide through a CVC over 3 hours. Mesna will be given
 by vein at the same time you are given each dose of cyclophosphamide, to help protect your
 bladder from bleeding.

 Study Visits:

 Beginning on Day -9, once a day while you are in the hospital:

 -  You will have a physical exam, including measurements of your vital signs.

 -  You will be asked if you have had any side effects.

 -  Blood (about 4 tablespoons) will be drawn to test your blood cell counts. Two (2) times
 a week, this blood will be also be used for routine tests.

 After you are out of the hospital, 2 times a month until it has been 100 days after the
 transplant:

 -  You will have a physical exam, including measurements of your vital signs and weight.

 -  You will be asked if you have had any side effects.

 -  Blood (about 4 tablespoons) will be drawn for routine tests.

 About 1, 3, 6, and 12 months after the transplant, blood (about 4 tablespoons) will be drawn
 to check the status of the disease. You will also have bone marrow aspirations to check the
 status of the disease. You will also have a physical exam.

 If the doctor thinks it is necessary, you may have extra tests and procedures.

 Length of Study:

 You will be on study for about 1 year. You will be taken off study if the disease gets worse
 or needs further treatment.

 Follow-Up:

 If you live close to M. D. Anderson, you will return to the clinical once every several
 months for a physical exam. At these visits, blood (about 3 teaspoons) will be drawn for
 routine tests.

 You and/or your local doctor will be called every several months and asked about your health
 status and if the leukemia or MDS has come back.
Inclusion Criteria:

 1. Diagnosed with one of the following diseases:

 2. Acute myelogenous leukemia (AML) in induction failure, relapse, past first remission,
 or CR1 considered at risk for relapse

 3. Myelodysplastic syndromes with International Prognostic Scoring System score (IPSS
 score) >/= 2 or myelodysplasia that has not responded to chemotherapy

 4. Biphenotypic leukemia

 5. Acute lymphocytic leukemia with induction failure, first complete remission with high
 risk cytogenetics (e.g. Philadelphia positive chromosome, t(4:11) Remission requiring
 more than 2 chemotherapy to achieve remission, or any stage beyond CR1

 6. Chronic Myelogenous Leukemia (CML): second chronic phase, accelerated phase or blast
 crises with less than 10% blasts in the bone marrow, or CR1 and resistance to Gleevec
 or other tyrosine kinase inhibitors

 7. Non-Hodgkin's Lymphoma - induction failures, second or third complete remission, or
 relapse (including relapse post autologous hematopoietic stem cell transplant)

 8. Hodgkin's disease - induction failure, second or later complete remission, or relapse
 (including relapse post autologous hematopoietic stem cell transplant).

 9. Chronic Lymphocytic Leukemia that has failed induction therapy or Rai Stages 2-4

 10. Related or unrelated donor which is HLA-matched or mismatched in 1 HLA A, B, C, DR, or
 DQ locus is acceptable (i.e. >/= 9/10 matched related or unrelated donor, matched with
 molecular high-resolution technique per current std. for BMT program). Cord blood
 units must match patient at 4, 5, or 6/6 HLA class 1 serological & II molecular
 antigens with a min. of 2 x 10e7 TNC/kg recipient weight in the pre-thawed fraction.
 For patient lacking a matched related or unrelated donor or acceptable cord blood
 unit(s), a related haploidentical donor (</= 7/8 allele matched at A, B, C, DR loci)
 may be used.

 11. Age </= 60 years.

 12. Lansky performance score >/= 50% for patients </= 16 years of age, or Zubrod
 performance status score of 0-2 for patients > 16 years of age.

 13. Cardiac function - left ventricular ejection fraction >/= 40%.

 14. Pulmonary function - diffusion capacity of at least 50% predicted. Children unable to
 perform pulmonary function tests (e.g. less than 7 years old) pulse oximetry of >/=
 92% on room air.

 15. Serum creatinine < 1.6 mg/dL or creatinine clearance >/= 50 ml/min.

 16. SGPT </= 200 IU/mL, serum bilirubin < 1.5 x normal.

 17. Written informed consent and assent as is age appropriate.

 18. No active infection.

 Exclusion Criteria:

 1. Pregnancy in women of child bearing potential (pregnancy test performed within 2 weeks
 of study entry).

 2. HIV positive (highly immunosuppressive treatment)

 3. Active CNS leukemia

 4. Chronic or active Hepatitis B or Hepatitis C. If questions about liver health discuss
 with PI and strongly consider liver biopsy.