Infusion of Expanded Cord Blood T Cells
Infusion of Expanded Cord Blood T Cells
The goal of this clinical research study is to learn if treating umbilical cord blood with
 growth factors before a transplant can help to improve the body's ability to accept the cord
 blood transplants.
Umbilical cord blood is a source of stem cells that can be used for transplantation. The
 major problem with this type of transplant is the small number of stem cells that are
 available in the cord blood. This delays the recipients body's ability to accept the cord
 blood. This may also cause the immune system to slow, making infection more likely. One
 method to help fix this problem is to treat a sample of the cord blood with growth factors,
 which may promote the growth of the needed T cells before they are given to the recipient as
 a transplant.

 For this study, participants will receive high-dose chemotherapy, then an untreated cord
 blood cells transplant, and then 14 days later receive the treated cord blood cells
 transplant.

 The Study Drugs:

 Melphalan is designed to damage the DNA (the genetic material) of cells, which may cause
 cancer cells to die.

 Thiotepa is designed to the damage DNA, which may cause cancer cells to die

 Fludarabine is designed to make cancer cells less able to repair damaged DNA. This may
 increase the likelihood of the cells dying.

 Rituximab is designed to attach to a specific protein on the surface of tumor cells, which
 may cause them to die.

 Etoposide is designed to block cell growth.

 Filgrastim is a drug that helps cells in the bone marrow to divide

 Anti-thymocyte globulin (ATG) is a drug that helps the immune system by attaching to and
 inactivating T cells.

 Mycophenolate mofetil (MMF) is a drug that suppresses the immune system.

 Tacrolimus is a drug that helps the immune system to prevent GVHD.

 IL-2 is a protein that is used to help the growth of T cells.

 Placement of Central Venous Catheter (CVC):

 Before you can have back-up stem cells collected or you receive chemotherapy, you will be
 required to have a CVC, which is a sterile flexible tube, placed into a large vein in the
 upper chest while you are under local anesthesia. Children are usually unable to hold still
 for this procedure and will be given drugs to make them sleep for the procedure. 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. If you are donating back-up cells (as described
 below) the catheter will be placed the day of the collection. If you are not donating back up
 cells, the CVC will be placed a few days before admission to the hospital. This catheter will
 be used to draw blood, give fluids, and give the study drugs.

 Collection of "back up" stem cells:

 Collection of additional stem cells from the donor of the cord blood will not be possible if
 the transplant with the cord blood fails. Back-up blood or additional bone marrow will be
 collected from you and frozen about a week before the high-dose chemotherapy begins. The
 study doctor will decide to collect or not collect this sample based on the status of the
 disease. The sample(s) will be collected by leukapheresis or with bone marrow aspirates.

 Selection of another donor as the alternate source of stem cells If the cord blood transplant
 is not successful, you will receive the back-up cells collected before admission as described
 above. If you are unable to donate these stem cells, for example it they are contamination
 with tumor cells, a family member or a second cord blood transplant will be used. The
 potential family member donor will have screening tests performed to find out if they are
 eligible to donate stem cells.

 Leukapheresis:

 If you are donating back-up stem cells, before the collection of the blood stem cells, you
 will be treated with a drug called filgrastim, which will make the stem cells in the marrow
 easier for the study doctor to collect and help to increase the number of white blood cells.
 This drug is given through a needle under the skin 1-2 times a day for 3-7 days. When the
 white cell count is high enough (usually around day 4), your blood stem cells will be
 collected from your CVC over 3-4 hours/day. The collection process will be repeated daily
 until a enough stem cells are collected. You will continue to receive filgrastim until all
 the stem cells are collected.

 Bone Marrow Collection:

 If the leukapheresis cannot be performed successfully, for example the white blood cell count
 does not increase enough with the filgrastim, you will have bone marrow collected. You will
 go to the operating room and be asleep for this. Multiple small bone marrow aspirates will be
 performed and the marrow collected. Only a small sample of your bone marrow (less than 5%)
 will be taken. To collect a bone marrow aspirate, an area of the hip is numbed with
 anesthetic, and a small amount of bone marrow is withdrawn through a large needle.

 High-Dose Chemotherapy Administration:

 Day 0 is the day of the stem cell transplant, so the negative day numbers are used to
 describe the treatment days before the transplant. All chemotherapy, fluids, and other drugs
 that must be given by vein will be infused through the CVC. After the "backup" stem cells are
 collected, you will be admitted to the hospital on Day -9 to begin receiving fluids.
 Chemotherapy may be stopped if intolerable side effects occur.

 You will be placed in 1 of 2 treatment groups. The study doctors will decide which treatment
 group will be the best treatment for you. If you are in Group 1, you will receive
 chemotherapy and the cord blood transfusion. If you are in Group 2, you will receive
 treatment with chemotherapy, radiation, and the cord blood transfusion.

 -  If you are in Group 1, you will receive melphalan by vein over 30 minutes as a single
 dose on Day -8, thiotepa by vein over 4 hours as a single dose on Day -7, followed by
 fludarabine by vein over about 30 minutes 1 time each day on Days -6 through -3.
 Rituximab may be given by vein over 4 - 6 hours on Day -9 if the doctor thinks it is
 necessary.

 -  If you are in Group 2, you will receive radiation on Days -7,-6, -5 and -4. You will
 sign a separate consent for the total body irradiation. Then you will be given etoposide
 by vein over 1-2 hours as a single dose on Day -3. Rituximab may be given by vein over
 4-6 hours on Day -8 if the doctor thinks it is necessary.

 -  Group 1 will receive anti-thymocyte globulin (ATG) by vein over 4-6 hours on the Days -4
 and -3 of treatment to lower the chances of the cord blood infusion being rejected.

 -  Group 2 will receive anti-thymocyte globulin (ATG) by vein over 4-6 hours on the Days
 -3, -2, and -1 of treatment to lower the chances of the cord blood infusion being
 rejected.

 Cord Blood Infusion:

 After your chemotherapy treatment, and total body irradiation (only for Group 2), your cord
 blood unit will be thawed. The larger portion of the cord blood will be infused through your
 CVC. A small portion of the cells will be expanded as described below.

 Expansion of Cord Blood T Cells:

 On Day 0, the smaller unit of your cord blood will be treated at the M. D. Anderson Stem Cell
 Laboratory with IL-2 and vitamin-like growth factors to produce the needed T cells. At this
 time, clinical beads will be used to help separate and expand the T cells. This will take 2
 weeks. On Day 14, you will then be given the treated cord blood as an infusion through your
 CVC.

 Infusion of Back-Up Cells:

 In case the stem cell transplant is rejected by your immune system, and if researchers were
 unable to collect a sample of your own stem cells, an unrelated donor or a second cord
 transplant will be used. The cord blood will be treated using a CliniMACs processing device.
 Mouse protein antibodies are used in CliniMACs processing procedures. Recipients who have
 pre-existing immunity to these proteins may be at risk for allergic reactions during the
 infusion of the processed cells. Epinephrine and antihistamines will be available at the
 recipient's bedside during the peripheral blood progenitor cell (PBSC) infusion to help treat
 any allergic reactions.

 Graft Versus Host Disease (GVHD) Preventive Therapy:

 GVHD may result from the transplanted cord blood cells reacting against certain tissues in
 your body. In an attempt to prevent or decrease the severity of GVHD, you will receive 2
 drugs (MMF and tacrolimus).

 Mycophenolate mofetil (MMF) pills will be given starting 3 days before your cord blood
 transplant, and will be continued until Day 100 after the transplant. If you cannot take
 pills, the drug can be given through your CVC. If you develop GVHD, you may have to continue
 to take MMF after Day 100.

 Tacrolimus will be given 2 days before your transplant as a 24 hour continuous infusion for
 several weeks. After you have the stem cell transplant and are able to eat and drink,
 tacrolimus will be given by mouth 2 times a day for up to 6 months. The number of tacrolimus
 pills may vary depending on the levels of the drug in the blood, but usually you will be
 given between 1-3 pills each time. If you are not able to swallow pills, a liquid form of
 this drug is available. This drug is used for about 6-9 months or longer if chronic GVHD
 occurs.

 Length of Study:

 You will be monitored closely for the first 100 days after receiving the transplant and then
 periodically after that. You may remain on study as long as the disease does not return and
 you do not experience any intolerable side effects. Your participation in this clinical trial
 may be ended at any time for any reason.

 Follow-Up Visits After Transplant:

 After you leave the hospital, you will come back for regular visits in the clinic at M. D.
 Anderson. How often you have follow-up visits may vary, but may be as often as daily.

 Blood (about 1-2 tablespoons) will be collected for routine tests. The number of blood and/or
 urine tests may also vary, but they may be performed daily.

 You will have a bone marrow aspirate collected before the transplant, about 30 days after the
 transplant, and then every 3 months for the first year after the transplant. After that, bone
 marrow samples will be collected 1 time a year for as long as the doctor thinks is necessary.
 To collect a bone marrow biopsy, an area of the bone is numbed with anaesthetic and a small
 amount of bone marrow is withdrawn through a large needle.

 Patients with lymphomas and Hodgkin's disease will need CT scans of the chest, abdomen, and
 pelvis performed within 30 days before the transplant, about 100 days after transplant, and
 then about every 3 months for the first year. After that, it will be done 1 time every year
 for as long as the doctor thinks it is necessary.

 This is an investigational study. The clinical beads that will be used for this study may be
 produced by either the University of Pennsylvania or Invitrogen Corporation. All of the study
 drugs are all FDA approved and commercially available for treatment in adults. These drugs
 alone or in any combination are not FDA approved for this treatment in children and their use
 in this study is considered to be experimental.

 The CliniMACS processing device used to process the cells for backup infusion is not FDA
 approved for this use.

 Up to 18 patients will take part in this study. All will be enrolled at M. D. Anderson.
Inclusion Criteria:

 1. Patient must have one of the following hematologic malignancies:

 -  AML

 -  ALL

 -  CML

 -  NHL

 -  HD, or

 -  CLL (Select from Criteria #2 through #7)

 2. Acute Myelogenous Leukemia (AML), Myelodysplastic Syndrome (MDS; Myelodysplastic
 syndromes with International Prognostic Scoring System score >2 or myelodysplasia that
 has not responded to chemotherapy): induction failure, high-risk for relapse 1st
 remission (with high-risk cytogenetics or FLT3 mutation), 2nd or 3rd complete
 remission, or 2nd relapse with less than 10% blasts in the bone marrow and/or
 peripheral blood.

 3. Acute Lymphoblastic Leukemia (ALL): induction failure, 1st complete remission with
 Philadelphia chromosome or translocation, 2nd or 3rd complete remission, or 2nd
 relapse with less than 10% blasts in the bone marrow and/or peripheral blood.

 4. Chronic Myelogenous Leukemia (CML) second chronic phase, accelerated phase or blast
 crisis with less than 10% blasts in the bone marrow and/or peripheral blood and
 failure of at least one tyrosine kinase inhibitor.

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

 6. Hodgkin's Disease (HD): Induction failures, second or third complete remission, or
 relapse (including relapse post autologous hematopoietic stem cell transplant).

 7. Chronic Lymphocytic Leukemia (CLL): Failure of one multi-agent regimen including
 fludarabine or other nucleoside analog

 8. Patient's Age Criteria: Age >/= 6 months and </= 55 years

 9. Performance score of < 3 (Zubrod score).

 10. Adequate major organ system function as demonstrated by: (SEE CRITERIA #11 through
 #14)

 11. Left ventricular ejection function of >/= 50%.

 12. Pulmonary function test demonstrating a diffusion capacity of at least 50% predicted.
 If unable to perform pulmonary function test (most children <6 years of age), pulse
 oximetry >/= 92% on room air.

 13. Creatinine </= 1.6 mg/dL in adults and </=2 times upper limit of normal in pediatric
 patients.

 14. SGPT/bilirubin </= 3.0 x normal.

 15. Signed informed consent.

 16. Negative Beta HCG or urine test in females of childbearing potential defined as not
 post-menopausal for 12 months or no previous surgical sterilization and willing to use
 an effective contraceptive measure while on the study.

 17. Cord Blood Requirements: Unrelated CB will be used as a source of hematopoietic
 support if a 5/6 or 6/6 related or 6/6 unrelated bone marrow donor is not available,
 or if the tempo of the patient's disease dictates it is not in the patient's best
 interest to wait for an unrelated marrow donor to be procured. The back up cord blood
 unit must match at 4 of 6 HLA.

 18. An unrelated donor, second cord blood transplant, or autologous stem cells harvested
 prior to high-dose chemotherapy will be used in the event of graft failure. Based on
 the health status of the patient, autologous harvest may or may not occur. To be
 determined by the treating physician. The cord blood unit will be identified prior to
 enrollment in this study.

 Exclusion Criteria:

 1. HIV positive (due to the extreme immunosuppressive nature of allogeneic stem cell
 transplant)

 2. Patient with active (untreated) CNS disease

 3. Availability of an appropriate, willing, HLA-matched related marrow donor

 4. Active invasive infections.

 5. Pregnant or breast-feeding