Patient case: 13-year-old male with acute myeloid leukemia; genetic feature: FLT3

Clinical trial: Cord Blood (CB) Ex-vivo Mesenchymal Stem Cell (MSC) Expansion + Fucosylation

Summary: The goal of this clinical research study is to learn if giving 1 unit of expanded cord blood combined with 1 unit of non-expanded cord blood to a patient with leukemia or lymphoma can help the transplant to "take" faster. The safety of this combination will also be studied. Chemotherapy and/or 1 dose of radiation therapy will also be given before the transplant.

Detailed description: Study Plans:
  If participant agrees to take part in this study, a back-up source of cord blood will be chosen for participant. This blood will be reserved through the National Marrow Donor Program and placed on hold in case it is needed quickly for an emergency. The blood will be placed on hold until the study doctor decides that the transplant has been successful.
  Once the back-up cord blood is collected, participant will be admitted to the hospital to follow participant's assigned schedule for the study treatment.
  Participant's doctor will choose one of the following 3 study plans based on the disease, participants's age, and participant's medical history.
  Plan 1: Fludarabine/Clofarabine/Busulfan/Rituximab/Total Body Irradiation:
  If participant is between 1 and 55 years of age and can receive high-dose chemotherapy, or if participant is between 55 and 65 years old and participant's doctor agrees, participant will receive fludarabine, clofarabine, busulfan, antithymocyte globulin (ATG), total body irradiation, and possibly rituximab.
  Please note Day 0 is the day of the cord blood transplant, so the negative day numbers are used to label the treatment days before the transplant.
  Participant will receive a test dose of busulfan by vein over about 60 minutes as an outpatient. If the test dose cannot be given as an outpatient, participant will be admitted to the hospital on Day -11 (11 days before participant's transplant) to receive fluids by vein and will receive the busulfan test dose on Day -10. This low-level "test" dose of busulfan is to check how the level of busulfan in participant's blood changes over time. This information will be used to decide the next dose needed to reach the target blood level that matches participant's body size.
  About 11 samples of blood will be drawn for pharmacokinetic (PK) testing of busulfan. PK testing measures the amount of study drug in the body at different time points. These blood samples will be drawn at various timepoints starting before the busulfan infusion and continuing over about the next 11 hours. The blood samples will be repeated again with the first day of high-dose busulfan treatment. Each sample will be about 1 teaspoon of blood. A temporary heparin lock will be placed in participants's vein to lower the number of needle sticks needed for these draws. If it is not possible for the PK tests to be performed for technical or scheduling reasons, participant will receive the standard fixed dose of busulfan.
  If participant will receive the test dose as an outpatient, participant will be admitted to the hospital on Day -10 and will receive fluids by vein. If participant's doctor thinks it is appropriate for the disease, participant will receive rituximab by vein over about 4-6 hours on Day -10.
  If participant will receive the test dose as an inpatient, participant will be admitted to the hospital on Day -11 and will receive fluids by vein. If appropriate for the disease, participant will receive rituximab by vein over about 4-6 hours on Day -11.
  Participant will receive ATG by vein over about 4 hours on Days -9 and -8. ATG is designed to weaken participant's immune system in order to lower the risk that participant's body will reject the transplant.
  On Days -7 through -4, participant will receive fludarabine by vein over about 1 hour, clofarabine by vein over about 1 hour, and busulfan by vein over about 3 hours.
  On Day -3, participant will receive a single treatment of low-dose total body irradiation.
  Participant will rest (not receive chemotherapy drugs) on Days -2 and -1.
  On Day 0, participant will receive participant's cord blood transplant through the CVC.
  Plan 2: Fludarabine/Melphalan:
  If participant's doctor chooses fludarabine and melphalan, participant will have the following schedule:
  On Day -9, participant will be admitted to the hospital and will receive fluids by vein.
  On Days -8 and -7, participant will receive ATG by vein over about 4 hours.
  On Day -6, participant will not receive any drugs.
  On Days -5, -4, and -3, participant will receive fludarabine by vein over about 30 minutes.
  On Day -2, participant will receive fludarabine by vein over about 30 minutes and melphalan by vein over about 30 minutes.
  On Day -1, participant will not receive any drugs.
  On Day 0, participant will receive participant's cord blood transplant through the CVC.
  Plan 3: Fludarabine/Cyclophosphamide/Total Body Irradiation:
  If participant's doctor chooses fludarabine, cyclophosphamide, and total body irradiation, participant will have the following schedule:
  On Day -9, participant will be admitted to the hospital and will receive fluids by vein.
  On Days -8 and -7, participant will receive ATG by vein over about 4 hours.
  On Day -6, participant will receive fludarabine by vein over about 30 minutes and cyclophosphamide by vein over about 1 hour. Participant will also receive mesna by vein over 30 minutes each time, before and after the cyclophosphamide dose. Mesna is given to lower the risk of side effects to the bladder caused by cyclophosphamide.
  On Days -5, -4, and -3, participant will receive fludarabine by vein over about 30 minutes.
  On Day -2, participant will not receive any drugs.
  On Day -1, participant will receive a single treatment of low-dose total body irradiation.
  On Day 0, participant will receive participant's cord blood transplant through the CVC.
  Supportive Drugs:
  Starting on Day -3, participant will receive MMF as a tablet by mouth 2 times a day. If participant is not able to take the tablet by mouth, participant will receive MMF by vein over 2 hours 2 times a day. If participant does not have graft-versus-host disease (GVHD) at Day 100 after participant's cord blood transplant, the dose of MMF will be gradually lowered. GVHD is when transplanted donor tissue attacks the tissues of the recipient's body. If participant has GVHD, MMF may be stopped 7 days after the GVHD is controlled.
  Starting on Day -2, participant will receive tacrolimus by vein as a continuous (nonstop) infusion until participant is able to take it by mouth. Participant will then take tacrolimus by mouth 2 times a day for about 6 months. After that, participant's tacrolimus dose may be gradually lowered if participant does not have GVHD. Participant's doctor will discuss this with participant.
  Starting on Day 0, participant will receive filgrastim (G-CSF) through a needle under the skin 1 time a day every day until participant's white blood count begins to recover. Nurses will teach participant and a caregiver how to perform the injections on participant's own. Filgrastim is designed to help cells in the bone marrow to divide, which helps raise white blood cell counts more quickly, lowers fever, and decreases the risk of infection.
  Length of Study:
  Participant will be on study for up to 1 year. Participant will be taken off study early if the disease gets worse, if intolerable side effects occur, if the cord blood is infected and cannot be transplanted, if participant is unable to follow study directions, or if participant's doctor thinks it is in participant's best interest.
  Participation on the study will be over after the last study visit.
  Study Visits:
  At about 1, 3, 6, and 12 months after the transplant:
  -  Participant will have a physical exam.
  -  Participant will be checked for possible reactions to the transplant and study drugs, including GVHD.
  -  Blood (about 4 teaspoons) will be drawn for routine tests, to check for infection, and for genetic tests to learn if the donor's cells have "taken". Urine will be collected for routine tests. The routine blood tests and urine collection for routine tests will be repeated as often as the doctor thinks is needed.
  -  If the doctor thinks it is needed, participant will have a bone marrow aspiration to check the status of the disease. To collect a bone marrow aspirate, an area of the hip or other site is numbed with anesthetic, and a small amount of bone marrow is withdrawn through a large needle.
  Participant will need to stay in the hospital for about 4 weeks. After participant leaves the hospital, participant will continue as an outpatient in the hospital area, which means participant will have to stay close enough to be able to come back for any visits for about 100 days after the transplant.
  This is an investigational study. Adding sugar to cord blood cells is not an FDA-approved process. It is currently being used for research purposes only. Fludarabine, busulfan, clofarabine, melphalan, mycophenolate mofetil (MMF), tacrolimus, and rituximab are FDA approved and commercially available to be given to patients with leukemia or lymphoma having a cord blood transplant. Total body irradiation is delivered using FDA-approved and commercially available methods. The study doctor can explain how the study treatments are designed to work.
  Up to 25 participants will be enrolled in this study. All will take part at MD Anderson.

Eligibility: Inclusion Criteria:
  1. Patients must have one of the following hematologic malignancies: a. Acute Myelogenous Leukemia (AML), induction failure, high-risk for relapse first remission (with intermediate-risk or high-risk cytogenetics, flt3 mutation positive and/or evidence of minimal residual disease by flow cytometry), secondary leukemia from prior chemotherapy and/or arising from MDS, Langerhan's cell histiocytosis, any disease beyond first remission.
  2. Myelodysplastic Syndrome (MDS): Primary or therapy related.
  3. Acute Lymphoblastic Leukemia (ALL): induction failure, primary refractory to treatment (do not achieve complete remission after first course of therapy) or are beyond first remission including second or greater remission or active disease. Patients in first remission are eligible if they are considered high risk, defined as any of the following detected at any time: with translocations 9;22 or 4;11, hypodiploidy, complex karyotype, secondary leukemia developing after cytotoxic drug exposure, and/or evidence of minimal residual disease, or acute biphenotypic leukemia, or double hit non-Hodgkin's lymphoma.
  4. Non-Hodgkin's Lymphoma (NHL) in primary induction failure, second or third complete remission, refractory disease, or relapse (including relapse post autologous hematopoietic stem cell transplant). Double hit lymphomas in first remission or more advanced disease.
  5. Small Lymphocytic Lymphoma (SLL), or Chronic Lymphocytic Leukemia (CLL) with progressive disease following standard therapy.
  6. CML second chronic phase or accelerated phase.
  7. Hodgkin's Disease (HD): Induction failures, second or third complete remission, or relapse (including relapse post autologous hematopoietic stem cell transplant).
  8. Patients Age Criteria: Age >/= 1 and </= 65 years old. Eligibility for pediatric patients will be determined in conjunction with an MDACC pediatrician.
  9. Performance score of at least 80% by Karnofsky or PS < 3 (ECOG) (age >/= 12 years), or Lansky Play-Performance Scale of at least 60% or greater (age < 12 years).
  10. Adequate major organ system function as demonstrated by: a. Left ventricular ejection fraction of > 40%; b. Pulmonary function test (PFT) demonstrating a diffusion capacity of least 50% predicted. For children </= 7 years of age who are unable to perform PFT, oxygen saturation >/= 92% on room air by pulse oximetry; c. Creatinine < 1.6 mg/dL; d. SGPT/bilirubin </= to 2.0 x normal.
  11. Negative Beta HCG test in a woman with child bearing potential defined as not post-menopausal for 12 months or no previous surgical sterilization and willing to use an effective contraceptive measure while on study.
  12. Patients must have two CB units available which are matched with the patient at 4, 5, or 6/6 HLA class I (serological) and II (molecular) antigens. Each cord must contain at least 1.5 x 10^7 total nucleated cells/Kg recipient body weight (pre-thaw).
  13. Have identified a back up cells source in case of engraftment failure. The source can be autologous, related or unrelated.
  Exclusion Criteria:
  1. Patients with known history of HIV/AIDS.
  2. Active CNS disease in patient with history of CNS malignancy.
  3. Patients with chronic active hepatitis or cirrhosis. If positive hepatitis serology, the Study Chair may deem the patient eligible based on the results of liver biopsy.
  4. Patients with uncontrolled serious medical condition such as persistent septicemia despite adequate antibiotic therapy, decompensated congestive heart failure despite cardiac medications or pulmonary insufficiency requiring intubation (excluding primary disease for which CB transplantation is proposed), or psychiatric condition that would limit informed consent.
  5. Positive beta HCG in female of child-bearing potential defined as not post-menopausal for 12 months or no previous surgical sterilization or breast-feeding.

Relevance to patient case: not relevant