Stem Cell Transplantation and T-Cell Add-Back to Treat Bone Marrow Malignancies
Condition: Hematologic Malignancies; Bone Marrow Transplant Rejection
MeSH terms: Neoplasms; Hematologic Neoplasms
Intervention: allogeneic hematopoietic stem cell transplantation
Intervention description: Manipulated Peripheral Blood Stem Cell graft on Day 0. Target CD34+ dose 6 x10e6/kg, (range 3 to 8x10e6/kg) CD3+ dose fixed to 2 x 10e4/kg.
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 50.0
Sex: All
Minimum age: 2 Years
Maximum age: 80 Years
Healthy volunteers: No
Keywords: Chronic Myelogenous Leukemia (CML); Acute Lymphoblastic Leukemia (ALL); Acute Myelogenous Leukemia (AML); Chronic Lymphocytic Leukemia (CLL); Myelodysplastic Syndromes (MDS); Peripheral Blood Stem Cells; Graft-Versus Leukemia/Myeloma; Graft-Versus-Host Disease (GVHD); Cyclosporine; Fludarabine; Leukemia; Myelodysplastic Syndrome; Myeloproliferative Syndrome; Non-Hodgkin Lymphoma

Summary:

      This study will evaluate the safety and effectiveness of stem cell transplantation in which
      the donor's T cells (a type of lymphocyte, or white blood cell) are removed and then added
      back. Certain patients with bone marrow malignancies undergo transplantation of donated stem
      cells to generate new and normally functioning bone marrow. However, T-cells from the donor
      may see the patient's cells as foreign and mount an immune response to reject them, causing
      what is called "graft-versus-host-disease" (GVHD). Therefore, in this protocol, T-cells are
      removed from the donor cells to prevent this complication. However, because T-cells are
      important in fighting viral infections as well as any remaining malignant cells (called
      graft-versus-leukemia effect), the donor T-cells are given to the patient (added back) at a
      later time after the transplant when they can provide needed immunity with less risk of
      causing GVHD.

      Patients between 10 and 55 years of age with acute or chronic leukemia, myelodysplastic
      syndrome, or myeloproliferative syndrome may be eligible for this study. Prospective
      participants and their donors are screened with a medical history and physical examination,
      blood tests (including a test to match for genetic compatibility), breathing tests, chest and
      sinus x-rays, and tests of heart function. They also undergo a bone marrow biopsy and
      aspiration. For this procedure, done under local anesthetic, about a tablespoon of bone
      marrow is withdrawn through a needle inserted into the hipbone.

      They undergo apheresis to collect lymphocytes for research studies. This procedure involves
      collecting blood through a needle in the arm, similar to donating a unit of blood. The
      lymphocytes are then separated and removed by a cell separator machine, and the rest of the
      blood is returned through a needle in the other arm.

      Before treatment begins, patients have a central intravenous line (flexible plastic tube)
      placed in a vein in the chest. This line remains in place during the stem cell transplant and
      recovery period for drawing and transfusing blood, giving medications, and infusing the
      donated cells. Preparation for the transfusion includes high-dose radiation and chemotherapy.
      Patients undergo total body irradiation in 8 doses given in two 30-minute sessions a day for
      4 days. Eight days before the transplant, they begin taking fludarabine, and 3 days before
      the procedure they start cyclophosphamide.
    

Eligibility criteria:

        INCLUSION CRITERIA:

        RECIPIENT:

          -  1. Ages 10-55 years inclusive (but less than 56)

          -  2. Chronic myelogenous leukemia (CML) in chronic phase

          -  3. Acute lymphoblastic leukemia (ALL) categories

               1. Adults in first remission with high-risk features

               2. All second or subsequent remissions, primary induction failure, partially
                  responding or untreated relapse

          -  4. Acute myelogenous leukemia (AML)

               1. AML in first remission Except AML with good risk karyotypes

               2. All AML in second or subsequent remission, primary induction failure and
                  resistant relapse

          -  5. Myelodysplastic syndromes categories

               1. refractory anemia with transfusion dependence

               2. refractory anemia with excess of blasts

               3. transformation to acute leukemia, chronic myelomonocytic leukemia

          -  6. Myeloproliferative disorders in transformation to acute leukemia

          -  7. Chronic lymphocytic leukemia refractory to fludarabine treatment and with bulky
             progressive disease or with thrombocytopenia (less than or equal to 100,000 /micro L)
             or anemia (less than or equal to 10g/dl) not due to recent chemotherapy

          -  8. Non-Hodgkin's lymphoma including Mantle cell lymphoma relapsing or refractory to
             current chemotherapy and monoclonal antibody treatment and unsuitable for autologous
             stem cell transplantation

          -  9. No major organ dysfunction precluding transplantation

          -  10. Diffusion capacity of lung for carbon monoxide (DLCO) greater than or equal to 60%
             predicted

          -  11. Left ventricular ejection fraction: greater than or equal to 40%

          -  12. Eastern Cooperative Oncology Group(ECOG) performance status of 0 or 1

          -  13. Able to give informed consent

          -  14. Negative pregnancy test for women of childbearing age

        INCLUSION CRITERIA:

        DONOR

          -  1. Human leukocyte antigen (HLA) 6/6 identical family donor

          -  2. Weight greater than or equal to 18 kg

          -  3. Age greater than or equal to 2 or less than or equal to 80 years old

          -  4. Fit to receive granulocyte colony -stimulating factor(G-CSF) and give peripheral
             blood stem cells (normal blood count, normotensive, no history of stroke)

        EXCLUSION CRITERIA:

        RECIPIENT

          -  1. Patient pregnant

          -  2. Age less than 10 years and 56 years or more

          -  3. Patients with CML in chronic phase who are 41 years or over in whom imatinib
             mesylate (STI-571)is the treatment of choice

          -  4. ECOG performance status of 2 or more

          -  5. Severe psychiatric illness

          -  6. Major anticipated illness or organ failure incompatible with survival from BMT

          -  7. DLCO less than 60% predicted

          -  8. Left ventricular ejection fraction: less than 40%

          -  9. Serum creatinine greater than 3mg/dl

          -  10. Serum bilirubin greater than 4 mg/dl

          -  11. HIV positive 12. Debilitation or age making the risk of intensive myeloablative
             therapy unacceptable

        EXCLUSION CRITERIA:

        DONOR

          -  1. Pregnant or lactating

          -  2. Donor unfit to receive G-CSF and undergo apheresis

          -  3. HIV positive

          -  4. Weight less than 18 kg

          -  5. Age less than 2 or greater than 80 years

          -  6. Severe psychiatric illness