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 For this procedure, done under local anesthetic, about a tablespoon of bone marrow is withdrawn through a needle inserted into the hipbone.

Participants have dental and eye examinations. 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. These are anti-cancer drugs that kill the cancer cells and prevent rejection of the donated cells. Patients with aggressive leukemia will also receive etoposide - a powerful anti-leukemic drug - 3 days before the transplant. While the patient is receiving chemotherapy, the donor receives daily injections for 5 days of G-CSF, a drug that moves stem cells from the bone marrow into the blood stream, and the white cells are then collected by apheresis. The day after chemotherapy is completed, the stem cells are infused into the patient through the central line.

Patients usually stay in the hospital about 4 weeks after the transplant to recover. Treatment with cyclosporine, an immune-suppressing drug that helps prevents both rejection of donated cells and GVHD, is given 6 days before the transplant until 21 days post-transplant. It is then stopped to allow the donor immunity to function and is resumed on day 59 post-transplant (1 day before the first T-cell add-back). Patients return to the clinic for follow-up with various tests, treatments and examinations as required, with a minimum of visits at least once or twice a week for 2 to 4 months after the transplant; then at 4, 6, 9, and 12 months, and then yearly for at least 5 years.

Condition	Treatment or Intervention	Phase
Leukemia Bone Marrow Transplantation	Device: Isolex 300i Magnetic Cell Selector	Phase II

Further Study Details: 

Expected Total Enrollment:  48

Bone marrow stem cell transplant studies carried out by the NHLBI BMT Unit have focused on approaches to optimize the stem cell and lymphocyte dose in order to improve transplant survival and increase the graft-versus-leukemia effect. The aim is to create the transplant conditions that permit rapid donor immune recovery without causing graft-versus-host disease (GVHD) by using reduced post-transplant immunosuppression in conjunction with a transplant depleted of T cells to a fixed low dose, below the threshold known to be associated with GVHD.

We have found that the outcome from transplant is improved by controlling the stem cell (CD34+ cell) and T lymphocyte (CD3+ cell) dose. We use the Nexell Isolex 300i system to obtain high CD34+ doses depleted of lymphocytes to a fixed CD3+ T cell dose of 2 x 104/kg. The use of the cell separator and the monoclonal antibodies is covered by IDE 8139. A persisting problem with these T cell depleted transplants has been the slow acquisition of full donor T cell engraftment (T cell chimerism). Two previous protocols have failed to increase the speed of donor T cell chimerism. Patients with mixed donor-recipient T cell populations are known to be at higher risk for late graft rejection and leukemic relapse after transplant. Therefore, the achievement of full donor chimerism remains an important therapeutic goal. In this study we will test whether cyclosporine given between day -6 and +21 after transplant can significantly improve day 30 T cell chimerism (the principle end-point). The study also will measure the incidence of acute and chronic GVHD, day 100 transplant related mortality, cytomegalovirus reactivation, relapse, and disease-free survival with appropriate safety stopping rules.

This protocol follows closely previous studies in this series. Three additional modifications will be made however: 1) The first T cell add-back will be delayed until day 60 (instead of day 45) so as to continue to allow a 45 day period without cyclosporine immunosuppression. 2) No day 100 T cell add-back will be given. (In previous studies many patients have, for protocol-defined reasons, not received the second transfusion and there is no evidence that it is required). 3) Patients with high-risk leukemias with a high relapse probability will receive an additional chemotherapy agent prior to transplant using etoposide (VP16) 60mg/kg to improve the chance of remaining in remission.

Genders Eligible for Study:  Both

Criteria

INCLUSION CRITERIA - RECIPIENT
Ages 10-55 years inclusive (but less than 56)
Chronic myelogenous leukemia in chronic phase
A) Patients not treated with STI 571 under the age of 41 (subject to regular DSMB review).
B) age limits as 5.1.1 patients in chronic phase who have failed treatment with STI-571,
C) age limits as 5.1.1 patients in accelerated phase or blast transformation.
Acute lymphoblastic leukemia, any of these categories: Adults (greater than 18 years) in first remission with high-risk features (presenting leukocyte count greater than100,000/cu mm, Karyotypes t9; 22, t4, t19, t11, biphenotypic leukemia) All second or subsequent remissions, primary induction failure, partially responding or untreated relapse.
Acute myelogenous leukemia (AML): AML in first remission Except AML with good risk karyotypes: AML M3 (t15; 17), AML M4Eo (inv 16), AML t (8; 21). All AML in second or subsequent remission, primary induction failure and resistant relapse
Myelodysplastic syndromes, any of these categories: refractory anemia with transfusion dependence, refractory anemia with excess of blasts, transformation to acute leukemia, chronic myelomonocytic leukemia
Myeloproliferative disorders (myelofibrosis, polycythemia vera, essential thrombocythemia ) in transformation to acute leukemia
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.
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.
No major organ dysfunction precluding transplantation
DLCO greater than or equal to 60% predicted
Left ventricular ejection fraction: greater than or equal to 40%
ECOG performance status of 0 or 1
For adults: Ability to comprehend the investigational nature of the study and provide informed consent. For minors: Written informed consent from one parent or guardian. Informed oral consent from minors: The process will be explained to the minor on a level of complexity appropriate for their age and ability to comprehend.
Negative pregnancy test for women of childbearing age
EXCLUSION CRITERIA - RECIPIENT (any of the following)
Patient pregnant
Age less than 10 years and 56 years or more
Patients with CML in chronic phase who are 41 years or over in whom STI 571 is the treatment of choice
ECOG performance status of 2 or more (See PBSCT Supportive Care Guidelines)
Severe psychiatric illness. Mental deficiency sufficiently severe as to make compliance with the BMT treatment unlikely, and making informed consent impossible.
Major anticipated illness or organ failure incompatible with survival from BMT
DLCO less than 60% predicted.
Left ventricular ejection fraction: less than 40%
Serum creatinine greater than 3mg/dl
Serum bilirubin greater than 4 mg/dl
HIV positive
Debilitation or age making the risk of intensive myeloablative therapy unacceptable
INCLUSION CRITERIA - DONOR
HLA 6/6 identical family donor
Weight greater than or equal to 18 kg
Age greater than or equal to 2 or less than or equal to 80 years old
Fit to receive G-CSF and give peripheral blood stem cells (normal blood count, normotensive, no history of stroke)
For adults: Ability to comprehend the investigational nature of the study and provide informed consent. For minors: Written informed consent from one parent or guardian and informed assent: The process will be explained to t he minor on a level of complexity appropriate for their age and ability to comprehend.
EXCLUSION CRITERIA - DONOR (any of the following)
Pregnant or lactating
Donor unfit to receive G-CSF and undergo apheresis. (Uncontrolled hypertension, history of congestive heart failure or unstable angina, thrombocytopenia)
HIV positive. Donors who are positive for HBV, HCV or HTLV-1 may be used if the risk-benefit ratio is considered acceptable by the patient and investigator.
Weight less than 18 kg
Age less than 2 or greater than 80 years
Severe psychiatric illness. Mental deficiency sufficiently severe as to make compliance with the BMT treatment unlikely, and making informed consent impossible

Maryland
      National Heart, Lung and Blood Institute (NHLBI), 9000 Rockville Pike,  Bethesda,  Maryland,  20892,  United States; Recruiting

Study ID Numbers:  040112; 04-H-0112
Record last reviewed:  January 5, 2005
Last Updated:  January 10, 2005
Record first received:  February 2, 2004
ClinicalTrials.gov Identifier:  NCT00076778
Health Authority: United States: Federal Government
ClinicalTrials.gov processed this record on 2005-04-08