Expired Study
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Bethesda, Maryland 20892


Purpose:

This study will evaluate the safety and effectiveness of stem cell transplantation in which the donors T lymphocytes (a type of white cell) have undergone "selective depletion." Certain patients with cancers of the blood undergo transplantation of donated stem cells (cells produced by the bone marrow that mature into the different blood components-white cells, red cells and platelets) to generate new and normally functioning bone marrow. In addition to producing the new bone marrow, the donor's T-lymphocytes also fight any tumor cells that might have remained in the body. This attack on tumor cells is called a "graft-versus-leukemia" (GVL) effect. However, another type of T-lymphocyte from the donor may cause what is called "graft-versus-host-disease" (GVHD), in which the donor cells recognize the patient's cells as foreign and mount an immune response to reject them. Selective depletion is a technique that was developed to remove the T-lymphocytes that cause harmful GVHD, while keeping those that produce the desirable GVL effect. Patients with leukemia, lymphoma or a myelodysplastic syndrome (pre-cancerous blood disorder) between 55 and 75 years of age may be eligible for this 4-year study. Candidates will be screened with a medical history and physical examination, dental and eye examinations, blood tests (including HLA typing for genetic compatibility with the donor), stress test, echocardiogram, 24-hour electrocardiogram (EKG), breathing test and chest and sinus X-rays. They will also have a bone marrow biopsy and aspiration, in which about a tablespoon of bone marrow will be withdrawn through a needle inserted into the hipbone. This procedure is done under local anesthetic. Participants will undergo apheresis to collect lymphocytes to test for interactions between the patient's and donor's white cells. In this procedure, blood is drawn through a needle in the arm, similar to donating a unit of blood. The lymphocytes are then separated by a cell separator machine and collected, and the rest of the blood is returned through a needle in the other arm. Patients will also have a central venous catheter (flexible plastic tube) placed in a vein before treatment begins. This line will remain in place during the stem cell transfusion and recovery period to draw and transfuse blood, give medications, and to infuse the donated cells. Seven days before the transfusion, patients will begin chemotherapy with cyclophosphamide and will start taking fludarabine 5 days before the procedure. These anti-cancer agents are given to kill the cancer cells and to prevent rejection of the donated cells. The day after chemotherapy is completed, the stem cells will be infused through the central line. Also, from 4 days before the transplantation until about 3 months after the procedure, patients will receive cyclosporine to help prevent both GVHD and rejection of the donated cells. Usually patients may be discharged from the hospital about 3 weeks after the transplant. They will return for follow-up clinic visits weekly or twice weekly for 3 months for a symptom check, physical examination and blood tests. Blood transfusions will be given if needed. Subsequent visits will be scheduled at 4, 6, 12, 18, 24, 30, 36 and 48 months after the transplant, or more often if required, and then yearly.


Study summary:

Despite improved prophylaxis and treatment, graft-versus-host disease (GVHD) remains a major complication after allogeneic stem cell transplantation. Although the most effective way to prevent GVHD is T cell depletion, this process results in poor immune function leading to increased rates of relapse, graft rejection, and post-transplant infections. Ideally, a method of removing GVHD-producing effector cells while retaining a broad T cell repertoire, including preservation of third party, antiviral and anti-tumor responses would be desirable. Preclinical studies from our lab have demonstrated that alloreactive T cells can be selectively removed from the donor lymphocyte pool in vitro with the use of a specific immunotoxin directed against the interleukin-2 (IL-2) receptor. To test this in a clinical setting, we will perform nonmyeloablative allogeneic stem cell transplants in older patients with hematologic malignancies. Although these patients can be cured with this approach, they have significant morbidity and mortality from GVHD. At our institution, nonmyeloablative transplantation is associated with an incidence of grade II-IV acute GVHD of approximately 50%. Although well tolerated in younger patients, patients over the age of 50 years have a transplant-related mortality (TRM) of approximately 35%, which is mostly related to GVHD. Through selective depletion of alloreactive donor lymphocytes, we hope to reduce mortality from GVHD, while preserving the efficacy of the transplant. Patients receive a reduced intensity preparative regimen, followed by a mobilized peripheral blood stem cell (PBSC) allograft from an HLA-identical sibling donor, containing "selectively-depleted" donor lymphocytes. To obtain such a graft, G-CSF-mobilized peripheral blood from the donor undergoes a positive CD34 selection followed by a negative T cell selection using the Nexell Isolex 300i system. This stem cell-rich, T cell-depleted product will contain a CD34+ cell dose of at least 5x10(6)/kg. The unabsorbed fraction, remaining after the positive CD34 selection, is then co-cultured for 72 hours with irradiated lymphocytes from the patient. The immunotoxin, RFT5-SMPT-dgA, is added during the last 24 hours of culture to remove alloreacting cells. The washed T cell product (CD3+ cell dose of 1-4 x 10(8)/kg) is cryopreserved. Following the preparative regimen, the patient receives successive infusions of the stem cell product and selected lymphocytes. All patients receive standard post transplant immunosuppression with cyclosporine for a minimum of 30 days, followed by dose reduction depending on the degree of donor lymphocyte chimerism. The primary end point of this study is the incidence and severity of acute GVHD. We will also examine the incidence of chronic GVHD, engraftment, degree of donor-host chimerism, transplant related morbidity and mortality, as well as disease-free and overall survival. Stopping rules will minimize the risk of untoward or unexpected side effects.


Criteria:

- INCLUSION CRITERIA - PATIENT Ages 50-75 years. Diseases to be included: Relapsed CML in chronic or accelerated phase after therapy with STI-571 (Gleevec). Acute lymphoblastic leukemia (ALL), all patients in complete or partial remission. Exceptions: T cell ALL. Acute myelogenous leukemia (AML): AML in first complete or partial remission including AML secondary to chemotherapy or prior hematological disease such as myelodysplastic syndrome, and myeloproliferative disorder. Exceptions: AML with good risk karyotypes: AML M3 t(5;17), AML M4Eo (inv. 16), AML t(8;21). All AML in second or subsequent complete remission. Myelodysplastic syndromes: (1) refractory anemia with excess of blasts (RAEB), (2) refractory anemia with excess blasts in transformation (RAEBT), (3) MDS with poor risk cytogenetics defined by a complex karyotype (greater than or equal to three anomalies) or chromosome 7 abnormalities, (4) secondary MDS after prior cytotoxic or radiation therapy, or (5) chronic myelomonocytic leukemia (CMML). Chronic lymphocytic leukemia (CLL) and prolymphocytic leukemia, refractory to nucleoside analog therapy, with either progressive bulky disease or anemia (less than 10 g/dl) or thrombocytopenia (less than 100,000/microliter) not due to recent chemotherapy. Mantle cell lymphoma; Relapsed intermediate- or high-grade non-Hodgkin's lymphoma: (1) post autologous marrow or PBSC transplant, or (2) chemorefractory relapse. Exceptions: T cell NHL. Relapse Hodgkin's disease: (1) post autologous marrow or PBSC transplant, or (2) chemorefractory relapse. Low-grade follicular or small lymphocytic lymphoma: (1) relapsed following conventional chemotherapy, (2) relapsed following autologous marrow or PBSC transplant, or (3) chemoresistant disease. Life expectancy greater than 3 months. Ability to comprehend the investigational nature of the study and provide informed consent. Availability of an HLA-identical family donor, 18 to 75 years old. INCLUSION CRITERIA - DONOR: HLA identical family donor, 18 to 75 years old. Fit to receive G-CSF and give peripheral blood stem cells (normal blood count, normotensive, no history of stroke, no history of severe heart disease). Ability to comprehend the investigational nature of the study and provide informed consent. EXCLUSION CRITERIA - RECIPIENT: Pregnant or lactating. ECOG performance status of 3 or more. Major anticipated illness or organ failure incompatible with survival from PBSC transplant. DLCO less than 60% predicted. Left ventricular ejection fraction less than 40%, or any angina. Absolute lymphocyte count less than 300/mm(3). Serum creatinine greater than 2.5 mg/dl. Serum bilirubin greater than 4 mg/dl, transaminases greater than 5x upper limit of normal. HIV positive. Other malignant diseases liable to relapse or progress within 2 years. EXCLUSION CRITERIA DONOR: Pregnant or lactating. HIV positive. Donors who are positive for HBV, HCV or HTLV will be used at the discretion of the investigator and with appropriate consent of the recipient. Donor unfit to receive G-CSF and undergo apheresis (uncontrolled hypertension, history of heart failure or unstable angina, platelet count less than 90,000/cu mm).


NCT ID:

NCT00025662


Primary Contact:

N/A


Backup Contact:

N/A


Location Contact:

Bethesda, Maryland 20892
United States



There is no listed contact information for this specific location.

Site Status: N/A


Data Source: ClinicalTrials.gov

Date Processed: September 19, 2017

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