Protocol Number: 01-H-0162

Title:

Ex Vivo Selective Depletion of Alloreactive Donor T-Lymphocytes Utilizing RFT5-SMPT-dgA, a Specific Anti-Interleukin-2 Receptor Immunotoxin: Reducing GVHD Risk Associated with HLA-Matched Nonmyeloablative Peripheral Blood Stem Cell Transplantation

Number:

01-H-0162

Summary:

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 They will also have a bone marrow biopsy and aspiration, in which about a tablespoon of bone marrow will be withdrawn through a needle inserted into the hipbone.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.

Sponsoring Institute:

National Heart, Lung and Blood Institute (NHLBI)

Recruitment Detail

Type: Active Accrual Of New Subjects

Gender: Male & Female

Referral Letter Required: No

Population Exclusion(s): Children

Eligibility 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 ad 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 smoke, no history of severe heart disease).

Ability to comprehend the investigational nature of the study ad 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% any angina.

Absolute lymphocyte count less than 1500/mm(3).

Serum creatinine greater than 2.5 mg/dl.

Serum bilirubin greater than 4 mg/dl and transaminases must not be greater than 5x upper limit of normal.

HIV positive.

Other malignant diseases liable to relapse or progress within 2 years.

EXCLUSION CRITERIA:

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 receipient.

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).

Special Instructions: Currently Not Provided

Keywords:

Peripheral Blood Stem Cell

Melphalan

Fludarabine

Donor Apheresis

Non-Myeloablative

MDS

Chronic Myeloid Leukemia

CML

Chronic Lymphocytic Leukemia

CLL

Recruitment Keywords:

Lymphoma

Non-Hodgkin's Lymphoma

Hodgkin's Disease

Mantle Cell Lymphoma

Acute Myelogenous Leukemia (AML)

Chronic Myeloid Leukemia (CML)

Chronic Lymphocytic Leukemia (CLL)

Myelodysplasia (MDS)

Acute Lymphoblastic Leukemia (ALL)

Bone Marrow Transplant

Conditions:

Graft vs Host Disease

Myelodysplastic Syndromes

Leukemia

Leukemia, Myeloid

Leukemia, Myelomonocytic, chronic

Leukemia, Lymphocytyc

Lymphoma

Lymphoma, Mantle-cell

Lymphoma, Non-Hodgkin

Hodgkin Disease

Investigational Drug(s):

dgA-SMPT-RFT5

Investigational Device(s):

None

Contacts:

Patient Recruitment and Public Liaison Office
Building 61
10 Cloister Court
Bethesda, Maryland 20892-4754
Toll Free: 1-800-411-1222
TTY: 301-594-9774 (local),1-866-411-1010 (toll free)
Fax: 301-480-9793

Electronic Mail:prpl@mail.cc.nih.gov

Citations:

Graft-versus-leukemia effect of donor lymphocyte transfusions in marrow grafted patients European Group for Blood and Marrow Transplantation Working Party Chronic Leukemia

Graft-versus-leukemia reactions after bone marrow transplantation

Adoptive immunotherapy evaluating escalating doses of donor leukocytes for relapse of chronic myeloid leukemiaafter bone marrow transplantation: separation of graft-versus-leukemia responses from graft-versus-host disease

• Questions about participating in a study, please contact the Patient Recruitment and Public Liaison Office, CC.
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