Protocol Number: 04-H-0112

Title:

Peripheral Blood Mobilized Hematopoietic Precursor Cell Transplantation Followed by T Cell Add-Back for Hematological Malignancies - Effect of Peritransplant Cyclosporine on Chimerism

Number:

04-H-0112

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 For this procedure, done under local anesthetic, about a tablespoon of bone marrow is withdrawn through a needle inserted into the hipbone.

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.

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): None

Eligibility 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

Special Instructions: Currently Not Provided

Keywords:

Chronic Myelogenous Leukemia

Acute Lymphoblastic Leukemia

Acute Myelogenous Leukemia (AML)

Chronic Lymphocytic Leukemia

Myelodysplastic Syndromes

Peripheral Blood Stem Cells

Graft-Versus Leukemia/Myeloma

Graft-Versus-Host Disease

Cyclosporine

Fludarabine

Recruitment Keywords:

Leukemia

Myelodysplastic Syndrome

Myeloproliferative Syndrome

Non-Hodgkin Lymphoma

ALL

CML

Conditions:

Leukemia

Bone Marrow Transplantation

Investigational Drug(s):

None

Investigational Device(s):

Isolex 300i Magnetic Cell Selector

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:

Barrett AJ. Antilymphocyte globulin and its use in skin diseases. Int J Dermatol. 1977 Nov;16(9):738-9. No abstract available. PMID: 144706

Barrett AJ. Bone marrow transplantation. Arch Dis Child. 1980 Oct;55(10):750-2. No abstract available. PMID: 7002049

Barrett AJ. Bone marrow transplantation. Practitioner. 1980 Oct;224(1348):1009-15. No abstract available. PMID: 6111789

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