Protocol Number: 09-C-0224

Title:

Pilot Study of Radiation-Enhanced Allogeneic Cell Therapy for Progressive Hematologic Malignancy After Allogeneic Hematopoietic Stem Cell Transplantation

Number:

09-C-0224

Summary:

Background:

- Allogeneic hematopoietic stem cell transplantation (allotransplant) has been used to treat many kinds of cancer that develop in cells from the blood or immune system. After allotransplant, donor cells take over production of the recipient's blood and immune cells, and donor immune cells can directly attack and control tumor. However, for cancers that do not respond to allotransplant, there are no proven cures.

- A single treatment with radiation can improve the potency of immune-cell therapies. This is probably because the tumor tissue is damaged in a way that new tumor proteins are exposed, attracting immune cells to the tumor. By giving only a single dose of radiation, the immune cells that are attracted to the tumor are allowed to survive and function in their usual way, traveling throughout the body and educating other immune cells to recognize tumor, and to activate and expand in order to kill the tumor cells. Some research has shown that radiation may have a widespread effect on stimulating the immune system, educating immune cells to recognize and control tumors that have not been radiated.

Objectives:

- To determine whether a single treatment of radiation will help donor immune cells control cancer after allotransplant without causing excessive side effects.

Eligibility:

- Recipients: Individuals 18 years of age and older who have blood cancers that have not responded to allotransplant.

- Donors: Healthy individuals 18 years of age and older who were previous allotransplant donors for one of the study recipients.

Design:

- Donors will provide additional blood immune cells, called lymphocytes, through apheresis. Apheresis involves drawing blood, separating out the lymphocytes, and returning the rest of the blood to the donor.

- Recipients will receive a single dose of radiation to the greatest amount of tumor that can be irradiated safely. Researchers will intentionally leave some tumor that will not be radiated in order to evaluate whether there is a widespread response to the treatment.

- There are two treatment arms on the study.

- Arm 1: Study participants who have donor lymphocytes available and who have not had major complications from the allotransplant will be given a dose of donor cells after they receive radiation, to provide an additional boost to the donor immune response.

- Arm 2: Study participants who cannot receive donor lymphocytes - because their donor is not available, they received an allotransplant from a partially matched relative, or they have had significant complications from the allotransplant - will receive radiation without additional donor lymphocytes.

- All recipients will be followed closely for side effects and for tumor response to radiation with or without donor lymphocytes. Additional tests will be performed, including tumor biopsies, bone marrow samples, and blood draws, in order to study the immune effects of radiation and donor lymphocytes.

- A separate, control group of allotransplant recipients will not receive radiation. This group will include participants whose transplant doctors plan to use donor lymphocyte therapy alone to control cancer progression. This group will donate blood immune cells through blood draws and apheresis. These cells will be examined to study the immune effects of receiving donor lymphocytes without radiation.

Sponsoring Institute:

National Cancer Institute (NCI)

Recruitment Detail

Type: Participants currently recruited/enrolled

Gender: Male & Female

Referral Letter Required: No

Population Exclusion(s): Children

Eligibility Criteria:

INCLUSION CRITERIA:

Treatment Subjects:

2.1.1- Patients must have received allotransplant for hematologic malignancies and have disease progression with solid-phase tumor.

2.1.2- At least two distinct sites of disease.

- At least one site must be solid-phase and amenable to g-irradiation.

- There is disease discrete from local effects of radiation that can be evaluated for systemic response to therapy.

2.1.3- Persistent disease at least four weeks after:

- donor T-cell engraftment (> 90% of PBL T cells).

- tapering immunosuppression, including trials discontinued due to GVHD.

2.1.4- Age 18 - 75.

2.1.5- ECOG less than or equal to 3 (Karnofsky greater than or equal to 50%).

2.1.6- Life expectancy greater than or equal to 1 month.

2.1.7- Arm A

- Patients with Grade O-I acute GVHD or mild-chronic GVHD off systemic immunosuppression.

- Available source of donor lymphocyte cell product.

- Donors are first-degree relatives with genotypic identity at 5-6/6 HLA loci (HLA- A, B, and DR).

2.1.8- Arm B

- Patients with GVHD:

-- resolved grade III acute GVHD or moderate/severe chronic GVHD no longer requiring systemic therapy.

-- GVHD prophylaxis with steroid-sparing agents, e.g., cyclosporine; sirolimus must be switched to another agent two weeks prior to enrollment.

-- GVHD controlled with topical therapy.

-- controlled acute GVHD (Grade I-III) or chronic-moderate/severe GVHD on stable (four weeks) or tapering dose of systemic immunosuppression.

- Patients with no donor lymphocytes available, including unrelated donor recipients.

- Patients whose allotransplant was from a haploidentical (< 5/6 genotypic identity) related donor.

2.1.9- Durable Power of Attorney.

2.1.10- Ability to give informed consent.

Donor Subjects:

2.1.11- Allotransplant Donors of enrolling Subjects.

2.1.12- Age 18 - 90.

2.1.13- Adequate venous access for peripheral apheresis or consent to use a temporary central venous catheter.

2.1.14- HIV negative, hepatitis B surface antigen negative, and hepatitis C antibody negative.

DLI Control Subjects (Arm A):

2.1.15- Patients who have received allotransplant and need an unmanipulated DLI for persistent tumor.

2.1.16- Meet Criteria per 2.1.3 through 2.1.7, 2.1.9 and 2.1.10, 2.1.13.

2.1.17- Permission from their treating transplant physician.

EXCLUSION CRITERIA:

Treatment Subjects:

2.1.18- Tumor-directed therapy within two weeks of DLI.

2.1.19- Rapid disease progression likely to require urgent therapy within 60 days, with reasonable standard therapy option.

2.1.20- Uncontrolled acute GVHD Grade III or chronic-moderate/severe GVHD, or history of steroid-refractory or Grade IV acute GVHD or chronic-severe GVHD.

2.1.21- Active infection not responding to antimicrobial therapy.

2.1.22- Psychiatric disorder which may compromise compliance or interfere with informed consent.

2.1.23- Pregnant or lactating (subjects of childbearing potential must use effective contraception).

2.1.24- Neutrophils less than 500 /microL, unless marrow tumor is probable etiology.

2.1.25- Untreated active leptomeningeal malignancy, brain metastasis, and other organ-threatening disease with palliative treatment options with reasonable efficacy (15%).

Donor Subjects:

2.1.26- Psychiatric disorder which may compromise compliance or interfere with informed consent.

2.1.27- Uncontrolled hypertension, history of stroke, or severe heart disease (donors with coronary revascularization and symptom-free may be eligible after cardiology evaluation).

2.1.28- Prior malignancy (donors who have received potentially curative therapy with no evidence of disease after 5 years may be eligible).

2.1.29- Anemia (Hb < 11 gm/dl) or thrombocytopenia (platelets < 100,000/ml) (donors with iron deficiency anemia will be eligible upon initiation of iron replacement and DTM approval).

2.1.30- Pregnancy (subjects of childbearing potential must use effective contraception).

DLI Control Subjects:

2.1.31- Tumor-directed therapy within two weeks of DLI.

2.1.32- Uncontrolled GVHD.

2.1.33- Pregnant or lactating (subjects of childbearing potential must use effective contraception).

2.1.34- Psychiatric disorder which may compromise compliance or interfere with informed consent.

2.1.35- Uncontrolled hypertension, history of stroke, or severe heart disease.

Special Instructions:

Currently Not Provided

Keywords:

Allotransplant

Relapse

Radiation

Donor Lymphocyte Infusion

Hematologic Malignancies

Recruitment Keyword(s):

Multiple Myeloma

Hodgkin Lymphoma

Non-Hodgkin Lymphoma

Chronic Lymphocytic Leukemia

Condition(s):

Hodgkin's Lymphoma

Non-Hodgkin's Lymphoma

Chronic Lymphocytic Leukemias

Multiple Myeloma with Plasmacytoma

Investigational Drug(s):

None

Investigational Device(s):

None

Intervention(s):

Procedure/Surgery: Single fraction radiation (8-Gy)

Procedure/Surgery: Donor Lymphocyte Infusion

Supporting Site:

National Cancer Institute

Contact(s):

NCI Referral Office
National Institute of Health Clinical Center (CC), 9000 Rockville Pike, Bethesda, Maryland 20892, United States: NCI Clinical Trials Referral Office
Phone: 1-888-NCI-1937
Fax: Not Listed
Electronic Address: ncicssc@mail.nih.gov

Citation(s):

Kolb HJ, Schattenberg A, Goldman JM, Hertenstein B, Jacobsen N, Arcese W, Ljungman P, Ferrant A, Verdonck L, Niederwieser D, van Rhee F, Mittermueller J, de Witte T, Holler E, Ansari H; European Group for Blood and Marrow Transplantation Working Party Chronic Leukemia. Graft-versus-leukemia effect of donor lymphocyte transfusions in marrow grafted patients. Blood. 1995 Sep 1;86(5):2041-50.

Collins RH Jr, Shpilberg O, Drobyski WR, Porter DL, Giralt S, Champlin R, Goodman SA, Wolff SN, Hu W, Verfaillie C, List A, Dalton W, Ognoskie N, Chetrit A, Antin JH, Nemunaitis J. Donor leukocyte infusions in 140 patients with relapsed malignancy after allogeneic bone marrow transplantation. J Clin Oncol. 1997 Feb;15(2):433-44.

Dazzi F, Szydlo RM, Goldman JM. Donor lymphocyte infusions for relapse of chronic myeloid leukemia after allogeneic stem cell transplant: where we now stand. Exp Hematol. 1999 Oct;27(10):1477-86.

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