Pilot Study of Radiation-Enhanced Allogeneic Cell Therapy for Progressive Hematologic Malignancy After Allogeneic Hematopoietic Stem Cell Transplantation
Condition: Hodgkin's Lymphoma; Non-Hodgkin's Lymphoma; Chronic Lymphocytic Leukemias; Multiple Myeloma With Plasmacytoma
MeSH terms: Lymphoma; Multiple Myeloma; Neoplasms; Lymphoma, Non-Hodgkin; Leukemia, Lymphoid; Leukemia, Lymphocytic, Chronic, B-Cell; Hodgkin Disease; Hematologic Neoplasms; Plasmacytoma
Intervention: Single fraction radiation; Donor Lymphocyte Infusion (DLI); Apheresis
Intervention description: 8-Gy fraction of radiation; Unmanipulated Donor Lymphocyte Infusion; Donors will undergo a 5-liter apheresis procedure on a CS-3000 or equivalent machine.
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 18.0
Sex: All
Minimum age: 18 Years
Maximum age: 75 Years
Healthy volunteers: Accepts Healthy Volunteers
Keywords: Allotransplant; Relapse; Radiation; Donor Lymphocyte Infusion; Hematologic Malignancies; Multiple Myeloma; Hodgkin Lymphoma; Non-Hodgkin Lymphoma; Chronic Lymphocytic Leukemia

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.
    

Eligibility criteria:

        -  INCLUSION CRITERIA:

        Treatment Subjects:

          -  Patients must have received allotransplant (related or unrelated donor) for
             hematologic malignancies and have disease progression with a component of solid-phase
             disease. Eligible diagnoses will include any acute or chronic leukemia with a
             solid-phase component, Hodgkin's lymphoma, any non-Hodgkin's lymphoma, including
             mantle cell lymphoma, multiple myeloma. Pathology slides from patients pretransplant
             diagnoses will be reviewed by National Cancer Institute (NCI)/Center for Cancer
             Research (CCR) Department of Pathology.

          -  Patients must have at least two distinct sites of disease:

          -  At least one site must be in solid phase and amenable to irradiation, determined by
             Radiation Oncology evaluation.

          -  In addition to the target(s) of irradiation, there must be disease that is discrete
             from local effects of the radiation that can be evaluated for systemic response to
             therapy.

          -  Patients must have disease that has failed to respond after a minimum of four weeks
             to:

          -  Evidence of complete donor-T cell engraftment (greater than 90% chimerism) of the
             circulating T cells

          -  A trial of tapering immunosuppressive therapy, including trials that are discontinued
             due to development or flare of graft versus host disease (GVHD)

          -  Patients must be 18 - 75 years of age.

          -  Eastern Cooperative Oncology Group (ECOG) less than or equal to 3 (Karnofsky greater
             than or equal to 50%).

          -  Life expectancy greater than or equal to 1 month.

        Arm A

          -  Patients with minimal to no clinical evidence of acute GVHD (Grade 0-I) or mild-
             chronic GVHD (GVHD Score of no more than 1 in no more than two organ systems) while
             off of systemic immunosuppressive therapy.

          -  Available source of clinical donor lymphocyte cell product, including stem
             cell-mobilized product.

          -  Patients whose related allotransplant donor is available, eligible and enrolled on
             this or another National Institutes of Health (NIH)/Clinical Center (CC) protocol that
             permits collection of a clinical donor lymphocyte cell product, and donors are
             first-degree relatives with genotypic identity at 5-6/6 human leukocyte antigen (HLA)
             loci (HLA- A, B, and DR. Haploidentical (less than 5/6 genotypic identity)
             allotransplant recipients will not be eligible, due to risk of severe GVHD with donor
             lymphocyte infusion (DLI).

          -  Patients whose related or unrelated allotransplant donors are unavailable or
             ineligible, but who have cryopreserved donor lymphocyte cell products available for
             use on this trial.

        Arm B

          -  Patients with history of GVHD. Specifically:

               -  Patients who have a past history of resolved grade III acute GVHD or
                  moderate/severe chronic GVHD and who are no longer requiring systemic therapy to
                  treat GVHD.

               -  Patients who require continued prophylaxis with steroid-sparing agents, e.g.,
                  cyclosporine. Due to concerns that sirolimus (rapamycin) could interfere with the
                  potential efficacy of radiation-enhanced allogeneic cell therapy, patients on
                  sirolimus as part of GVHD control must be switched to another agent two weeks
                  prior to enrollment.

               -  Patients with GVHD controlled with local therapy, e.g., topical steroids,
                  budesonide.

               -  Patients with controlled acute GVHD (Grade I-III) or chronic-moderate/severe GVHD
                  on a stable (at least four weeks) or tapering dose of systemic immunosuppression
                  will be eligible for enrollment.

          -  Patients who do not have donor lymphocytes available for use on this trial, including
             recipients of unrelated donor allografts.

          -  Patients whose allotransplant was from a haploidentical (less than 5/6 genotypic
             identity) related donor.

          -  Provision for a Durable Power of Attorney.

          -  Ability to give informed consent.

        Donor Subjects:

          -  Donors are the same individual whose cells were used as the source for the enrolling
             Arm A Treatment Subject or DLI Control Subjects original allotransplant.

          -  Age 18 - 90.

          -  Adequate venous access for peripheral apheresis, or consent to use a temporary central
             venous catheter for apheresis.

          -  Donors must be human immunodeficiency virus (HIV) negative, hepatitis B surface
             antigen negative, and hepatitis C antibody negative.

        DLI Control Subjects:

        The DLI Control Subjects will serve as a comparison for Arm A, and eligibility criteria are
        intended to enroll subjects who are similar with respect to allotransplant characteristics.

          -  Patients must be 18-75 years of age.

          -  Patients who have received an allotransplant to treat malignancy and who are going to
             receive an unmanipulated or stem-cell mobilized DLI to treat persistent tumor as part
             of their treatment program on another National Institutes of Health (NIH)/Clinical
             Center (CC) protocol.

          -  Eastern Cooperative Oncology Group (ECOG) performance status of less than or equal to
             3 (Karnofsky performance status of greater than or equal to 50%).

          -  Life expectancy greater than or equal to 1 month.

          -  Patients with minimal to no clinical evidence of acute GVHD (Grade 0-I) or mild-
             chronic GVHD while off of systemic immunosuppressive therapy.

          -  Available source of clinical donor lymphocyte cell product, including a stem
             cell-mobilized product.

               -  Patients whose related allotransplant donor is available, eligible and enrolled
                  on this or another NIH/CC protocol that permits collection of a clinical donor
                  lymphocyte cell product, and donors are first-degree relatives with genotypic
                  identity at 5-6/6 human leukocyte antigen (HLA) loci (HLA- A, B, and DR.
                  Haploidentical (less than 5/6 genotypic identity) allotransplant recipients will
                  not be eligible, for consistency with Arm A Subjects.

               -  Patients whose related or unrelated allotransplant donors are unavailable or
                  ineligible, but who have cryopreserved donor lymphocyte cell products available
                  for clinical use on this trial.

          -  Patients must have disease that has failed to respond after a minimum of four weeks
             to:

          -  Evidence of complete donor-T cell engraftment (greater than 90% chimerism) of the
             circulating T cells.

          -  A trial of tapering immunosuppressive therapy, including trials that are discontinued
             due to development or flare of GVHD.

          -  Adequate venous access for peripheral apheresis, or consent to use a temporary central
             venous catheter for apheresis or consent to a large-volume (70cc) blood draw.

          -  Permission from their treating transplant physician or designee to participate on
             study.

          -  Ability to give informed consent.

        EXCLUSION CRITERIA:

        Treatment Subjects:

          -  Tumor-directed therapy within two weeks of DLI.

          -  Patients with rapid disease progression or aggressive tumor histology which, in the
             opinion of the principal investigator (PI), is likely to require urgent therapy within
             60 days in order to preserve organ function or quality of life, and there is an
             available standard therapy to which the patient has a reasonable chance of responding.

          -  Progressive disease that, in the opinion of the PI, requires urgent standard therapy,
             e.g., threatened organ function, acceptable quality of life, etc.

          -  Uncontrolled GVHD, i.e., either acute GVHD Grade III or chronic-moderate/severe GVHD
             that has not responded to the current dose of systemic therapy or any history of
             steroid-refractory acute GVHD, Grade IV acute GVHD, or chronic-severe GVHD.

          -  Active infection that is not responding to antimicrobial therapy.

          -  Active psychiatric disorder which may compromise compliance with transplant protocol,
             or which does not allow for appropriate informed consent (as determined by Principal
             Investigator and/or her designee).

          -  Pregnant or lactating. Subjects of childbearing potential must use an effective method
             of contraception. The effects of the immunosuppressive medications that could be
             required to treat GHVD are likely to be harmful to a fetus. The effects upon breast
             milk are also unknown and may be harmful to an infant.

          -  Absolute neutrophil count of less than 500 cells/microL. At the PIs discretion,
             patients with marrow replacement by tumor as the probable etiology of an absolute
             neutrophil count of less than 500 cells/microL may be eligible for enrollment.

          -  In order to prevent delay of potentially stabilizing palliative therapy, the following
             conditions will exclude eligibility: untreated active leptomeningeal involvement with
             malignancy, untreated brain metastasis, and other organ-threatening diseases in which
             palliative treatment options with reasonable probability of efficacy (15% or higher)
             are available. Patients with these conditions for whom available palliative options
             have been tried or deemed unacceptable but who otherwise meet eligibility criteria
             may, at the discretion of the PI, be considered for enrollment.

        Donor Subjects:

          -  History of a psychiatric disorder that the PI determines might compromise compliance
             with transplant protocol, or that does not allow for appropriate informed consent.

          -  Hypertension that is not controlled by medication, history of stroke, or severe heart
             disease (donors with symptomatic angina will be excluded). Donors with a history of
             coronary artery bypass grafting or angioplasty who are symptom free will receive a
             cardiology evaluation and be considered on a case-by-case basis.

          -  History of prior malignancy. However, cancer survivors who have undergone potentially
             curative therapy and have had no evidence of that disease for at least 5 years may be
             considered for lymphocyte donation on a case-by-case basis.

          -  Anemia (hemoglobin (Hb) less than 11 gm/dl) or thrombocytopenia (platelets less than
             100,000 per ml). However, potential donors with Hb levels less than 11 gm/dl that is
             due to iron deficiency will be eligible as long as the donor is initiated on iron
             replacement therapy and the case is individually approved by NIH Department of
             Transfusion Medicine (DTM).

          -  Pregnancy. Donor Subjects of childbearing potential must use an effective method of
             contraception until after completion of apheresis. The effects of apheresis are
             unknown to be safe to a fetus.

        DLI Control Subjects:

          -  Tumor-directed therapy within two weeks of DLI.

          -  Uncontrolled GVHD

          -  Pregnant or lactating. Subjects of childbearing potential must use an effective method
             of contraception until after completion of apheresis. The effects of apheresis are
             unknown to be safe to a fetus.

          -  History of a psychiatric disorder that the PI determines might compromise compliance
             with protocol, or that does not allow for appropriate informed consent.

          -  Hypertension that is not controlled by medication, history of stroke, or severe heart
             disease (subjects with symptomatic angina will be excluded).