Modified Stem Cell Transplant Procedure to Treat Patients With Blood and Immune System Cancers
Condition: Hematologic Neoplasms
MeSH terms: Hematologic Neoplasms
Intervention: Stem cell transplantation; Fludarabine; Cyclophosphamide; Etoposide; Doxorubicin; Vincristine; Prednisone; Methotrexate; Cyclosporine; Apheresis
Intervention description: Recipients will receive donor stem cells 3 days after conditioning therapy is completed.; Recipients will receive induction therapy with fludarabine, cyclophosphamide, etoposide, doxorubicin, vincristine, and prednisone. One cycle is 5 days on drug therapy followed by a 16 day rest period.; Recipients will receive induction therapy with fludarabine, cyclophosphamide, etoposide, doxorubicin, vincristine, and prednisone. One cycle is 5 days on drug therapy followed by a 16 day rest period.; Recipients will receive induction therapy with fludarabine, cyclophosphamide, etoposide, doxorubicin, vincristine, and prednisone. One cycle is 5 days on drug therapy followed by a 16 day rest period.; Recipients will receive induction therapy with fludarabine, cyclophosphamide, etoposide, doxorubicin, vincristine, and prednisone. One cycle is 5 days on drug therapy followed by a 16 day rest period.; Recipients will receive induction therapy with fludarabine, cyclophosphamide, etoposide, doxorubicin, vincristine, and prednisone. One cycle is 5 days on drug therapy followed by a 16 day rest period.; Recipients will receive induction therapy with fludarabine, cyclophosphamide, etoposide, doxorubicin, vincristine, and prednisone. One cycle is 5 days on drug therapy followed by a 16 day rest period.; Recipients will receive 4 doses of methotrexate by vein after the transplant to help prevent graft-versus-host disease (GVHD)..; Recipients will receive cyclosporine by vein or by mouth for about 6 months after the transplant to help prevent graft-versus-host disease (GVHD).; Donors will undergo apheresis to collect stem cells for a stem cell transplant for the recipient.
Intervention MeSH terms: Cyclosporine; Prednisone; Cyclophosphamide; Doxorubicin; Methotrexate; Fludarabine; Etoposide; Vincristine; Cyclosporins
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 62.0
Sex: All
Minimum age: 18 Years
Maximum age: 75 Years
Healthy volunteers: No
Keywords: Lymphoma; Leukemia; Hodgkin's Disease; Multiple Myeloma; Immunotherapy

Summary:

      This study will investigate the safety and effectiveness of a modified stem cell transplant
      procedure for treating cancers of the blood and immune system. Patients with cancers and
      pre-cancerous conditions originating in blood or immune system cells can sometimes benefit
      greatly from, and even be cured by, transplants of stem cells (cells produced by the bone
      marrow that mature into blood cells). In addition to producing new bone marrow and restoring
      normal blood production and immunity, the donated cells fight any residual tumor cells that
      might have remained in the body, in what is called a graft-versus-tumor effect.

      However, severe problems, and sometimes death, may follow these transplants as a result of
      the high-dose chemotherapy and radiation that accompany the procedure. Also, donated immune
      system cells called T cells sometimes attack healthy tissues in a reaction called
      graft-versus-host-disease (GVHD), damaging organs such as the liver, intestines and skin.
      This study will use the following strategies to try to reduce these risks:

        -  induction chemotherapy to reduce patient's immunity in an attempt to prevent rejection
           of the donated stem cells;

        -  reduced-intensity conditioning chemotherapy that is easier for the body to tolerate and
           involves a shorter period of complete immune suppression;

        -  donation of immune cells called T helper type 2 (Th2) cells instead of T cells to try to
           reduce the risk of serious GVHD;

        -  treatment with methotrexate and cyclosporine to try to reduce the risk of serious GVHD.

      Patients between 12 and 75 years of age with non-Hodgkin's lymphoma, Hodgkin's lymphoma,
      multiple myeloma, chronic lymphocytic leukemia, chronic myelogenous leukemia, acute
      myelogenous leukemia, acute lymphocytic leukemia, myelodysplasia, idiopathic myelofibrosis,
      polycythemia vera, or chronic myelomonocytic leukemia may be eligible for this study.
      Candidates will have a medical history, physical and dental examinations, blood and urine
      tests (including a blood test for genetic match with the donor), lung and heart function
      tests, and X-ray studies. A bone marrow biopsy may be done to evaluate disease status.
      Patients with lymphoma may have a nuclear medicine test called a positron emission tomography
      (PET) scan.

      Participants will have a central venous line (large plastic tube) placed into a major vein.
      This tube can stay in the body and be used during the entire treatment period to deliver the
      donated stem cells and give medications, including chemotherapy and other drugs, antibiotics
      and blood transfusions, and to withdraw blood samples. Treatment will start with induction
      chemotherapy, which will include the drugs fludarabine, cyclophosphamide, etoposide,
      doxorubicin, vincristine, and prednisone. Some patients may also receive an antibody called
      rituximab. Patients will receive one to three cycles of this treatment, depending on their
      response to the drugs. (One cycle consists of 5 days on drug therapy followed by a 16-day
      rest period.) Several days before the transplant procedure, patients will start conditioning
      chemotherapy with cyclophosphamide and fludarabine. Three days after the conditioning therapy
      is completed, the stem cells will be infused. To help prevent GVHD, patients will take four
      doses of methotrexate (by vein) shortly after the transplant, and cyclosporine (by mouth or
      by vein) for about 6 months after the transplant.

      The average hospital stay for stem cell transplantation is 3 to 4 weeks. After discharge,
      patients will return for frequent follow-up visits for 3 months. Monthly visits will be
      scheduled for the next 3 months, then every 3 months for the next 18 months, and less
      frequently for a total of at least 5 years post-transplant. These visits will include bone
      marrow aspirates and biopsies, blood draws, and other tests to monitor disease status.
    

Eligibility criteria:

        -  INCLUSION CRITERIA:

        Inclusion Criteria Patient (Recipient):

        Patients with hematologic malignancies, myelodysplasia, or myeloproliferative disorders, as
        summarized below:

        Disease: Chronic Lymphocytic Leukemia; Disease Status: (a) Relapse post-fludarabine, (b)
        Non-Complete Remission (CR) after salvage regimen; Age: 18 to 75.

        Disease: Hodgkin's and Non-Hodgkin's Lymphoma (all types, including Mantle Cell Lymphoma);
        Disease Status: (a) Primary treatment failure, (b) Relapse after autologous stem cell
        transplant (SCT), (c) Hepatosplenic gamma/delta T cell lymphoma; Age: 18 to 75.

        Disease: Multiple Myeloma; Disease Status: (a) Primary treatment failure, (b) Relapse after
        autologous SCT, (c) Non-CR after salvage regimen; Age: 18 to 75.

        Disease: Acute Myelogenous Leukemia; Disease Status: (a) In Complete Remission #1, with
        high-risk cytogenetics [abnormalities other than t(8;21), t(15;17), or inv(16)], (b) In
        Complete Remission #2 or greater; Age: 18 to 75.

        Disease: Acute Lymphocytic Leukemia; Disease Status: (a) In Complete Remission #1, with
        high-risk cytogenetics [t(9;22) or bcr-abl rearrangement; t(4;11), 1(1;19), t(8;14)], (b)
        In Complete Remission #2 or greater; Age: 18 to 75.

        Disease: Myelodysplastic Syndrome; Disease Status: (a) refractory anemia with excess blasts
        (RAEB), (b) refractory anemia with excess blasts in transformation (RAEB-T) (if blasts are
        less than 10% in marrow and blood after induction chemotherapy); Age: 18 to 75.

        Disease: Myeloproliferative disorders; Disease Status: (a) Idiopathic myelofibrosis, (b)
        Polycythemia vera, (c) Essential thrombocytosis, (d) Chronic myelomonocytic leukemia; Age:
        18 to 75.

        Disease: Chronic Myelogenous Leukemia (CML); Disease Status: (a) Chronic phase CML, (b)
        Accelerated phase CML; Age 50 to 75; (c) Not eligible for myeloablative allogeneic HSCT;
        Age: 18 to 50.

        Patients 18-75 years of age. Patients older than 75 years of age will be considered on an
        individual basis.

        Consenting first degree relative matched at 6/6 human leukocyte antigen (HLA) antigens (A,
        B, and DR).

        Patient or legal guardian must be able to give informed consent.

        All previous therapy must be completed at least 2 weeks prior to study entry, and any grade
        3 or 4 non-hematologic toxicity of previous therapy must be resolved to grade 2 or less,
        unless specified elsewhere.

        Eastern Cooperative Oncology Group (ECOG) performance status equal to 0 or 1.

        Life expectancy of at least 3 months.

        Patients with acute leukemia must be in hematologic remission, defined as less than 5%
        blasts present in blood or bone marrow.

        Left ventricular ejection fraction greater than 45% by either multi-gated acquisition
        (MUGA) scan or 2-D echo, obtained within 28 days of enrollment. The cumulative dose of
        doxorubicin received by patients will not be considered, as the cardiac ejection fraction
        appears to indicate the safe cumulative doxorubicin dose in the setting of etoposide
        phosphate, prednisone, vincristine, cyclophosphamide, and doxorubicin hydrochloride
        (EPOCH)-based chemotherapy.

        Diffusing capacity for carbon monoxide (DLCO) greater than 50% of the expected value when
        correlated for hemoglobin (Hb), obtained within 28 days of enrollment.

        Creatinine less than or equal to 1.5 mg/dl and creatinine clearance greater than or equal
        to 50 ml/min/1.73 m(2).

        Serum total bilirubin less than 2.5 mg/dl, and serum alanine aminotransferase (ALT) and
        aspartate aminotransferase (AST) values less than or equal to 2.5 times the upper limit of
        normal. Values above these levels may be accepted, at the discretion of the principal
        investigator (PI) or study chairman, if such elevations are thought to be due to liver
        involvement by malignancy. If these values do not normalize during induction chemotherapy,
        such patients will not be eligible for the transplant phase of the protocol, and will thus
        be taken off study.

        Minimum absolute neutrophil count of 1,000 cells/microliter and minimum platelet count
        (without transfusion) of 20,000/mm(3).

        Inclusion Criteria Donor:

        First-degree relative with genotypic identity at 6/6 HLA loci (HLA-A, B and DR).

        Ability to give informed consent. For donors under 18 years of age, the donor must complete
        an assent form, and the donors legal guardian must complete an informed consent form.

        Age 12-75 years. As the potential cerebrovascular and cardiac complications may potentially
        increase with age, age 75 has been chosen arbitrarily as the upper age limit. However, if
        it is determined after initial accrual of patients in this upper age range that this
        procedure is relatively safe, the age range may be extended.

        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. This is to prevent the possible transmission
        of these infections to the recipient.

        A donor who is lactating must substitute formula feeding for her infant during the period
        of cytokine administration. Filgrastim may be secreted in human milk, although its
        bioavailability from this source is not known. Limited clinical data suggest that
        short-term administration of filgrastim or sargramostim to neonates is not associated with
        adverse outcomes.

        EXCLUSION CRITERIA:

        Exclusion Criteria Patient:

        Active infection that is not responding to antimicrobial therapy.

        Active central nervous system (CNS) involvement by malignancy.

        HIV infection. There is theoretical concern that the degree of immune suppression
        associated with the treatment may result in progression of HIV infection.

        Chronic active hepatitis B. Patients may be hepatitis B core antibody positive but must be
        surface antigen negative and without evidence of active infection.

        Hepatitis C infection.

        Pregnant or lactating. Patients of childbearing potential must use an effective method of
        contraception. The effects of chemotherapy, the subsequent transplant and the medications
        used after the transplant are highly likely to be harmful to a fetus. The effects upon
        breast milk are also unknown and may be harmful to the infant.

        History of psychiatric disorder which may compromise compliance with transplant protocol,
        or which does not allow for appropriate informed consent (as determined by principal
        investigator or study chairman).

        Exclusion Criteria Donor:

        History of psychiatric disorder which may compromise compliance with transplant protocol,
        or which does not allow for appropriate informed consent.

        History of hypertension that is not controlled by medication, stroke, or severe heart
        disease. Individuals with symptomatic angina will be considered to have severe heart
        disease will not be eligible to be a donor.

        No other medical contraindications to stem cell donation (i.e. severe atherosclerosis,
        autoimmune disease, cerebrovascular accident, prior malignancy). Patients with a history of
        coronary artery bypass grafting or angioplasty will receive a cardiology evaluation and be
        considered on a case-by-case basis. Persons with a history of non-hematologic malignancy
        must have undergone potentially curative therapy for that malignancy and (1) have had no
        evidence of that disease for 5 years, and/or (2) be deemed at low risk for recurrence (less
        than or equal to 20% at 5 years). Such persons will be considered eligible for stem cell
        donation at the discretion of the principal investigator. Prospective donors with a history
        of non-hematologic malignancy who have received potentially curative therapy and are in
        remission, but whose estimated risk of recurrence is greater than 20% at 5 years, will be
        considered on an individual basis in consultation with the National Cancer Institute (NCI)
        Institutional Review Board (IRB).

        Donors must not be pregnant. The effects of cytokine administration on a fetus are unknown.
        Donors of childbearing potential must use an effective method of contraception.

        Anemia (Hb less than 11 gm/dl) or thrombocytopenia (platelets less than 100,000 per
        microliter).