Specialized Blood Cell Transplants for Cancers of the Blood and Bone Marrow
Condition: Myeloproliferative Disorders; Acute Myelogenous Leukemia; Chronic Myelogenous Leukemia; Myelodysplastic Syndrome; Acute Lymphoblastic Leukemia
MeSH terms: Leukemia; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Leukemia, Myeloid; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Leukemia, Myeloid, Acute; Myelodysplastic Syndromes; Myeloproliferative Disorders
Intervention: T-cell replete PBPC allograft; Methotrexate; Cyclosporine; G-CSF
Intervention description: Subjects will receive a non-myeloablative preparative regimen of cyclophosphamide 60mg/kg/d x 2 days, and fludarabine 25mg/m2 intravenously (IV) over 30 minutes daily x 5 days with or without ATG followed by a PBPC graft targeted to deliver >5x10^6 CD34+ cells/kg.; IV MTX on days +1, +3, and +6 will be given; CSA will be given beginning on day -4 for graft versus host disease prophylaxis. Participants with mixed T-cell chimerism on day 30 will begin a CSA taper. Participants with 100% donor T-cell chimerism by day 30 will be tapered off CSA from days 60 through 100 (25% reduction in dose every 10 days-off by day 100). CSA will not be tapered in any subjects with grade > II acute GVHD regardless of chimerism results. In addition, participants with evidence of disease progression without grade > II GVHD will have CSA discontinued regardless of chimerism results.; G-CSF will be administered based on body weight for at least 5, and up to 7 days, subcutaneously.
Intervention MeSH terms: Cyclosporine; Methotrexate; Cyclosporins; Lenograstim
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 202.0
Sex: All
Minimum age: 2 Years
Maximum age: 80 Years
Healthy volunteers: No
Keywords: Graft vs. Host Disease; Peripheral Blood Stem Cells; Non-Myeloablative Bone Marrow Transplantation; Engraftment; graft versus leukemia

Summary:

      The are a variety of cancerous diseases of the blood and bone marrow that can be potentially
      cured by bone marrow transplantation (BMT). Diseases like leukemia, lymphoma, and multiple
      myeloma are among the conditions that can be treated with BMT.

      Some patients with these diseases can be treated with medical chemotherapy alone. However,
      patients who relapse following chemotherapy are usually not curable with additional
      chemotherapy treatments. The only option known to provide a potential cure if this occurs is
      BMT.

      Allogenic transplants are cells collected from relatives of the patient. The transplant
      requires additional high intensity chemotherapy and radiation in order to destroy cancerous
      cells. In the process, many normal bone marrow cells are also destroyed. This is the reason
      for transplanting stem cells. The stem cells help to build new functioning bone marrow, red
      cells, white cells, and platelets. In addition, the immune cells from the donor are implanted
      into the recipient s body and help to fight off infection and kill remaining cancerous cells.

      Unfortunately, the powerful doses of chemotherapy and radiation therapy associated with
      allogenic BMT have toxic side effects and often make BMTs too dangerous to attempt in many
      patients.

      In order to reduce the complications of BMT, and make it a safer available option for
      patients with cancers of the blood and bone marrow, researchers have developed a new approach
      to the BMT.

      In this study researchers plan to use stem cells collected from the blood stream of patient s
      relatives rather than from the bone marrow (blood progenitor/stem cell transplant). In
      addition, researchers plan to use low doses of chemotherapy and no radiation therapy to
      reduce side effects. The majority of the cancer killing effect will be the responsibility of
      the stem cell transplant rather than the chemotherapy.
    

Eligibility criteria:

        -  INCLUSION CRITERIA - Recipients:

        Group A: Subjects at high risk for transplant related complications and mortality as
        defined below:

        Ages 10 to 75 (both inclusive) with a history of one of the following:

          -  Treatment with dose intensive chemotherapy and/or radiotherapy

          -  Previous history of allo/auto transplant

          -  History of multiple myeloma or extramedullary plasmacytoma

          -  Chronic disease or co-morbid medical condition including subjects with symptoms or
             signs of significant pulmonary disease, hepatic disease, kidney disease, cardiac
             disease or disease of other organ systems which would result in increased risk of
             morbidity or death from a standard myeloablative transplant.

        Diseases to be included:

          -  CML chronic phase

          -  Acute lymphoblastic leukemia (ALL), all subjects in complete or partial remission.

          -  AML: AML in first complete or partial remission Exceptions: AML with good risk
             karyotypes: AML M3 t(15:17), AML M4Eo (inv. 16), AML t(8;21). All AML in second or
             subsequent complete remission.

          -  MDS: refractory anemia with excess blasts (RAEB), or chronic myelomonocyte leukemia
             (CMML).

          -  Myeloproliferative diseases associated with either cytopenia or uncontrolled
             proliferation.

          -  CLL or small lymphocytic lymphoma (SLL) with bulky or progressive disease despite
             prior treatment with chemotherapy which includes purine analogs.

          -  NHL

        A) Intermediate or high grade relapsed or progressive despite treatment with standard
        therapy ineligible for autologous PBSC transplant.

        B) NHL intermediate or high grade relapsing despite prior autologous transplant.

        C) Low grade follicular or small lymphocytic lymphoma (1) high risk patients who have
        relapsed following conventional chemotherapy, (2) relapsed following autologous marrow or
        PBSC transplant, or (3) chemo resistant disease.

        D) Mantle cell lymphoma

        E) NHL intermediate or high grade with concurrent BCL2 and MYC translocations who are at
        high risk for relapsed and who have low survival with conventional chemotherapy.

          -  HD, relapsed after prior autologous transplant or after 2 or more combination
             chemotherapy regimens and ineligible for autologous PBSC transplant.

          -  EBV driven lymphoproliferative disorders progressing despite standard therapies.

          -  MM: MM subjects must be between the ages of 8 and 65 (both inclusive)

          -  Mycosis fungoides, which has been shown to be amenable to allogeneic stem cell
             transplants.

        Group B: (Closed to enrollment Oct 2010) Subjects with hematologic diseases associated with
        reasonable longevity, shown to be curable by allogeneic BMT but where concern for a high
        procedural mortality with conventional BMT may delay or prevent such treatment.

        Ages 8 to 80 (both inclusive) with a history of one of the following

          -  PNH associated with either life-threatening thrombosis, cytopenia, transfusion
             dependence or recurrent and debilitating hemolytic crisis.

          -  Aplastic anemia or PRCA (acquired or congenital) in subjects associated with
             transfusion dependence and/or neutropenia who are not candidates for or who have
             failed immunosuppressive therapy

          -  RA or RARS MDS subjects who have associated transfusion dependence and/or neutropenia.

        Ability to comprehend the investigational nature of the study and provide informed consent.
        The procedure will be explained to subjects age 8-17 years with formal consent being
        obtained from parents or legal guardian.

        Availability of HLA identical or single HLA locus mismatched family donor

        INCLUSION CRITERIA - Donor:

        HLA identical or single HLA mismatched family donor

        Age greater than or equal to 2 up to 80 years old

        Weight greater than or equal to 18 kg

        Ability of donor or guardian of donor to comprehend the investigational nature of the study
        and provide informed consent.

        EXCLUSION CRITERIA - Recipient - any of the following:

        Pregnant or lactating

        Group A: age less than 10 or greater than 75 (multiple myeloma age less than 8 or greater
        than 65);

        Group B: Age less than 8 or greater than 80 years.

        ECOG performance status of 3 or more (See NIH Bone and Marrow Consortium Supportive Care
        Guidelines for Allogeneic Hematopoietic Stem Cell Transplant Recipients -
        http://intranet.cc.nih.gov/bmt/_pdf/ECOG_Karnofsky_Lansky_Scales.pdf)

        Psychiatric disorder or mental deficiency 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 PBSC transplant

        Diffusion capacity of carbon monoxide (DLCO) less than 40% predicted.

        Left ventricular ejection fraction: less than 30%.

        Serum creatinine greater than 2.5 mg/dl or creatinine clearance less than 50 cc/min by 24
        hr urine collection

        Serum bilirubin greater than 4 mg/dl, transaminases greater than 5x upper limit of normal,

        Other malignant diseases liable to relapse or progress within 5 years.

        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 donor. Donors who are positive for hepatitis B (HBV), hepatitis C (HCV) or
        human T-cell lymphotropic virus (HTLV I/II) will be used at the discretion of the
        investigator following counseling and approval from the recipient