Fludarabine and Cyclophosphamide in Treating Patients Who Are Undergoing Donor Stem Cell Transplant for Chronic Lymphocytic Leukemia or Waldenstrom's Macroglobulinemia
Condition: Chronic Lymphocytic Leukemia
MeSH terms: Leukemia; Leukemia, Lymphoid; Leukemia, Lymphocytic, Chronic, B-Cell; Waldenstrom Macroglobulinemia
Study type: Interventional
Phase: Phase 1/Phase 2

Summary: 
      RATIONALE: Giving chemotherapy before a donor bone marrow transplant helps stop the growth of
      cancer cells. It also helps stop the patient's immune system from rejecting the donor's stem
      cells. Also, monoclonal antibodies, such as alemtuzumab, can find cancer cells and either
      kill them or deliver cancer-killing substances to them without harming normal cells. When the
      healthy stem cells from a donor are infused into the patient they may help the patient's bone
      marrow make stem cells, red blood cells, white blood cells, and platelets. Sometimes the
      transplanted cells from a donor can make an immune response against the body's normal cells.
      Giving methotrexate, cyclosporine and mycophenolate mofetil after the transplant may stop
      this from happening. Once the donated stem cells begin working, the patient's immune system
      may see the remaining cancer cells as not belonging in the patient's body and destroy them
      (called graft-versus-tumor effect). Giving an infusion of the donor's white blood cells
      (donor lymphocyte infusion) may boost this effect.

      PURPOSE: This phase I/II trial is studying the side effects of giving fludarabine together
      with cyclophosphamide and to see how well they work in treating patients who are undergoing
      donor stem cell transplant for B-cell chronic lymphocytic leukemia or Waldenström's
      macroglobulinemia.
    

Detailed description: 
      OBJECTIVES:

      Primary

        -  Determine the feasibility and safety of induction therapy comprising fludarabine and
           cyclophosphamide followed by allogeneic stem cell transplantation in patients with
           high-risk B-cell chronic lymphocytic leukemia or lymphoplasmocytic lymphoma
           (Waldenstrom's macroglobulinemia).

      Secondary

        -  Determine the incidence and kinetics of clinical and molecular remissions in patients
           treated with this regimen.

        -  Determine event-free and overall survival of patients treated with this regimen.

        -  Determine the duration of clinical and molecular remission in relation to the underlying
           cytogenetic deviation in patients treated with this regimen.

        -  Determine the kinetics and extent of lympho-hematopoietic donor chimerism in patients
           treated with this regimen.

      OUTLINE: This is a multicenter, open-label, nonrandomized, pilot study.

        -  Cytoreductive therapy: Patients receive up to 3 courses of cytoreductive therapy
           comprising fludarabine IV and cyclophosphamide IV on days 1-3 (with or without rituximab
           IV on day 1). Patients refractory to fludarabine-containing therapy may receive
           alemtuzumab IV for 12 weeks OR any other cytotoxic salvage regimen for cytoreduction.

        -  Conditioning regimen: Patients receive 1 of the following conditioning regimens*:

      NOTE: *Patients who did not achieve partial response after cytoreductive therapy receive
      regimen 3.

        -  Regimen 1: Patients receive fludarabine IV and cyclophosphamide IV on days -7 to -3. If
           stem cells are collected from an unrelated donor, patients also receive anti-thymocyte
           globulin (ATG) IV on days -4 to -1.

        -  Regimen 2: Patients undergo total-body irradiation on day -9. Patients then receive
           alemtuzumab IV on days -8 to -4 and fludarabine IV and cyclophosphamide IV on days -6 to
           -2.

        -  Regimen 3: Patients receive fludarabine IV on days -7 to -3, busulfan IV or orally on
           days -7 to -5, and cyclophosphamide IV on days -3 to -2. If stem cells are collected
           from an unrelated donor, patients also receive ATG on days -3 to -1.

             -  Allogeneic peripheral blood stem cell transplantation (PBSCT): Patients undergo
                allogeneic PBSCT on day 0. Patients receive filgrastim (G-CSF) subcutaneously daily
                starting on day 5 and continuing until blood count recover.

             -  Graft-versus-host-disease (GVHD) prophylaxis: Patients receive cyclosporine IV
                beginning on day -1 and continuing until approximately day 100. Patients treated
                with conditioning regimen 1 or 3 also receive methotrexate IV on days 1, 3, and 6
                OR oral mycophenolate mofetil twice daily on days 0-50. Patients with evidence of
                residual disease at least 4 weeks after completion of cyclosporine undergo donor
                lymphocyte infusion (DLI).

             -  DLI: The donor T-lymphocytes are collected from the PBSCT donor without prior G-CSF
                mobilization. Patients receive DLI every 8 weeks in the presence of residual
                disease and the absence of GVHD.

      After completion of study treatment, patients are followed periodically.

      PROJECTED ACCRUAL: A total of 70 patients will be accrued for this study.
    

Intervention name(s): alemtuzumab; anti-thymocyte globulin; filgrastim; rituximab; therapeutic allogeneic lymphocytes; busulfan; cyclophosphamide; cyclosporine; fludarabine phosphate; methotrexate; mycophenolate mofetil; peripheral blood stem cell transplantation; radiation therapy
Intervention type(s): Biological; Biological; Biological; Biological; Biological; Drug; Drug; Drug; Drug; Drug; Drug; Procedure; Radiation
Intervention MeSH terms: Cyclosporine; Mycophenolic Acid; Cyclophosphamide; Busulfan; Rituximab; Methotrexate; Fludarabine; Fludarabine phosphate; Alemtuzumab; Cyclosporins; Antilymphocyte Serum
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: B-cell chronic lymphocytic leukemia; refractory chronic lymphocytic leukemia; stage III chronic lymphocytic leukemia; stage IV chronic lymphocytic leukemia; Waldenström macroglobulinemia