Chemotherapy and Unrelated Donor Stem Cell Transplantation for Patients With Cancers of the Blood and Immune System
Condition: Myelodysplastic Syndrome; Hodgkin's Lymphoma; Non-Hodgkin's Disease; Acute Leukemia; Multiple Myeloma
MeSH terms: Lymphoma; Leukemia; Multiple Myeloma; Preleukemia; Myelodysplastic Syndromes
Study type: Interventional
Phase: Phase 1/Phase 2

Summary: 
      Background:

      Major problems with stem cell transplantation (SCT) for cancer treatment are a lack of
      suitable donors for patients without a human leukocyte-antigen (HLA) tissue-matched sibling
      and graft-versus-host disease (GVHD), a serious side effects of immune-suppressing
      chemotherapy that is given to bring the cancer under control before SCT. In GVHD, the
      patients immune system attacks the transplanted donor cells.

      This study will try to improve the results of SCT from unrelated HLA-matched donors using
      targeted immune-depleting chemotherapy to bring the cancer under control before
      transplantation and to lower the chance of graft rejection, followed by reduced-intensity
      transplant chemotherapy to make the procedure less toxic.

      Objectives:

      To evaluate the safety and effectiveness of targeted immune-depleting chemotherapy followed
      by reduced-intensity transplant chemotherapy in patients with advanced cancers of the blood
      and immune system.

      To evaluate the safety and effectiveness of two different drug combinations to prevent GVHD.
      Both regimens have been successful in preventing GVHD, but they work by different mechanisms
      and affect the rebuilding of the immune system after the transplant.

      Eligibility:

      People 18 to 74 years of age with advanced or high-risk cancers of the blood and immune
      system who do not have a suitable HLA-matched sibling.

      Design:

      All patients receive chemotherapy before transplant to treat the cancer and suppress immune
      function.

      All patients receive a conditioning regimen of cyclophosphamide for 4 days and fludarabine
      for 4 days before SCT to prepare for the transplant.

      Patients are randomly assigned to one of two combination drug treatments to prevent GHVD as
      follows:

        -  Group 1: Tacrolimus starting 3 days before SCT and continuing for 6 months, plus
           methotrexate on days 1, 3, 6, and 11 post-SCT, plus sirolimus starting 3 days before the
           SCT and continues for 6 months following SCT.

        -  Group 2: Alemtuzumab for 4 days starting 8 days before SCT, plus cyclosporine starting 1
           day before SCT and continuing for 6 months.

      Patients receive the donors stem cells and immune cells 2 days after completing the
      conditioning regimen.

      Patients are followed at the clinic regularly for the first 6 months after SCT, and then less
      often for at least 5 years. Some visits may include bone marrow aspirates and biopsies, blood
      draws, and other tests to monitor disease status.

      A skin biopsy, oral mucosa biopsy, and saliva collection are done to study chronic GVHD.

      ...
    

Detailed description: 
      Background:

        -  The major limitations to the broader applicability of allogeneic hematopoietic stem cell
           transplantation (HSCT) for the treatment of malignancies are lack of suitable donors and
           therapy-related toxicities which include delayed and incomplete immune reconstitution
           and graft-versus-host disease (GVHD). Based on the theory that the rapid establishment
           of donor chimerism was essential for an optimal graft-versus-tumor effect, we have
           employed a strategy of targeted immune depleting chemotherapy prior to reduced-intensity
           allogeneic HSCT. It is our intent to investigate this approach in the setting of human
           leukocyte-antigen (HLA)-matched unrelated donors in a pilot manner.

        -  A clearly superior GVHD prophylaxis regimen has not been established in the unrelated
           donor transplant setting. The best results that have been reported are with the
           combination of alemtuzumab plus cyclosporine [AC] and the combination of tacrolimus,
           methotrexate, and sirolimus [TMS]. These two regimens work by mechanisms which are
           biologically distinct and potentially have markedly different effects upon immune
           reconstitution that have not been well studied. In addition, neither of these regimens
           has been assessed for their effects on chronic GVHD using the National Institutes of
           Health (NIH) Consensus Conference Criteria. It is our intent to study the effects that
           these two regimens have on immune reconstitution and chronic GVHD in the setting
           sequential targeted immune-depleting chemotherapy and reduced-intensity allogeneic HSCT
           from HLA-matched unrelated donors.

      Objectives:

        -  Primary objectives:

             1. to assess the effects of two biologically distinct GVHD prophylaxis regimens, TMS
                and AC, on immune reconstitution in patients receiving targeted-immune depletion
                and reduced-intensity allogeneic HSCT from HLA-matched unrelated donors. As part of
                a comprehensive assessment of immune reconstitution, the primary immunologic
                endpoint will be the determination of cluster of differentiation 4 (CD4)+ T cell
                receptor V BETA repertoire by complementarity determining region 3 (CDR3)
                spectratyping at 3 months post-transplant.

             2. to assess overall safety of these two regimens in this setting, as determined by
                engraftment, acute GVHD, early and late treatment-related mortality, and overall
                survival.

             3. to determine and monitor incidence, organ severity and overall severity of chronic
                GVHD prospectively using the newly developed NIH Consensus Conference diagnosis and
                staging criteria and preliminarily validate those tools for use in clinical
                practice and trials.

        -  Secondary objectives include further assessment of immune reconstitution, study of
           engraftment kinetics, and assessment of those patients who receive higher doses of
           anthracyclines for long and short term toxicities

      Eligibility:

        -  Adults (18-74 years) with advanced or high risk hematologic malignancies including acute
           myeloid leukemia (AML), acute lymphocytic leukemia (ALL), myelodysplastic syndrome
           (MDS), chronic lymphocytic leukemia (CLL), non-hodgkin lymphoma (NHL), hodgkin lymphoma
           (HL), chronic myelogenous leukemia (CML), multiple myeloma, and myeloproliferative
           disorder (MPD) who lack a suitable HLA matched sibling.

        -  An unrelated donor matched at a minimum of 7 of 8 alleles (HLA-A,-B,-C, and DRB1) by
           high resolution typing, identified through the National Marrow Donor Program.

        -  Life expectancy of at least 3 months, Eastern Cooperative Oncology Group (ECOG) less
           than or equal to 2 and relatively normal major organ functions.

      Design:

        -  Patients will receive disease-specific induction chemotherapy (etoposide, prednisone,
           vincristine, cyclophosphamide and doxorubicin (EPOCH-fludarabine (F)/rituximab (R) or
           fludarabine, cytarabine, and granulocyte colony-stimulating factor (FLAG)) prior to
           transplant for disease control and immune depletion. If disease is controlled (greater
           than partial response (PR)) and immune depletion objectives have been met, patients may
           forgo induction chemotherapy and move forward to the transplant conditioning regimen.

        -  All patients will receive an identical conditioning regimen consisting of
           cyclophosphamide 1200 mg/m(2)/day intravenous (IV) for 4 days and fludarabine 30
           mg/m(2)/day for 4 days.

        -  Patients will be stratified according to degree of HLA-match and randomized at the time
           of enrollment to one of two GHVD prophylaxis regimens:

             -  Group 1: Tacrolimus starting 3 days before stem cell transplant (SCT), and
                continuing for 6 months, plus methotrexate on days 1, 3, 6, and 11 post-SCT, plus
                sirolimus starting 3 days before the SCT and continues for 6 months following SCT.

             -  Group 2: Alemtuzumab for 4 days starting 8 days before SCT, plus cyclosporine
                starting 1 day before SCT and continuing for 6 months.

        -  A maximum of 105 patients will be enrolled and randomly assigned to the two arms in
           order to yield 44 patients per arm (88 total patients) who are able to be evaluated for
           development of severe chronic GVHD.
    

Intervention name(s): Rituximab; Cyclosporine; Allogenic stem cell transplant (ASCT); Conditioning Chemotherapy; TMS; FLAG; EPOCH-F; Alemtuzumab
Intervention type(s): Biological; Drug; Drug; Drug; Drug; Drug; Drug; Biological
Intervention description(s): Rituximab: 375 mg/m(2) intravenous (IV), day 1 for patients with cluster of differentiation 20 (CD20)-positive disease.; Cyclosporine: IV over 2 hours or orally every 12 hours on days -1 to 100, followed by a taper if graft versus host disease (GVHD) does not develop.; Allogenic stem cell transplant; Fludarabine:30 mg/m(2) per day IV infusion over 30 minutes, daily. On days -6, -5, -4, and -3.
Cyclophosphamide:1200 mg/m(2) per day IV infusion over 2 hours on Days 6, -5, -4, -3 Mesna: 1200 mg/m(2) per day IV infusion, Daily on days 6, -5,-4, and -3; Tacrolimus: starting day -3 before transplant, given initially at 0.02 mg/kg/day CIV. Continue IV and then switch to an equivalent oral dose (when patient taking po) titrated for a goal level of 5 to 10 ng/ml; Sirolimus: given as an initial loading dose of 12 mg p.o. on day -3 pre-transplant, 4 mg starting day -2 pre-transplant and titrated for levels 3-12 ng/ml; Methotrexate 5 mg/m2 IV on days +1, +3, +6, and +11 post-transplant. Tacrolimus and sirolimus will be tapered at day +63, day +119 and day +180 post-transplant as tolerated.; Fludarabine:25 mg/m(2) per day IV over 30 minutes, Daily on days 1-5 Cytarabine: 2,000 mg/m(2) IV over 4 hours,on Days 1, 2, 3, 4, 5 Filgrastim: 5 mcg/kg per day subcutaneous (SC) beginning 24 hours PRIOR to initiation of chemotherapy; Fludarabine:25 mg/m(2) per day IV infusion over 30 minutes, daily on days 1-4 Etoposide :50 mg/m(2) per day continuous IV infusion over 24 hours on days 1-4 Doxorubicin:10 mg/m(2)/day CIV, days 1-4 Vincristine:0.4 mg/m(2) per day continuous IV infusion over 24 hours daily on days 1-4 Cyclophosphamide:750 mg/m(2) IV infusion over 30 minutes on day 5; Alemtuzumab:20 mg/day IV over 8 h on days 8 to 4 pre-transplant.
Other intervention name(s): Rituxan; Neoral; Prograf; Fludarabine+high-dose cytarabine+G-CSF (Filgrastim)); Campath
Intervention MeSH terms: Cytarabine; Cyclosporine; Rituximab; Alemtuzumab; Fludarabine; Cyclosporins
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Unrelated Donors; Reduced Intensity Stem Cell Transplant; Leukemia; Lymphoma; Allogeneic Stem Cell Transplant; Myelodysplastic Syndrome; Multiple Myeloma