Modified Stem Cell Transplant Procedure to Treat Patients With Blood and Immune System Cancers
Condition: Hematologic Neoplasms
MeSH terms: Hematologic Neoplasms
Study type: Interventional
Phase: Phase 2

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.
    

Detailed description: 
      Allogeneic hematopoietic stem cell transplantation (HSCT) is potentially curative for
      refractory hematologic malignancies, but its application has been limited historically by
      morbidity and mortality from conventional transplant preparative regimens and
      graft-versus-host disease (GVHD). Donor T cells mediate GVHD and also help to eradicate
      malignancies through an immune-dependent graft-versus-tumor effect. Efforts to decrease
      preparative regimen toxicity have led to reduced-intensity or 'nonmyeloablative' regimens,
      facilitating the study of allogeneic HSCT in a broader population. As a promising strategy
      for reducing GVHD, donor T helper type 2 (Th2) cells were shown to abrogate T helper type 1
      (Th1)-mediated GVHD without impairing engraftment in murine models of allogeneic HSCT. These
      findings led to a phase I/II clinical study of donor Th2 cells for the prevention of GVHD
      during reduced-intensity allogeneic HSCT (CC 99-C-0143); preliminary results suggest that a
      randomized trial will be necessary to evaluate donor Th2 cells further.

      In CC 99-C-0143, a novel induction chemotherapy regimen, etoposide phosphate, prednisone,
      vincristine sulfate, cyclophosphamide, and doxorubicin hydrochloride (EPOCH)-Fludarabine
      (EPOCH-F), was well tolerated and effective for sequential host immune depletion. However, a
      significant proportion of patients failed to achieve satisfactory disease control before
      transplant, providing a basis for intensifying this induction regimen. Furthermore, the
      initial 20 patients treated on this study experienced relatively high rates of acute GVHD and
      considerable morbidity associated with cyclosporine monotherapy for GVHD prevention,
      indicating that future studies should use more aggressive prophylaxis. These observations
      warrant modifying our approach to allogeneic HSCT before undertaking a randomized study of
      donor Th2 cells.

      We now propose a pilot study of human leukocyte antigens (HLA)-matched, related,
      reduced-intensity allogeneic HSCT in refractory hematologic malignancies, using an
      intensified etoposide, vincristine, doxorubicin, prednisone, cyclophosphamide and fludarabine
      (EPOCH-F) induction chemotherapy regimen with rituximab added for patients with cluster of
      differentiation 20 (CD20)+ malignancies fludarabine, etoposide, prednisone, vincristine,
      cyclophosphamide, and doxorubicin plus with or without rituximab (DA-EPOCH-F/R). This regimen
      will be evaluated for toxicity and disease control before transplantation. GVHD prophylaxis
      will consist of a standard dual-agent regimen, cyclosporine/methotrexate; the impact of this
      change on hematopoietic recovery, donor/recipient chimerism, and the incidence of acute GVHD
      will be assessed.

      Immune reconstitution following allogeneic HSCT is an important research interest among
      Experimental Transplantation and Immunology Branch Investigators. Current evidence suggests a
      critical role for interleukin-7 (IL-7) in cluster of differentiation 4 (CD4)+ T cell
      homeostasis, and interleukin-15 (IL-15) appears crucial to cluster of differentiation 8
      (CD8)+ T cell and NK cell homeostasis. The relationships between these cytokines and
      lymphocyte subpopulations have not been studied in the setting of allogeneic HSCT; such
      analysis may enhance our understanding of engraftment kinetics, graft-versus-host disease,
      and immune reconstitution. We will correlate serum IL-7 and IL-15 levels with changes in
      circulating T-cell and natural killer (NK)-cell subpopulations during EPOCH-F/R induction
      chemotherapy, after transplantation, and with the development of GVHD.
    

Intervention name(s): Stem cell transplantation; Fludarabine; Cyclophosphamide; Etoposide; Doxorubicin; Vincristine; Prednisone; Methotrexate; Cyclosporine; Apheresis
Intervention type(s): Procedure; Drug; Drug; Drug; Drug; Drug; Drug; Drug; Drug; Procedure
Intervention description(s): 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.
Other intervention name(s): hematopoietic stem cell transplant (HSCT); Fludara; Cytoxan; Toposar; Doxil; Oncovin; Deltasone; Rasuvo; Neoral; extracorporeal therapy
Intervention MeSH terms: Cyclosporine; Prednisone; Cyclophosphamide; Doxorubicin; Methotrexate; Fludarabine; Etoposide; Vincristine; Cyclosporins
Allocation: Non-Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Lymphoma; Leukemia; Hodgkin's Disease; Multiple Myeloma; Immunotherapy