Stem Cell Transplantation for Patients With Cancers of the Blood
Condition: CML (Chronic Myelogenous Leukemia); CLL (Chronic Lymphocytic Leukemia); AML (Acute Myelogenous Leukemia); Acute Lymphocytic Leukemia; MDS (Myelodysplastic Syndrome)
MeSH terms: Leukemia; Preleukemia; Leukemia, Lymphoid; Leukemia, Lymphocytic, Chronic, B-Cell; Leukemia, Myeloid; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Leukemia, Myeloid, Acute; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Myelodysplastic Syndromes
Study type: Interventional
Phase: Phase 2

Summary: 
      This study will try to improve the safety and effectiveness of stem cell transplant
      procedures in patients with cancers of the blood. It will use a special machine to separate
      immune cells (T cells) from the blood of both the donor and the patient and will use
      photodepletion, a laboratory procedure that selectively kills cancer cells exposed to light.
      These special procedures may reduce the risk of graft-versus-host-disease (GVHD), a serious
      complication of stem cell transplants in which the donor's immune cells destroy the patient's
      healthy tissues, and at the same time may permit a greater graft-versus-leukemia effect, in
      which the donated cells fight any residual tumor cells that might remain in the body.

      Patients between 18 and 75 years of age with a life-threatening disease of the bone marrow
      (acute or chronic leukemia, myelodysplastic syndrome, or myeloproliferative syndrome) may be
      eligible for this study. Candidates must have a family member who is a suitable tissue match.
    

Detailed description: 
      Peripheral blood stem cell transplant research carried out by the NHLBI BMT Unit focus on
      approaches in transplant techniques designed to decrease graft versus host disease (GVHD),
      increase the graft-versus-leukemia (GVL) effect, and/or reduce the risk for post-transplant
      graft rejection or disease relapse.

      Ex vivo selective depletion of alloreacting T cells, hereafter referred as selective
      depletion (SD), represents a translational strategy aiming to reduce severe GVHD whilst
      preserving GVL. We found that selectively depleted transplants are safe to administer and
      associated with less severe acute GVHD. This protocol is designed to evaluate the safety and
      efficacy of photodepletion (PD) as an improved selective depletion procedure in the
      HLA-matched peripheral blood stem cell transplant setting and to determine whether
      post-transplant immunosuppression with cyclosporine is necessary to prevent severe GVHD after
      a photodepleted transplant.

      The protocol will accrue subjects ages 18-75 who are diagnosed with a hematological
      malignancy where allogeneic stem cell transplantation from an HLA-matched sibling would be
      normally indicated. Diagnostic categories will include acute and chronic leukemias,
      myelodysplastic syndromes, B-cell lymphomas, multiple myeloma, and myeloproliferative
      syndromes.

      Participants have a central intravenous (IV) line placed into a large vein. The tube is used
      for giving the donated stem cells and antibiotics and other medicines, for transfusions of
      red blood cells and platelets, and for collecting blood samples. Treatment starts with a
      conditioning regimen of chemotherapy (fludarabine and cyclophosphamide) and total body
      irradiation to suppress immunity and prevent rejection of the donated stem cells. The day
      after chemotherapy ends, the stem cells are given through the central line. This is followed
      by transfusion of the donor's immune cells, which have been treated to remove cells that
      could cause severe GVHD. Also to minimize the risk of GVHD, patients are given cyclosporine.
      Not all participants receive the same amount of this drug; in order to determine how much
      immunosuppression is needed to protect against severe GVHD, the length of treatment with
      cyclosporine varies among patients, depending on when they entered the study and how well
      preceding patients did.

      The average hospital stay for stem cell transplantation is 3 to 4 weeks. Patients return for
      frequent follow-up visits for the first 2 to 4 months after transplantation. The patient's
      referring physician is asked to send results of any laboratory testing to the NIH researchers
      at least every 3 months for the first 3 years and annually thereafter. Patient follow-up
      visits are scheduled at NIH at 1, 2, and 3 years after transplantation. After 3 years,
      participants are offered the opportunity to enroll in NHLBI's long-term evaluation and
      follow-up care protocol.

      Subjects will receive a myeloablative conditioning regimen of cyclophosphamide, fludarabine
      and total body irradiation, followed by an infusion of a stem cell product prepared using the
      Miltenyi CliniMacs system for CD34 selection and a lymphocyte product that has been
      selectively depleted using the photodepletion approach (Kiadis Pharma). Older subjects will
      receive a lower dose of irradiation to reduce the regimen intensity.

      To determine appropriate level of post transplant immunosuppression, we will utilize a three
      sequential de-escalation stage design involving 17 subjects per cohort (minimum 17, maximum
      51 total evaluable subjects in study). Stopping rules for non-relapse mortality in each
      cohort will determine whether to continue to the next stage; to continue accumulating
      subjects at the same level; or to stop the protocol.

      Cohort 1: Low dose cyclosporine until day 90 then dose tapered to stop within 2 weeks.

      Cohort 2: If no severe GVHD is encountered in Cohort 1, the cyclosporine withdrawal will
      begin on day 45.

      Cohort 3: If no severe GVHD is encountered in Cohort 2, cyclosporine will not be used in the
      post-transplant period.

      Primary endpoints will be the incidence of acute grade III/IV GVHD at day 90. Secondary
      endpoints will be standard transplant outcome variables: toxicity, non relapse mortality and
      survival.
    

Intervention name(s): Miltenyi system
Intervention type(s): Combination Product
Intervention description(s): Subjects will receive a myeloablative conditioning regimen of cyclophosphamide, fludarabine and total body irradiation, followed by an infusion of a stem cell product prepared using the Miltenyi CliniMacs system for CD34 selection and a lymphocyte product that has been selectively depleted using the photodepletion approach.
Intervention model: Single Group Assignment
Intervention model description: Evaluation of selective depletion of alloreactive T cells to prevent graft vs host disease
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: CML (Chronic Myelogenous Leukemia); CLL (Chronic Lymphocytic Leukemia); AML (Acute Myelogenous Leukemia); Leukemia; Chronic Lymphocytic Leukemia; CLL; Chronic Myelogenous Leukemia; CML; Acute Myelogenous Leukemia; AML; Acute B-Lymphoblastic Leukemia; ALL; Myelodysplastic Syndrome; MDS