Lymphocyte Depletion and Stem Cell Transplantation to Treat Severe Systemic Lupus Erythematosus
Condition: Lupus Erythematosus, Systemic
MeSH terms: Lupus Erythematosus, Systemic
Study type: Interventional
Phase: Phase 2

Summary: 
      This study will examine a new approach to treating patients with severe systemic lupus
      erythematosus (SLE) that involves collecting stem cells (cells produced by the bone marrow
      that develop into blood cells) from the patient, completely shutting down the patient's
      immune system, and then giving back the patient's stem cells. SLE is a chronic, inflammatory
      disorder of the immune system that can affect many organs. It is called an autoimmune disease
      because the patient's lymphocytes (white blood cells that normally protect against invading
      organisms), go out of control and attack the body's own tissues.

      Patients between 15 and 40 years of age with severe SLE affecting a major organ that is
      resistant to standard treatment may be eligible for this study. Candidates are screened with
      a medical history and physical examination, blood and urine tests, skin tuberculin test, and
      radiology studies to evaluate the extent of disease. They have endocrinology, nutrition,
      dental, and social work consultations, ultrasound or MUGA (multi-gated acquisition scan) scan
      heart imaging, electrocardiogram and lung function tests, bone marrow biopsy, and lymph node
      aspirate. Depending on which organs are affected, patients may have additional tests, such as
      lumbar puncture (spinal tap), kidney or lung biopsy, MRI (magnetic resonance imaging) of the
      brain and spinal cord, and PET (positron emission tomography) scan. They also complete
      quality of life questionnaires and have disability functional testing and neurocognitive
      (thinking) assessments.

      Participants have a central venous line (plastic tube) inserted into a neck or chest vein for
      administering stem cells and medicines and for drawing blood. They undergo seven apheresis
      procedures during the course of the study to collect stem cells for transplant and for
      research. For apheresis, whole blood is collected through a needle in an arm vein and
      directed to a cell-separating machine where the white cells are extracted and the rest of the
      blood is returned to the patient through the same needle.

      Patients are primed with three medications (methylprednisolone, rituximab, and
      cyclophosphamide) through the central line to help control the disease. In addition, a
      medication called G-CSF (growth colony stimulating factor) is injected under the skin for
      several days to boost production of stem cells. After enough stem cells have been collected
      for transplantation (infusion through the central line), patients are admitted to the
      hospital for an 8-day conditioning regimen followed by transplantation. The conditioning
      treatment consists of rituximab, fludarabine, and cyclophosphamide to eliminate all the white
      blood cells from the blood and bone marrow. The stem cells are then infused and the patient
      is closely monitored by a team of physicians and nurses. When the stem cells have engrafted,
      the bone marrow has recovered, and the patient feels well enough - usually 2 to 3 weeks after
      transplant - the patient is discharged from the hospital. Prednisone tapering begins as soon
      as feasibly possible, but no later then 28 days after transplant.

      Patients return to the National Institutes of Health (NIH) Clinical Center for frequent
      follow-up visits during the first 2 to 3 months following transplant. The time between visits
      is then extended to once every 3 months the first year, then every 6 months the second year,
      and then at least yearly for 5 years after the transplant. These visits include a physical
      examination, blood and urine tests, lumbar puncture (if there is central nervous system
      involvement), other appropriate biopsies and tests as needed to monitor the patient's health,
      short apheresis procedures to collect blood for research purposes, and quality of life
      questionnaires. Some select procedures will be optional. Bone marrow biopsies and lymph node
      aspirates are done at beginning and at 6, 12, and 24 months after transplant. PET scans are
      done at 1, 6, 12, and 24 months.

      ...
    

Detailed description: 
      Background:

        -  Systemic lupus erythematosus (SLE) is a systemic autoimmune disease that can involve
           almost any organ and can range in severity from mild to life-threatening. In spite of
           significant improvements in survival of SLE patients over last 20 years, a small but
           significant portion of patients still develop progressive therapy-refractory disease
           that impairs organ function and overall survival.

        -  Since 1996, more than 500 patients have been treated worldwide in pilot trials of
           autologous hematopoietic stem cell transplantation (autoHSCT) for autoimmune diseases,
           including about 80 patients with SLE.

        -  The rationale for autoHSCT in autoimmune disease is to ablate autoreactive immune
           effectors and allow reconstitution of a new self-tolerant immune system from the

      hematopoietic stem cell. Studies have demonstrated acceptable safety and promising short term
      efficacy of high-dose cyclophosphamide-based (200 mg/kg) autoHSCT for about 60% of patients
      with advanced refractory SLE and reacquisition of sensitivity to conventional drugs have been
      demonstrated in many cases. However, these trials were designed to address the primary
      endpoint of safety and were inadequate for assessing the disease response.

      -Numerous questions about the true efficacy of autoHSCT, optimal transplant regimen, patient
      selection and mechanisms of action remain unaddressed.

      Objectives:

        -  The primary objective is to assess the rate of continuous relapse-free complete clinical
           responses at 24 months post-transplant, with statistical power of 84% to detect, if
           greater than 70 percent of patients meet the primary endpoint.

        -  The long-term goal of this research is to develop a basis for future transplant
           protocols that would incorporate new cellular or other immunotherapeutic interventions
           to further improve results of transplants with the ultimate goal to cure SLE.

      Eligibility:

      -Subjects age 15-40 years who fulfill at least 4 of the 11 criteria for SLE as defined by the

      American College of Rheumatology

      -Have severe and active lupus, refractory to immunosuppressive therapy. Included are subjects
      with nephritis, central nervous system (CNS) lupus, pulmonary lupus or hematologic disease

      Design:

        -  Fourteen patients with active and standard dose cyclophosphamide-resistant SLE will be
           enrolled on this phase II pilot study.

        -  Study design is intended to improve the efficacy of autoHSCT. A lymphoablative
           conditioning regimen (rituximab, fludarabine and cyclophosphamide) is explored for the
           first time in autoimmune disease.

        -  The treatment schedule consists of two parts; the priming regimen prior to stem cell
           mobilization and collection, and the conditioning regimen with transplant.

        -  In contrast to other studies, this study has precisely defined eligibility and disease
           response criteria with strict schema of tapering immunosuppression that should allow
           accurate interpretation of the treatment results.

        -  The study includes a carefully chosen battery of laboratory research studies designed to
           investigate SLE biology and mechanisms of post-transplant responses.
    

Intervention name(s): fludarabine phosphate; cyclophosphamide; Rituxan (rituximab); filgrastim; methylprednisolone; immunologic technique; laboratory biomarker analysis; autologous hematopoietic stem cell transplantation; Diphenhydramine; Mesna
Intervention type(s): Drug; Drug; Biological; Biological; Drug; Other; Other; Procedure; Drug; Drug
Intervention description(s): Conditioning and transplant regimen: 30 mg/m^2 day intravenous infusion over 30 minutes daily, 4 days (transplant days -6, -5, -4, -3); Priming regimen: 2000 mg/m^2 intravenous infusion over 2 hours, day 2. Conditioning and transplant regimen: 1200 mg/m^2 day intravenous infusion daily, 4 days (-6, -5, -4, -3).; Priming regimen: 375 mg/m^2 intravenous day 1, 4. Conditioning and transplant regimen: 750 mg/m^2 intravenous infusion, day -7.; Priming regimen: 10 micrograms/kg/day subcutaneous, starting day 6. Conditioning and transplant regimen: 5 micrograms/kg/day subcutaneous, day +1 until ANC >500 microliters.; Priming regimen:1000 mg intravenous over 30 minutes, day 1.; Lymphoablative regimen using cyclophosphamide, rituximab, and fludarabine followed by a CD34 cell selected autologous stem cell transplant.; Standard human immunology research laboratory ex vivo studies.; Day 0, product will be infused rapidly intravenously after premedication with diphenhydramine 25-60 mg orally or intravenous.; Conditioning and transplant regimen 25-50 mg orally or intravenously.; Priming regimen: 600 mg/m^2 intravenous immediately prior to cyclophosphamide and repeat at 4 and 7 hours after the first dose, day 2. Conditioning and transplant regimen:1200 mg/m^2 per day continuous 24 hour intravenous infusion, daily for 4 days, start concurrently with the start of cyclophosphamide.
Other intervention name(s): Fludara; Cytoxan; Rituximab; GCSF (growth colony stimulating factor); Medrol; Benadryl; Mesnex
Intervention MeSH terms: Diphenhydramine; Promethazine; Methylprednisolone; Cyclophosphamide; Rituximab; Fludarabine; Fludarabine phosphate
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Refractory SLE; Immunoablation; Immunological Recovery; Efficacy; Mechanism of Disease; Lupus; Systemic Lupus Erythematosus; SLE