A Pilot Study of Intensified Lymphodepletion Followed by Autologous Hematopoietic Stem Cell Transplantation in Patients With Severe Systemic Lupus Erythematosus
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 9
- 试验地点
- 1
- 主要终点
- Relapse-free Complete Clinical Response
研究概览
简要总结
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.
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详细描述
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:
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 15 Years 至 40 Years（Child, Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- 未提供
排除标准
- 未提供
研究组 & 干预措施
Autologous HSCT in SLE
Autologous hematopoietic stem cell transplantation (HSCT) in systemic lupus erythematosus (SLE).
SLE is a chronic, inflammatory disease of the immune system. Participants received a priming, conditioning and transplant regimen. Priming regimen consisted of treatment with rituxan, filgrastim, cyclophosphamide, mesna, fludarabine phosphate, and methylprednisolone. Conditioning and transplant regimen consisted of fludarabine, cyclophosphamide, rituxan, filgrastim, mesna, diphenhydramine and stem cell transplant infusion.
干预措施: fludarabine phosphate (Drug)
Autologous HSCT in SLE
Autologous hematopoietic stem cell transplantation (HSCT) in systemic lupus erythematosus (SLE).
SLE is a chronic, inflammatory disease of the immune system. Participants received a priming, conditioning and transplant regimen. Priming regimen consisted of treatment with rituxan, filgrastim, cyclophosphamide, mesna, fludarabine phosphate, and methylprednisolone. Conditioning and transplant regimen consisted of fludarabine, cyclophosphamide, rituxan, filgrastim, mesna, diphenhydramine and stem cell transplant infusion.
干预措施: cyclophosphamide (Drug)
Autologous HSCT in SLE
Autologous hematopoietic stem cell transplantation (HSCT) in systemic lupus erythematosus (SLE).
SLE is a chronic, inflammatory disease of the immune system. Participants received a priming, conditioning and transplant regimen. Priming regimen consisted of treatment with rituxan, filgrastim, cyclophosphamide, mesna, fludarabine phosphate, and methylprednisolone. Conditioning and transplant regimen consisted of fludarabine, cyclophosphamide, rituxan, filgrastim, mesna, diphenhydramine and stem cell transplant infusion.
干预措施: Rituxan (rituximab) (Biological)
Autologous HSCT in SLE
Autologous hematopoietic stem cell transplantation (HSCT) in systemic lupus erythematosus (SLE).
SLE is a chronic, inflammatory disease of the immune system. Participants received a priming, conditioning and transplant regimen. Priming regimen consisted of treatment with rituxan, filgrastim, cyclophosphamide, mesna, fludarabine phosphate, and methylprednisolone. Conditioning and transplant regimen consisted of fludarabine, cyclophosphamide, rituxan, filgrastim, mesna, diphenhydramine and stem cell transplant infusion.
干预措施: filgrastim (Biological)
Autologous HSCT in SLE
Autologous hematopoietic stem cell transplantation (HSCT) in systemic lupus erythematosus (SLE).
SLE is a chronic, inflammatory disease of the immune system. Participants received a priming, conditioning and transplant regimen. Priming regimen consisted of treatment with rituxan, filgrastim, cyclophosphamide, mesna, fludarabine phosphate, and methylprednisolone. Conditioning and transplant regimen consisted of fludarabine, cyclophosphamide, rituxan, filgrastim, mesna, diphenhydramine and stem cell transplant infusion.
干预措施: methylprednisolone (Drug)
Autologous HSCT in SLE
Autologous hematopoietic stem cell transplantation (HSCT) in systemic lupus erythematosus (SLE).
SLE is a chronic, inflammatory disease of the immune system. Participants received a priming, conditioning and transplant regimen. Priming regimen consisted of treatment with rituxan, filgrastim, cyclophosphamide, mesna, fludarabine phosphate, and methylprednisolone. Conditioning and transplant regimen consisted of fludarabine, cyclophosphamide, rituxan, filgrastim, mesna, diphenhydramine and stem cell transplant infusion.
干预措施: immunologic technique (Other)
Autologous HSCT in SLE
Autologous hematopoietic stem cell transplantation (HSCT) in systemic lupus erythematosus (SLE).
SLE is a chronic, inflammatory disease of the immune system. Participants received a priming, conditioning and transplant regimen. Priming regimen consisted of treatment with rituxan, filgrastim, cyclophosphamide, mesna, fludarabine phosphate, and methylprednisolone. Conditioning and transplant regimen consisted of fludarabine, cyclophosphamide, rituxan, filgrastim, mesna, diphenhydramine and stem cell transplant infusion.
干预措施: laboratory biomarker analysis (Other)
Autologous HSCT in SLE
Autologous hematopoietic stem cell transplantation (HSCT) in systemic lupus erythematosus (SLE).
SLE is a chronic, inflammatory disease of the immune system. Participants received a priming, conditioning and transplant regimen. Priming regimen consisted of treatment with rituxan, filgrastim, cyclophosphamide, mesna, fludarabine phosphate, and methylprednisolone. Conditioning and transplant regimen consisted of fludarabine, cyclophosphamide, rituxan, filgrastim, mesna, diphenhydramine and stem cell transplant infusion.
干预措施: autologous hematopoietic stem cell transplantation (Procedure)
Autologous HSCT in SLE
Autologous hematopoietic stem cell transplantation (HSCT) in systemic lupus erythematosus (SLE).
SLE is a chronic, inflammatory disease of the immune system. Participants received a priming, conditioning and transplant regimen. Priming regimen consisted of treatment with rituxan, filgrastim, cyclophosphamide, mesna, fludarabine phosphate, and methylprednisolone. Conditioning and transplant regimen consisted of fludarabine, cyclophosphamide, rituxan, filgrastim, mesna, diphenhydramine and stem cell transplant infusion.
干预措施: Diphenhydramine (Drug)
Autologous HSCT in SLE
Autologous hematopoietic stem cell transplantation (HSCT) in systemic lupus erythematosus (SLE).
SLE is a chronic, inflammatory disease of the immune system. Participants received a priming, conditioning and transplant regimen. Priming regimen consisted of treatment with rituxan, filgrastim, cyclophosphamide, mesna, fludarabine phosphate, and methylprednisolone. Conditioning and transplant regimen consisted of fludarabine, cyclophosphamide, rituxan, filgrastim, mesna, diphenhydramine and stem cell transplant infusion.
干预措施: Mesna (Drug)
结局指标
主要结局
Relapse-free Complete Clinical Response
时间窗: 60 months
Complete clinical response is defined as complete clinical response in the target organ and no clinical signs of active lupus as determined by a Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) score of ≤3; prednisone ≤10mg/day at 6 months and ≤5mg/day at 12 months or later.
次要结局
- Number of Participants With Adverse Events(18 months)
- Extractable Nuclear Antigen (ENA)(Day -7, day 0, 1 3, and 6 months, 1 year, 18 months, 2 years and 3 years.)
- White Blood Cells(Day -7, day 0, 1 3, and 6 months, 1 year, 18 months, 2 years and 3 years.)
- Anti-Smith-Ribonuclear Protein Antibody(Day -7, day 0, 1 3, and 6 months, 1 year, 18 months and 2 years.)
- Absolute Lymphocyte Count(Day -7, day 0, 1 3, and 6 months, 1 year, 18 months, 2 years and 3 years.)
- Platelet Count(Day -7, day 0, 1 3, and 6 months, 1 year, 18 months, 2 years and 3 years.)
- Cluster of Differentiation 4 (CD4) + Cells(Day 0, 1 month, 3 months, 6 months, 1 year and 2 years.)
- Anti-Nuclear Antibody(Day -7, day 0, 1 3, and 6 months, 1 year, 18 months, 2 years and 3 years.)
- Anti-Double Stranded Deoxyribonucleic Acid (DNA) Antibody(Day -7, day 0, 1 3, and 6 months, 1 year, 18 months, 2 years and 3 years.)
- Absolute Neutrophil Count(Day -7, day 0, 1 3, and 6 months, 1 year, 18 months, 2 years and 3 years.)
- Cluster of Differentiation 3 (CD3) + Cells(Day 0, 1 month, 3 months, 6 months, 1 year and 2 years.)
- Cluster of Differentiation 8 (CD8) + Cells(Day 0, 1 month, 3 months, 6 months, 1 year and 2 years.)
- Natural Killer Cells(Day 0, 1 month, 3 months, 6 months, 1 year and 2 years.)
- Systemic Lupus Erythematosus Disease Activity Index (SLEDAI)(Day -7, day 0, 1 month, 3 months, 6 months, 1 year, 18 months, 2 years and 3 years.)
- Cluster of Differentiation 19 (CD19) + Cells(Day 0, 1 month, 3 months, 6 months, 1 year and 2 years.)
研究者
Steven Pavletic, M.D.
Principal Investigator
National Cancer Institute (NCI)