Lymphocyte Depletion and Stem Cell Transplantation to Treat Severe Systemic Lupus Erythematosus
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.
Lupus Erythematosus, Systemic
Drug: fludarabine phosphate
Biological: Rituxan (rituximab)
Other: immunologic technique
Other: laboratory biomarker analysis
Procedure: autologous hematopoietic stem cell transplantation
|Study Design:||Endpoint Classification: Safety Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||A Pilot Study of Intensified Lymphodepletion Followed by Autologous Hematopoietic Stem Cell Transplantation in Patients With Severe Systemic Lupus Erythematosus|
- Relapse-free Complete Clinical Response [ Time Frame: 60 months ] [ Designated as safety issue: No ]
- Number of Participants With Adverse Events [ Time Frame: 18 months ] [ Designated as safety issue: Yes ]Here is the number of participants with adverse events. For a detailed list of adverse events, see the adverse event module.
|Study Start Date:||January 2004|
|Study Completion Date:||October 2013|
|Primary Completion Date:||October 2013 (Final data collection date for primary outcome measure)|
Experimental: 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.
Drug: fludarabine phosphate
Conditioning and transplant regimen: 30 mg/m^2 day intravenous infusion over 30 minutes daily, 4 days (transplant days -6, -5, -4, -3)
Other Name: FludaraDrug: cyclophosphamide
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).
Other Name: CytoxanBiological: Rituxan (rituximab)
Priming regimen: 375 mg/m^2 intravenous day 1, 4. Conditioning and transplant regimen: 750 mg/m^2 intravenous infusion, day -7.
Other Name: RituximabBiological: filgrastim
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.
Other Name: GCSF (growth colony stimulating factor)Drug: methylprednisolone
Priming regimen:1000 mg intravenous over 30 minutes, day 1.
Other Name: MedrolOther: immunologic technique
Lymphoablative regimen using cyclophosphamide, rituximab, and fludarabine followed by a CD34 cell selected autologous stem cell transplant.Other: laboratory biomarker analysis
Standard human immunology research laboratory ex vivo studies.Procedure: autologous hematopoietic stem cell transplantation
Day 0, product will be infused rapidly intravenously after premedication with diphenhydramine 25-60 mg orally or intravenous.Drug: Diphenhydramine
Conditioning and transplant regimen 25-50 mg orally or intravenously.
Other Name: BenadrylDrug: Mesna
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 Name: Mesnex
- 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.
- 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.
-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
- 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.
Please refer to this study by its ClinicalTrials.gov identifier: NCT00076752
|United States, Maryland|
|National Institutes of Health Clinical Center, 9000 Rockville Pike|
|Bethesda, Maryland, United States, 20892|
|Principal Investigator:||Steven Pavletic, M.D.||National Cancer Institute (NCI)|