Lymphocyte Depletion and Stem Cell Transplantation to Treat Severe Systemic Lupus Erythematosus

NCT00076752 | Completed Phase 2 Results DMC FDA Drug

• 2 other identifiers: 04009504-C-0095
• Study Type: interventional
• Target: 9
• Locations: 1 country
• Sites: 1

Brief 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. ...

Conditions

Lupus Erythematosus, Systemic

Keywords

Refractory SLE; Immunoablation; Immunological Recovery; Efficacy; Mechanism of Disease; Lupus; Systemic Lupus Erythematosus; SLE

Outcome Measures

Primary Outcomes (1)

• Relapse-free Complete Clinical Response

  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.

  60 months

Secondary Outcomes (15)

• Number of Participants With Adverse Events

  18 months

• Anti-Nuclear Antibody

  Day -7, day 0, 1 3, and 6 months, 1 year, 18 months, 2 years and 3 years.

• Extractable Nuclear Antigen (ENA)

  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.

• Anti-Smith-Ribonuclear Protein Antibody

  Day -7, day 0, 1 3, and 6 months, 1 year, 18 months and 2 years.

Study Arms (1)

Autologous HSCT in SLE

EXPERIMENTAL

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; Drug: cyclophosphamide; Biological: Rituxan (rituximab); Biological: filgrastim; Drug: methylprednisolone; Other: immunologic technique; Other: laboratory biomarker analysis; Procedure: autologous hematopoietic stem cell transplantation; Drug: Diphenhydramine; Drug: Mesna

Interventions

fludarabine phosphate DRUG

Conditioning and transplant regimen: 30 mg/m\^2 day intravenous infusion over 30 minutes daily, 4 days (transplant days -6, -5, -4, -3)

Also known as: Fludara

Autologous HSCT in SLE

cyclophosphamide DRUG

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).

Also known as: Cytoxan

Autologous HSCT in SLE

Rituxan (rituximab) BIOLOGICAL

Priming regimen: 375 mg/m\^2 intravenous day 1, 4. Conditioning and transplant regimen: 750 mg/m\^2 intravenous infusion, day -7.

Also known as: Rituximab

Autologous HSCT in SLE

filgrastim BIOLOGICAL

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.

Also known as: GCSF (growth colony stimulating factor)

Autologous HSCT in SLE

methylprednisolone DRUG

Priming regimen:1000 mg intravenous over 30 minutes, day 1.

Also known as: Medrol

Autologous HSCT in SLE

immunologic technique OTHER

Lymphoablative regimen using cyclophosphamide, rituximab, and fludarabine followed by a CD34 cell selected autologous stem cell transplant.

Autologous HSCT in SLE

laboratory biomarker analysis OTHER

Standard human immunology research laboratory ex vivo studies.

Autologous HSCT in SLE

autologous hematopoietic stem cell transplantation PROCEDURE

Day 0, product will be infused rapidly intravenously after premedication with diphenhydramine 25-60 mg orally or intravenous.

Autologous HSCT in SLE

Diphenhydramine DRUG

Conditioning and transplant regimen 25-50 mg orally or intravenously.

Also known as: Benadryl

Autologous HSCT in SLE

Mesna DRUG

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.

Also known as: Mesnex

Autologous HSCT in SLE

Eligibility Criteria

• Age: 15 Years - 40 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• Age 15-40 years
• Must fulfill at least 4 of the following 11 criteria for systemic lupus erythematous (SLE) as defined by the American College of Rheumatology:
• Malar rash. Fixed erythema, flat or raised, over the malar eminences, tending to spare the nasolabial folds.
• Discoid rash. Erythematous raised patches with adherent keratotic scaling and follicular plugging; atrophic scarring may occur in older lesions.
• Photosensitivity. Skin rash as a result of unusual reaction to sunlight, by patient history or physician observation.
• Oral ulcers. Oral or nasopharyngeal ulcerations, usually painless, observed by a physician.
• Arthritis. Nonerosive arthritis involving two or more peripheral joints, characterized by tenderness, swelling, or effusion.
• Serositis. a.) Pleuritis - convincing history of pleuritic pain or rub heard by a physician or evidence of pleural effusion
• b.) Pericarditis - documented by electrocardiogram (ECG) or rub or evidence of pericardial effusion
• Renal disorder. a.) Persistent proteinuria greater than 0.5 grams per day or greater than 3+ if quantitation not performed
• b.) Cellular casts - may be red cell, hemoglobin, granular, tubular, or mixed.
• Neurologic disorder. a.) Seizures - in the absence of offending drugs or known metabolic derangements; eg, uremia, ketoacidosis, or electrolyte imbalance
• b.) Psychosis - in the absence of offending drugs or known metabolic derangements; eg, uremia, ketoacidosis, or electrolyte imbalance
• Hematologic disorder. a.) Hemolytic anemia - with reticulocytosis
• b.) Leukopenia - less than 4000/ L total on two or more occasions

You may not qualify if:

• \. Inability to provide written informed consent prior to entry in the protocol
• \. Pregnant or lactating women. Women of childbearing potential are required to have a negative pregnancy test at screening
• \. Women of childbearing potential who are not practicing or who are unwilling to practice birth control during the entire study
• \. Men who are unwilling to practice birth control for the first 6 months after the transplant
• \. Evidence of infection with hepatitis B, hepatitis C, or human immunodeficiency virus (HIV)
• \. History of malignancy other than basal cell carcinoma of the skin
• \. Carbon monoxide diffusing capacity (DLCO) corrected less than 45%
• \. Left ventricular ejection fraction (LVEF) less than 45%, determined by ECHO cardiogram or MUGA
• \. Serum glutamic oxaloacetic transaminase (SGOT) or serum glutamic pyruvic transaminase (SGPT) greater than 2x upper limit of normal (unless active myopathy is proven by elevation of serum aldolase levels and the patient has no obvious hepatic disease) and/or bilirubin greater than 2.0 (unless due to isolated hemolysis).
• \. Calculated glomerular filtration rate less than 30 ml/min using the modification of diet in renal disease (MDRD) equation estimate:
• Glomerular filtration rate (GFR) (ml/min/173 m\^2) =186.3 x (Pcr) exponential -1.154 x (age) exponential -0.203 x 1.212 (if black) x 0.742 (if female)
• \. Late flare (patients who have target organ flare, that is not within the time frame defined as early flare, will not be considered as treatment failures until they receive the minimally required therapy for this flare episode and fail to respond to it)
• \. Abnormal bone marrow cytogenetics
• \. Significant concurrent medical condition or any significant circumstance that could affect the patient's ability to tolerate or complete the study
• \. Live vaccines within 4 weeks of starting the priming regimen

Sponsors & Collaborators

• National Cancer Institute (NCI): lead

Study Sites (1)

National Institutes of Health Clinical Center, 9000 Rockville Pike

Bethesda, Maryland, 20892, United States

Location

Related Publications (5)

• Shlomchik MJ, Craft JE, Mamula MJ. From T to B and back again: positive feedback in systemic autoimmune disease. Nat Rev Immunol. 2001 Nov;1(2):147-53. doi: 10.1038/35100573.

  PMID: 11905822 BACKGROUND

• Manzi S, Meilahn EN, Rairie JE, Conte CG, Medsger TA Jr, Jansen-McWilliams L, D'Agostino RB, Kuller LH. Age-specific incidence rates of myocardial infarction and angina in women with systemic lupus erythematosus: comparison with the Framingham Study. Am J Epidemiol. 1997 Mar 1;145(5):408-15. doi: 10.1093/oxfordjournals.aje.a009122.

  PMID: 9048514 BACKGROUND

• Lipsky PE. Systemic lupus erythematosus: an autoimmune disease of B cell hyperactivity. Nat Immunol. 2001 Sep;2(9):764-6. doi: 10.1038/ni0901-764. No abstract available.

  PMID: 11526379 BACKGROUND

• Illei GG, Cervera R, Burt RK, Doria A, Hiepe F, Jayne D, Pavletic S, Martin T, Marmont A, Saccardi R, Voskuyl AE, Farge D. Current state and future directions of autologous hematopoietic stem cell transplantation in systemic lupus erythematosus. Ann Rheum Dis. 2011 Dec;70(12):2071-4. doi: 10.1136/ard.2010.148049. Epub 2011 Aug 26.

  PMID: 21873334 RESULT

• Goklemez S, Hasni S, Hakim FT, Muraro PA, Pirsl F, Rose J, Memon S, Fowler DF, Steinberg SM, Baker EH, Panch SR, Gress R, Illei GG, Lipsky PE, Pavletic SZ. Long-term follow-up after lymphodepleting autologous haematopoietic cell transplantation for treatment-resistant systemic lupus erythematosus. Rheumatology (Oxford). 2022 Aug 3;61(8):3317-3328. doi: 10.1093/rheumatology/keab877.

  PMID: 34875023 DERIVED

MeSH Terms

Conditions

Lupus Erythematosus, Systemic

Interventions

fludarabine phosphate; Cyclophosphamide; Rituximab; Filgrastim; Methylprednisolone; Immunologic Techniques; Diphenhydramine; Mesna

Condition Hierarchy (Ancestors)

Connective Tissue Diseases; Skin and Connective Tissue Diseases; Autoimmune Diseases; Immune System Diseases

Intervention Hierarchy (Ancestors)

Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Hydrocarbons; Organic Chemicals; Phosphoramides; Organophosphorus Compounds; Antibodies, Monoclonal, Murine-Derived; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Granulocyte Colony-Stimulating Factor; Colony-Stimulating Factors; Glycoproteins; Glycoconjugates; Carbohydrates; Hematopoietic Cell Growth Factors; Cytokines; Intercellular Signaling Peptides and Proteins; Peptides; Biological Factors; Prednisolone; Pregnadienetriols; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Investigative Techniques; Ethylamines; Amines; Benzhydryl Compounds; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Alkanesulfonates; Alkanesulfonic Acids; Alkanes; Hydrocarbons, Acyclic; Sulfhydryl Compounds; Sulfur Compounds; Sulfonic Acids; Sulfur Acids

Results Point of Contact

• Title: Dr. Steven Pavletic
• Organization: National Cancer Institute, National Institutes of Health

pavletis@mail.nih.gov

301-402-4899

Study Officials

• Steven Pavletic, M.D.

  National Cancer Institute (NCI)

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: NIH
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: February 2, 2004
• First Posted: February 3, 2004
• Study Start: January 30, 2004
• Primary Completion: October 15, 2013
• Study Completion: October 15, 2013
• Last Updated: January 5, 2021
• Results First Posted: June 10, 2014

Record last verified: 2020-12

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)