Lymphocyte Depletion and Stem Cell Transplantation to Treat Severe Systemic Lupus Erythematosus
Condition: Lupus Erythematosus, Systemic
MeSH terms: Lupus Erythematosus, Systemic
Intervention: fludarabine phosphate; cyclophosphamide; Rituxan (rituximab); filgrastim; methylprednisolone; immunologic technique; laboratory biomarker analysis; autologous hematopoietic stem cell transplantation; Diphenhydramine; Mesna
Intervention description: 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.
Intervention MeSH terms: Diphenhydramine; Promethazine; Methylprednisolone; Cyclophosphamide; Rituximab; Fludarabine; Fludarabine phosphate
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 9.0
Sex: All
Minimum age: 15 Years
Maximum age: 40 Years
Healthy volunteers: No
Keywords: Refractory SLE; Immunoablation; Immunological Recovery; Efficacy; Mechanism of Disease; Lupus; Systemic Lupus Erythematosus; SLE

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.

      ...
    

Eligibility criteria:

        -INCLUSION CRITERIA

          1. Age 15-40 years

          2. 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

             OR

             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

             OR

             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

             OR

             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

             OR

             b.) Leukopenia - less than 4000/ L total on two or more occasions

             OR

             c.) Lymphopenia - less than 1500/ L on two or more occasions

             OR

             d.) Thrombocytopenia - less than 100,000/ L in the absence of offending drugs

               -  Immunologic disorder. a.) Anti-deoxyribonucleic acid (DNA): antibody to native
                  DNA in abnormal titer

             OR

             b.) Anti-SM: presence of antibody to SM nuclear antigen

             OR

             c.) Positive finding of antiphospholipid antibodies based on (1) an abnormal serum
             level of immunoglobulin G (IgG) or immunoglobulin M (IgM) anti-cardiolipin antibodies,
             (2) a positive test result for lupus anticoagulant using a standard method, or (3)
             false positive serologic test for syphilis known to be positive for at least 6 months
             and confirmed by Treponema Pallidum immobilization or fluorescent treponemal antibody
             absorption test

             -Antinuclear antibodies. An abnormal titer of ANAs by immunofluorescence or an
             equivalent assay at any point in time in the absence of drugs known to be associated
             with drug-induced lupus syndrome.

          3. Have severe and active lupus, refractory to immunosuppressive therapy, defined as one
             of the following (a-d):

             a.Nephritis: Biopsy proven Diffuse Proliferative Glomerulonephritis (World Health
             Organization (WHO) Class IV) with or without superimposed membranous changes

             i.Active disease:

          1. A kidney biopsy within three months of enrollment showing active WHO Class IV disease.
             Activity will be determined based on the presence of endocapillary cellular
             proliferation compromising the capillary loops or cellular crescents or necrosis on
             light microscopy or subendothelial deposits on electron microscopy.

          2. If a biopsy is contraindicated patients can be enrolled if they had a previous biopsy
             showing Diffuse Proliferative Glomerulonephritis (WHO Class IV) and at the time of
             enrollment have all of the following:

               1. Proteinuria greater than 1gm/day

               2. Active urine sediment defined as hematuria (greater than 10 red blood cell
                  (RBC)/hpf (high power field) on a nephrology urinalysis of a 50 mL urine sample)
                  with dysmorphic RBC and/or cellular casts on a nephrology urinalysis of a 50 mL
                  urine sample

               3. Low C3 (less than 69 mg/dL) and/or elevated dsDNA antibodies (greater than 25EU)

          3. Need for prednisone greater than 20 mg/day due to increased renal activity after at
             least 6 months of cyclophosphamide.

        ii. Treatment resistant:

          1. Patients with active disease after at least 6 months of intravenous pulse
             cyclophosphamide +/- iv methylprednisolone and daily oral prednisone, or

          2. Early flare: those who have reactivation of their nephritis during or within 6 months
             of completing cyclophosphamide therapy

          3. Recalcitrant disease: two or more recurrences of lupus nephritis within five years of
             enrollment. All flares must have received adequate therapy and least one of the
             episodes must have been treated with minimum 6 months of intravenous pulse
             cyclophosphamide plus iv methylprednisolone and maintenance oral prednisone.

             Central nervous system (CNS) lupus: Lupus CNS manifestations indicative of
             encephalitis or myelitis or vasculitis. Concomitant CNS diseases should be excluded.
             (e.g. infections, multiple sclerosis; patients fulfilling multiple sclerosis (MS) and
             SLE criteria will be excluded). Clinical signs and symptoms must be supported by
             objective findings of CNS inflammation.

             i. Active disease:

             Signs/symptoms that are accepted for disease activity:

             -Clinical signs and symptoms compatible with focal CNS damage -Severe global
             neurocognitive/psychiatric impairment (eg: psychosis, organic brain syndrome, severe
             depression)

             -Intractable seizures

             Clinical findings must be supported by at least one of the following:

               1. Magnetic resonance imaging (MRI) findings consistent with transverse myelitis or

                  Central nervous system (CNS) vasculitis

                  - Signs of inflammation on MRI are either the presence of Gadolinium
                  (Gd)-enhancing lesions, or the increase of the number and/or volume of
                  T2-weighted lesions (or lesions showing up on fluid attenuated inversion recovery
                  (FLAIR) imaging). We will use the standard MS protocol sequences, which are
                  routinely used in the Clinical Center to evaluate inflammatory CNS lesions.

               2. If patient has seizures/psychiatric signs and symptoms in the absence of clear
                  signs of vasculitis or cerebritis by MRI, the cerebral spinal fluid (CSF) should
                  show protein elevation above normal levels and abnormal number of white blood
                  cells (WBCs) or intrathecal IgG synthesis/or oligoclonal bands.

               3. Need for prednisone greater than 20 mg/day due to increased CNS activity (see
                  above) after at least three months of cyclophosphamide therapy.

             ii-Treatment resistant:

             a) Active disease after a minimum of three months of oral or intravenous
             cyclophosphamide, or

             b) Early flare: reactivation of CNS lupus within 6 months of completing
             cyclophosphamide therapy

             c. Recalcitrant disease: two or more recurrences of CNS lupus within five years of
             enrollment. All flares must have received adequate therapy and at least one of the
             episodes must have been treated with minimum three months of oral or intravenous
             cyclophosphamide.

             Pulmonary lupus

             i. Active disease:

               1. Lung biopsy showing active pneumonitis, alveolitis or pulmonary vasculitis after
                  the minimally required therapy within one month of enrollment or

               2. If a biopsy is contraindicated within one month of enrollment, patients may be
                  included if they had a biopsy at the start or during cyclophosphamide treatment
                  showing active pneumonitis, alveolitis or pulmonary vasculitis (as above) and
                  have abnormal or worsening pulmonary function tests with a chest computed
                  tomography (CT) consistent with active pneumonitis, alveolitis or vasculitis
                  within 2 weeks of enrollment and at the time of enrollment have a CT consistent
                  with active disease.

               3. Need for prednisone greater than 20 mg/day due to increased pulmonary lupus
                  activity after minimum of three months of cyclophosphamide.

                  ii. Treatment resistant:

               4. Ongoing or recurrent active pulmonary lupus after a minimum of three months of
                  oral or intravenous cyclophosphamide, or

               5. Early flare: reactivation of pulmonary lupus (as defined above) within 6 months
                  of completing cyclophosphamide therapy.

               6. Recalcitrant disease: two or more recurrences of pulmonary as described above
                  within five years of enrollment. All flares must have received adequate therapy
                  and at least one of the episodes must have been treated with minimum 3 months of
                  oral or intravenous cyclophosphamide.

             i) Active disease:

             a) Severe immune-mediated thrombocytopenia (platelet count less than 20,000/mm^3 or
             less than 50,000/mm^3 with history of bleeding), or

             b) Severe immune-mediated anemia (requiring transfusions to maintain hemoglobin (Hb)
             greater than 8.0 g/dL or to treat symptoms of anemia) c) Need for prednisone greater
             than 20 mg/day due to increased hematologic lupus activity after therapy as described
             in section ii.a).

             ii) Treatment resistant:

             a) Active disease as defined above after a minimum of three months of high dose oral
             or pulse corticosteroids +/- intravenous immunoglobulin (IVIg) (or WinRho) and
             splenectomy, or

             b) Early flare: reactivation of hematologic lupus (as defined above) within 6 months
             of completing above therapy.

             c) Recalcitrant disease: two or more recurrences of immune-mediated thrombocytopenia
             or anemia, as described above, within five years of enrollment. All flares must have
             received adequate therapy and at least one of the episodes must have been treated by
             splenectomy.

             EXCLUSION CRITERIA

        1. Inability to provide written informed consent prior to entry in the protocol

        2. Pregnant or lactating women. Women of childbearing potential are required to have a
        negative pregnancy test at screening

        3. Women of childbearing potential who are not practicing or who are unwilling to practice
        birth control during the entire study

        4. Men who are unwilling to practice birth control for the first 6 months after the
        transplant

        5. Evidence of infection with hepatitis B, hepatitis C, or human immunodeficiency virus
        (HIV)

        6. History of malignancy other than basal cell carcinoma of the skin

        7. Carbon monoxide diffusing capacity (DLCO) corrected less than 45%

        8. Left ventricular ejection fraction (LVEF) less than 45%, determined by ECHO cardiogram
        or MUGA

        9. 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).

        10. 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)

        11. 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)

        12. Abnormal bone marrow cytogenetics

        13. Significant concurrent medical condition or any significant circumstance that could
        affect the patient's ability to tolerate or complete the study

        14. Live vaccines within 4 weeks of starting the priming regimen