• Continuous relapse-free complete clinical response at 24 months post-transplantation [ Designated as safety issue: No ]
  

• Toxicity [ Designated as safety issue: Yes ]
  
• Time to flare-free complete response [ Designated as safety issue: No ]
  
• Time to complete clinical response [ Designated as safety issue: No ]
  
• Time to partial response [ Designated as safety issue: No ]
  
• Time to relapse [ Designated as safety issue: No ]
  
• Improvement in general disease activity measured by Systemic Lupus Activity Measure (SLAM) and Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) [ Designated as safety issue: No ]
  
• Time to normalization of dsDNA and complement levels [ Designated as safety issue: No ]
  
• Pain scale and quality of life [ Designated as safety issue: No ]
  
• Functional assessment by HAQ score, neurocognitive testing, and depression scale [ Designated as safety issue: No ]
  

OBJECTIVES:

Primary

• To evaluate the rate of durable relapse-free complete clinical responses after using a lymphodepleting non-myeloablative regimen for autologous hematopoietic stem cell transplantation (HSCT) in patients with severe systemic lupus erythematosus (SLE).

Secondary

• To evaluate the toxicity of this regimen in these patients.
• To evaluate the biological markers of disease after autologous HSCT for severe SLE.
• To investigate immunological efficacy and mechanisms of responses after this regimen in these patients.

OUTLINE:

• Priming regimen: Patients receive methylprednisolone IV over 30 minutes on day 1, rituximab IV over 1-2 hours on days 1 and 4, cyclophosphamide IV over 2 hours on day 2, and filgrastim (G-CSF) subcutaneously (SC) starting on day 6 until the day of leukapheresis. Stem cells are collected for 1-3 days and T-cell depletion is performed for CD34-positive selection. Patients who do not collect the minimal number of stem cells are taken off the study. Samples of the stem cell product are obtained for extended immunophenotyping including surface markers and for fluorescence in situ hybridization (FISH) cytogenetics.
• Conditioning regimen and transplant: Beginning 3 weeks after completion of the priming regimen, patients receive rituximab IV on day -7 and fludarabine phosphate IV over 30 minutes and cyclophosphamide IV over 2 hours on days -6, -5, -4, and -3. Patients then undergo autologous hematopoietic stem cell transplantation (HSCT) IV on day 0 followed by G-CSF SC beginning on day 1 and continuing until blood counts recover.

Blood, bone marrow, and secondary lymphoid organs (e.g., lymph nodes and thymus either directly or indirectly) are collected periodically for biomarker studies. Patients also complete a quality of life questionnaire at baseline and periodically during follow up.

After completion of study treatment, patients are followed monthly for 6 months, at 9, 12, 18, and 24 months, and then yearly for up to 5 years.

DISEASE CHARACTERISTICS:

• Must have severe and active lupus, refractory to immunosuppressive therapy, defined as 1 of the following:

  • Nephritis: Biopsy-proven diffuse proliferative glomerulonephritis (WHO class IV) with or without superimposed membranous changes

    • Active disease, meeting 1 of the following criteria:

      • A kidney biopsy within 3 months of enrollment showing active WHO class IV disease (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)
      • If a biopsy is contraindicated, patients are eligible if they had a previous biopsy showing diffuse proliferative glomerulonephritis (WHO class IV) AND meeting all of the criteria (at the time of enrollment): proteinuria > 1 g/day; active urine sediment defined as hematuria (> 10 RBC/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; and low C3 (< 69 mg/dL) and/or elevated dsDNA antibodies (> 25 EU)
      • Requires > 20 mg/day of prednisone due to increased renal activity after at least 6 months of cyclophosphamide

    • Treatment-resistant disease, meeting 1 of the following criteria:

      • Active disease after at least 6 months of mycophenolate mofetil or IV pulse cyclophosphamide with or without IV methylprednisolone and daily oral prednisone
      • Early flare defined as patients who have reactivation of their nephritis during or within 6 months of completing cyclophosphamide therapy
      • Recalcitrant disease defined as 2 or more recurrences of lupus nephritis within 5 years of enrollment (all flares must have received adequate therapy and at least 1 of the episodes must have been treated with a minimum of 6 months of IV pulse cyclophosphamide with or without IV methylprednisolone and maintenance oral prednisone)

  • CNS lupus: Lupus CNS manifestations indicative of encephalitis, myelitis, or vasculitis (clinical signs and symptoms must be supported by objective findings of CNS inflammation)

    • Active disease, meeting 1 of the following criteria:

      • Any of the signs and symptoms: clinical signs and symptoms compatible with focal CNS damage; severe global neurocognitive/psychiatric impairment (e.g., psychosis, organic brain syndrome, or severe depression); or intractable seizures
      • Clinical findings supported by at least 1 of the following: MRI findings consistent with transverse myelitis or CNS vasculitis (signs of inflammation on MRI are either the presence of gadolinium-enhancing lesions or the increase in the number and/or volume of T2-weighted lesions [or lesions showing up on FLAIR imaging]); if the patient has seizures/psychiatric signs and symptoms in the absence of clear signs of vasculitis or cerebritis by MRI, the CSF protein shows elevation above normal levels and an abnormal number of WBCs or intrathecal IgG synthesis/or oligoclonal bands; or requires > 20 mg/day of prednisone due to increased CNS activity after at least 3 months of cyclophosphamide therapy

    • Treatment-resistant disease, meeting 1 of the following criteria:

      • Active disease after at least 3 months of oral or IV cyclophosphamide
      • Early flare defined as reactivation of CNS lupus within 6 months of completing cyclophosphamide therapy
      • Recalcitrant disease defined as 2 or more recurrences of CNS lupus within 5 years of enrollment (all flares must have received adequate therapy and at least 1 of the episodes must have been treated with a minimum of 3 months of oral or IV cyclophosphamide)

  • Pulmonary lupus

    • Active disease, meeting 1 of the following criteria:

      • Lung biopsy showing active pneumonitis, alveolitis, or pulmonary vasculitis after the minimally required therapy within 1 month of enrollment
      • If a biopsy is contraindicated within 1 month of enrollment, patients may be included if they had a biopsy at the start of or during cyclophosphamide treatment showing active pneumonitis, alveolitis, or pulmonary vasculitis; have abnormal or worsening pulmonary function tests with a chest 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
      • Requires > 20 mg/day of prednisone due to increased pulmonary lupus activity after at least 3 months of cyclophosphamide

    • Treatment-resistant disease, meeting 1 of the following criteria:

      • Ongoing or recurrent active pulmonary lupus after at least 3 months of oral or IV cyclophosphamide
      • Early flare defined as reactivation of pulmonary lupus within 6 months of completing cyclophosphamide therapy
      • Recalcitrant disease defined as 2 or more recurrences of pulmonary lupus within 5 years of enrollment (all flares must have received adequate therapy and at least 1 of the episodes must have been treated with a minimum of 3 months of oral or IV cyclophosphamide)

  • Hematologic disease

    • Active disease, meeting 1 of the following criteria:

      • Severe immune-mediated thrombocytopenia (platelet count < 20,000/mm³ OR < 50,000/mm³ with a history of bleeding)
      • Severe immune-mediated anemia (requiring transfusions to maintain hemoglobin > 8.0 g/dL OR to treat symptoms of anemia)
      • Requires > 20 mg/day of prednisone due to increased hematologic lupus activity after therapy

    • Treatment-resistant disease, meeting 1 of the following criteria:

      • Active disease after at least 3 months of high-dose oral or pulse corticosteroids with or without IV immunoglobulin (or WinRho) and splenectomy
      • Early flare defined as reactivation of hematologic lupus within 6 months of completing therapy
      • Recalcitrant disease defined as 2 or more recurrences of immune-mediated thrombocytopenia or anemia within 5 years of enrollment (all flares must have received adequate therapy and at least 1 of the episodes must have been treated by splenectomy)

• Must meet at least 4 of the following criteria for systemic lupus erythematosus (SLE), as defined by the American College of Rheumatology:

  • Malar rash
  • Discoid rash
  • Photosensitivity
  • Oral ulcers
  • Arthritis

  • Serositis, meeting 1 of the following criteria:

    • Pleuritis

      • Convincing history of pleuritic pain, rub heard by a physician, or evidence of pleural effusion

    • Pericarditis

      • Documented by ECG or rub or evidence of pericardial effusion

  • Renal disorder, meeting 1 of the following criteria:

    • Persistent proteinuria > 0.5 g/day OR > 3+ if quantitation not performed

    • Cellular casts, meeting any of the following types:

      • Red cell
      • Hemoglobin
      • Granular
      • Tubular
      • Mixed

  • Neurologic disorder, meeting 1 of the following criteria:

    • Seizures in the absence of offending drugs or known metabolic derangements (e.g., uremia, ketoacidosis, or electrolyte imbalance)
    • Psychosis in the absence of offending drugs or known metabolic derangements (e.g., uremia, ketoacidosis, or electrolyte imbalance)

  • Hematologic disorder, meeting 1 of the following criteria:

    • Hemolytic anemia with reticulocytosis
    • Leukopenia (less than 4,000/µL total on 2 or more occasions)
    • Lymphopenia (less than 1,500/μL on 2 or more occasions)
    • Thrombocytopenia (less than 100,000/µL in the absence of offending drugs)

  • Immunologic disorder, meeting 1 of the following criteria:

    • Antibody to native DNA in abnormal titer
    • Presence of antibody to SM nuclear antigen

    • Positive finding of antiphospholipid antibodies based on 1 of the following:

      • An abnormal serum level of IgG or IgM anti-cardiolipin antibodies
      • A positive test result for lupus anticoagulant using a standard method
      • A 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
    • An abnormal titer of antinuclear antibodies 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

• No late flare

  • Patients who have a single episode of 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
• No abnormal bone marrow cytogenetics
• No concurrent CNS diseases (e.g., infections, multiple sclerosis [MS], and patients fulfilling MS and SLE criteria)

PATIENT CHARACTERISTICS:

• SGOT or SGPT ≤ 2 times upper limit of normal (ULN) (unless active myopathy is proven by elevation of serum aldolase levels and the patient has no obvious hepatic disease)
• Bilirubin ≤ 2.0 times ULN (unless due to isolated hemolysis)
• Glomerular filtration rate ≥ 30 mL/min
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception during and for 2 years (females) or 6 months (males) after completion of study therapy
• No DLCO corrected < 45%
• No LVEF < 45%, determined by ECHO cardiogram or MUGA scan
• No evidence of hepatitis B or C infection
• No evidence of HIV infection
• No history of malignancy except for basal cell carcinoma of the skin
• No significant concurrent medical condition or any significant circumstance that could affect the patient's ability to tolerate or complete the study

PRIOR CONCURRENT THERAPY:

• See Disease Characteristics
• At least 4 weeks since prior live vaccines
• At least 3 weeks since prior pulse cyclophosphamide
• At least 2 weeks since prior antimalarials
• At least 1 week since prior methotrexate, mycophenolate mofetil, azathioprine, oral daily cyclophosphamide, leflunomide, cyclosporine, or any other medication for lupus

• All immunosuppressive and disease-modifying treatments must be discontinued before study therapy

  • Steroids and analgesics (except for NSAIDS), including narcotics, are allowed