Autologous Stem Cell Transplantation for Refractory Systemic Lupus Erythematosus (ASSIST)

An Open-Label, Phase II Multicenter Cohort Study of Immunoablation With Cyclophosphamide and Antithymocyte-Globulin and Transplantation of Autologous Cd34-Enriched Hemapoietic Stem Cells Versus Currently Available Immunosuppressive/Immunomodulatory Therapy for Treatment of Refractory Systemic Lupus Erythematosus

While glucocorticoids and immunosuppressants ameliorate manifestations of SLE in many patients, current therapies are insufficient to control the disease in a subset of patients, and their clinical prognosis remains poor due to the development of vital organ failure, cumulative drug toxicity and to the increased risk of cardiovascular disease and malignancy. Immunoablative chemotherapy followed by autologous hematopoietic stem cell transplantation (ASCT) has recently emerged as a promising experimental therapy for severely affected patients, providing them the potential to achieve treatment-free, long-term remission. The investigators postulate that immunoablative therapy eliminates or effectively reduces the level of autoreactive T and B lymphocytes and then regeneration of de novo immunity resets the autoreactive immune system into a self-tolerant, protective immune system resulting in prolonged and treatment-free remission.

Inclusion Criteria:

1. Diagnosis of SLE according to American College of Rheumatology (ACR) classification criteria

2. Age between 18 and 60 years, inclusive

3. Provision of informed consent

4. Active disease, refractory to standard immunosuppressive therapy defined as:

   • BILAG level A and a SLEDAI-score of at least 10, despite treatment with high-dose corticosteroids and pulse intravenous CYC at doses of 500-1000mg/m2 for at least 6 months or mycophenolate mofetil (MMF) at doses of at least 2g -
   • Lupus nephritis with renal biopsy performed within one year prior to screening showing glomerulonephritis WHO class III or IV
   • Parenchymal disease of heart or lung
   • Neuropsychiatric lupus
   • Autoimmune cytopenia OR
   • recurrence of disease activity (defined as BILAG level A and a SLEDAI of at least 10) within one year after successful induction therapy with cyclophosphamide or MMF in the presence of an adequate maintenance therapy with either cyclophosphamide (at least 500mg/m2 monthly), mycophenolate mofetil (at least 2g daily), azathioprine (at least 1.5mg/kg/d), methotrexate (at least 15mg weekly), cyclosporine (at least 3mg/kg/d) in patients with persistent anti-dsDNA antibodies

Exclusion Criteria:

1. Severe concomitant disease or organ damage

   • renal: renal insufficiency with glomerular filtration rate below 40ml/min
   • cardiac: congestive heart failure, LVEF < 40% determined by echocardiogram, uncontrolled arrhythmia
   • pulmonary: mean pulmonary arterial pressure >50mmHg, DLCO < 40 % predicted
   • gastrointestinal: liver cirrhosis; SGOT, SGPT greater than 2 x the upper limit of normal, unless due to active lupus

2. Ongoing cancer or history of malignancy within 5 years of screening

3. Women who are pregnant or breastfeeding or use non-reliable methods of contraception

4. Subjects with active systemic infection

5. Subjects with history of active viral infection within 6 months prior to screening, known HIV-infection or chronic Hepatitis B or Hepatitis C

6. History of allergic reaction to cyclophosphamide, G-CSF or ATG

7. Use of immunosuppressive agents for indications other than SLE

8. Any comorbidity that in the opinion of the investigator would jeopardize the ability of the subject to tolerate therapy