Lupus Immunosuppressive/Immunomodulatory Therapy or Stem Cell Transplant (LIST)

SLE is a chronic, multisystem, inflammatory autoimmune disease in which the body's immune cells wrongly attack its own tissues. It is defined by the presence of circulating antinuclear antibodies that are directed against nucleosomal DNA-histone complexes, native double-stranded DNA (dsDNA), small nuclear ribonucleoproteins (Sm and RNP), single-stranded DNA, and phospholipids moieties on platelets and other tissues, indicating a failure of the regulatory systems involved in maintenance of immunologic tolerance to self-antigens. Despite use of currently available therapies, patients experience relapses of their lupus. Over time, patients develop significant morbidity from the disease as well as from medications, including glucocorticoids, used for treatment. The main purpose of this study is to compare two ways of treating SLE: 1) high-dose immunosuppressive therapy (HDIT) followed by HSCT and 2) currently available immunosuppressive/immunomodulatory therapies.

1. One group of study participants will undergo autologous hematopoietic stem cell transplantation. With this treatment, they will first undergo mobilization, a process that removes hematopoietic stem cells from their blood. Then they will receive high doses of chemotherapy to suppress their abnormal immune systems, followed by the reintroduction of the purified stem cells to re-establish their immune systems. Medications are used to mobilize (i.e., encourage) blood cell precursors to multiply and move from the bone marrow to the bloodstream. These precursors (or autologous stem cells) can be harvested (collected) from the bloodstream during a process called apheresis and then transplanted (infused) back into the patient's body after chemotherapy has been given. HDIT can suppress the immune system, reducing the effectiveness or perhaps eliminating most of the immune cells that cause the progression of SLE. Autologous hematopoietic stem cell transplantation (HSCT) following HDIT hastens the return of the body's ability to produce blood cells. HDIT with HSCT has been identified as a potential treatment alternative to standard chemotherapy treatments. One group of study participants will undergo autologous hematopoietic stem cell transplantation. With this treatment, they will first undergo mobilization, a process that removes hematopoietic stem cells from their blood. Then they will receive high doses of chemotherapy to suppress their abnormal immune systems, followed by the reintroduction of the purified stem cells to re-establish their immune systems. Medications are used to mobilize (i.e., encourage) blood cell precursors to multiply and move from the bone marrow to the bloodstream. These precursors (or autologous stem cells) can be harvested (collected) from the bloodstream during a process called apheresis and then transplanted (infused) back into the patient's body after chemotherapy has been given. HDIT can suppress the immune system, reducing the effectiveness or perhaps eliminating most of the immune cells that cause the progression of SLE. Autologous hematopoietic stem cell transplantation (HSCT) following HDIT hastens the return of the body's ability to produce blood cells. HDIT with HSCT has been identified as a potential treatment alternative to standard chemotherapy treatments. Participants assigned to the first treatment group will undergo mobilization with CTX and granulocyte colony stimulating factor (G-CSF) beginning 2 weeks after randomization. In preparation for the transplant process. a central venous line (plastic tube) will be inserted into the neck or chest vein; this tube will be used to administer stem cells and medications and for drawing blood. IV CTX, followed by G-CSF, will be given injected under the skin beginning 3 days after CTX. G-CSF will be given for about 4 to 7 days, to boost the body's production of blood precursor cells. These precursor cells will be collected through the central venous line through apheresis. In this process, whole blood is collected through a needle in an arm vein and directed to a cell-separating machine, where the white cells are separated and saved. The rest of the blood is returned to the patient through the same needle. Several apheresis procedures will be required to collect enough cells for the autologous transplant. Within 3 weeks of the apheresis stem cell collection, the first group's participants will be admitted to the hospital and will undergo a five-day conditioning regimen consisting of IV CTX and rabbit anti-thymocyte globulin (rATG). This regimen will suppress the malfunctioning immune system and prepare the patient's body to receive the precursor cells previously collected during apheresis. The stem cells will be infused after the five-day conditioning regimen. The return of the precursor cells is called autologous stem cell transplantation. During the hospitalization a specialized team of transplant physicians and nurses will closely monitor the participants until their bone marrow recovers and the participants are well enough to be discharged. The hospital stay will be approximately 21 days after the autologous stem cell transplant. Upon discharge, the patient will return home and will follow-up at the treatment center at Weeks 1 and 3 post-transplantation for close monitoring by the transplant team. Participants will also be followed by the study rheumatologist monthly at the treatment center for 30 months.
2. The other group of study participants will receive immunosuppressive/immunomodulatory therapy as prescribed by the study rheumatologist, based on the organ systems affected and prior treatment history. Therapy may include one or a combination of the following treatments: corticosteroids, azathioprine, methotrexate, cyclosporine, MMF, plasmapheresis, IVIG, rituximab, and leflunomide. As new drugs become available and a part of the usual medications for the treatment of SLE, they may be approved for use in this study. Treatment may be changed as frequently as necessary within the first year of the study to control the manifestations of SLE in each patient. Treatment for the second group will begin 1 week after randomization; patients will be seen monthly at the treatment center for 30 months.

Corticosteroid dosage tapering will be monitored closely; the schedule for tapering will be the same in both groups. To reduce the possibility of disease flare. a slow tapering of 10% per month will occur for the first six months. Tapering will continue in a prescribed manner to achieve a dose equivalent of 10 mg/day of prednisone or less by one year post-treatment.

All participants will have monthly follow-up visits for 30 months after treatment has been initiated. Study visits will include a physical exam, clinical assessments, rheumatology evaluations, and blood and urine collections. Participants will be asked to complete questionnaires assessing their lupus disease. Neuropsychiatric assessments, echocardiogram, CT scan of brain, renal biopsy, pulmonary function test, dual-energy x-ray absorptiometry scan (DEXA scan), magnetic resonance imagery scan, electromyograph scan (EMG), bone marrow biopsy and aspiration and lumbar puncture may occur at selected visits, based on each individual's manifestations of lupus and clinical indication. Participants will also receive certain vaccinations at selected visits. Participants will be contacted by phone each and every week throughout the study. There will be an extension period for those patients that have completed their treatment and follow-up visits during the study's 5-year duration. Participants will be contacted via telephone, e-mail, or visit every 3 months to assess their use of concomitant medications and immunosuppressive/immunomodulatory therapy and corticosteroids.

Five treatment centers across the United States, all leaders in the fields of transplantation and rheumatology, are participating in this research study.