Allogeneic Blood Stem Cell Transplantation for Patients With Life-Threatening Systemic Lupus Erythematosus

The purpose of this study is to evaluate the effectiveness of allogeneic blood stem cell
transplantation in individuals with life-threatening SLE. A non-bone marrow ablative regimen
consisting of total lymphoid irradiation (TLI) and anti-thymocyte globulin (ATG) will be
used to condition the recipients for transplantation. Appropriately HLA-matched donors will
undergo "mobilization" of their peripheral blood mononuclear cells using G-CSF and
collection by apheresis.

The preparative regimen will consist of targeted low dose radiation of lymphoid tissue
administered over a 2-week period of time. During the first week of irradiation, the
patients will also receive the ATG treatment. Patients will be admitted to the in-patient
service for the first 5 days of the transplant preparative regimen while receiving the ATG
infusion. Patients will be discharged for the second half of the preparative regimen and
followed in the out-patient clinic thereafter. Patients will start immunosuppressive
treatment with cyclosporine and mycophenolate mofetil prior to the infusion of mobilized
peripheral blood stem cells. The mycophenolate mofetil will be stopped at approximately 1
month post-transplantation and the cyclosporine will be tapered beginning at 2 months
post-transplantation and discontinued by 6 months in the presence of stable blood chimerism
and the absence of graft-versus-host disease. In the pre-transplant and post-transplant
setting, patients will be evaluated by an integrated team of Rheumatology and BMT
physicians. During the first 21-28 days post-transplantation, these evaluations will be
performed on a daily or every other day basis. Patients will be clinically assessed and
evaluated for engraftment of donor cells and disease response. Patients will then be
followed as needed with maximum time between evaluations of 1 to 2 weeks in the first 100
days, and then monthly for 6 months and every 6 months to 12 months thereafter.

Inclusion Criteria:

- Meet the American College of Rheumatology (ACR) criteria for classification of SLE
(i.e., at least 4 of the 11 criteria; see Appendix 2 of the protocol for more
information)

- SLE disease activity index (SLEDAI) greater than 20 (i.e., active, multi-system SLE;
see Appendix 3 of the protocol for more information)

- History of one or more of the following conditions that have not responded to
conventional therapy with pulse intravenous or oral cyclophosphamide and
corticosteroids:

1. Lupus pneumonitis with a progressive decline in lung function tests and evidence
of oxygen desaturation on effort in which the lung CT scans and chest X-rays
show active disease without irreversible extensive scarring

2. Diffuse alveolar hemorrhage associated with oxygen desaturation with persistent
abnormalities of the lung CT scan or X-rays that have not resolved after
conventional therapy

3. Central nervous system lupus that has resulted in neurological deficits
requiring hospitalization with a brain CT scan and/or brain MRI and shows
evidence of lupus activity without extensive irreversible lesions

4. Lupus nephritis with a progressive decline in the creatinine clearance that has
not fallen below 25 ml/min in which a biopsy shows active disease without
irreversible extensive scarring

- Refractory disease, as determined by failure of the following two conditions:

1. Trial of corticosteroids (equivalent to prednisone 0.5 mg/kg/day for 2 months
and/or at least 3 pulses of methylprednisolone 1,000 mg over 3 days) on at least
one occasion within the 6 months prior to study entry

2. Trial of cyclophosphamide of at least 500 mg/m² IV pulse at least 3 times or
oral cyclophosphamide for at least 30 days

- Must have a fully HLA identical sibling or a matched unrelated donor

- Willing to use contraception throughout the study and for 12 months following
treatment

Exclusion Criteria:

- Allergic to rabbit ATG

- Score of less than 60% on Karnofsky Performance Scale

- Organ dysfunction, defined as follows:

1. Cardiac function ejection fraction less than 40% or uncontrolled malignant
arrhythmias or clinical evidence of congestive heart failure (New York Class
3-4, see Appendix 4 of the protocol for more information)

2. Pulmonary diffusion capacity (DLCO) less than 30% of predicted

3. Liver function abnormalities with direct bilirubin levels greater than 3.0 mg/dL
on two repeated tests and/or transaminases greater than 4 times the upper limit
of normal

4. Measured creatinine clearance of less than 40 ml/min (24 hour urine collection)

- Pregnant