Allogeneic Stem Cell Transplantation in Systemic Lupus Erythematosus

This phase I study is designed to select patients with refractory and intractable disease.
SLE patients with impaired visceral organ function and chronic exposure to glucocorticoid
therapy are complicated by significant morbidity, frequent hospitalizations and high-risk of
mortality. For participants in whom the indication is nephritis, active disease must be
present despite at least 6 cycles of monthly pulse cyclophosphamide. Participants with
extra-renal lupus need to fail 3 months of monthly cyclophosphamide. Patients who have an
HLA matched sibling, will be offered allogeneic HSCT. Because of high transplant related
toxicity and mortality in conventional myeloablative regimens, we will utilize a
mini-conditioning regimen. To minimize GvHD, candidates must be 50 years old or younger and
in vivo CAMPATH will be used in the conditioning regimen to deplete infused donor
lymphocytes.

Peripheral Blood Stem Cell (PBSC) Harvest from Donor PBSC will be mobilized with G-CSF 10
mcg/kg/day (dose may be adjusted to 5-16 mcg/kg/day by PI for toxicity, e.g. flu-like
symptoms) with stem cell collection beginning on day 4. Leukapheresis may be repeated up to
three consecutive days.

1) If these criteria are not meet the patient (recipient) may not be treated.

1. CD34+ cell count >2.0 x106 CD34+ cells/kg recipient weight

2. Gram stein negative

3. Culture negative ( after 14 days)

4. Cell viability at time of final formulation in cyroprotectant media≥ 70% Conditioning
Regimen Cyclophosphamide 50mg/kg/day x 4 days will be given IV over 1 hour in 500 cc of
normal saline. If actual weight is < ideal weight, cyclophosphamide will be given based
on actual weight. If actual weight is > ideal weight, cyclophosphamide will given as
adjusted weight. Adjusted weight = ideal weight + 25% (actual weight minus ideal
weight).

Mesna 50mg/kg/day will be given IV over 24 hours in 250 cc of normal saline or D5W starting
2 hours before the first cyclophosphamide dose. Weight base is calculated same as
cyclophosphamide as above.

Hydration approximately 50-200cc/hour in adults should begin 6 hours before cyclophosphamide
and continue until 24 hours after the last cyclophosphamide dose. Hydration rates need to be
individually adjusted by daily weights to maintain dry weight count. BID weights will be
obtained. Warning: Participants with renal insufficiency are prone to volume overload. Early
institution of ultra filtration or dialysis is recommended. Three-way bladder irrigation may
be needed for those participants who cannot tolerate fluid hydration during cyclophosphamide
administration and for 24 hours after the last dose of cyclophosphamide. In patients on
hemodialysis, cyclophosphamide will be given in the evening and hemodialysis will be
performed in the morning daily until the last dose of cyclophosphamide is administered.
Close coordination with nephrology service is required.

CAMPATH-1H 30mg/day x 2 days (no dose adjustment) will be given IV over 2 hours in 100 cc of
normal saline. Premedication with acetaminophen 650mg and benadryl 50mg PO/IV will be given
30-60min before infusion. These medications can be repeated as needed. Solumedrol 1 gram
will be given IV 30 min prior to CAMPATH-1H.

G-CSF 5 mcg/kg/day will be started on day 6 if engraftment has not occurred. It will be
continued until absolute neutrophil count reaches at least 500/ul. The dose may be rounded
up or down in order to not waste medication in the vial. NOTE: GCSF may be started earlier,
e.g. day 0, per investigator's discretion.

Cyclosporine* will be started on day -3 at 200 mg po BID and adjusted by HPLC levels to
between 150 - 250 or by toxicity (e.g., tremor, renal insufficiency, TTP, etc.). CSA will be
continued for 2 months unless stopped for toxicity. If patient cannot tolerate oral
cycloporine, intravenous cyclosporine continuous infusion (3mg/kg/24hours) and adjusted by
levels can be used.

Mycophenolate mofetil (MMF)* 1g PO/IV q 12 hrs will be started on day -3 and continued for 6
months. The dosage will be adjusted and tapered off before stopping, unless toxicity
mandates abrupt cessation. MMF will be adjusted by PI according to toxicity, GVHD, and donor
engraftment or donor chimerism.

*Cyclosporine and MMF guidelines dosage and duration can be modified according to
investigators discretion based on side effects, renal function, CBC and GVHD status.

Recipient Inclusion Criteria:

- Ages 18 to 50 years old.

- Meet at least 4 of 11 American College of Rheumatology (ACR) Classification criteria
for SLE (see Appendix 1).

- Able to give informed consent.

- HLA matched sibling donor available.

- Meet one of following three:

1. For lupus nephritis, participants must fail pulse cyclophosphamide (500 to 1000
mg/m2 monthly for a minimum of 6 months). Failure is defined as meeting criteria
to be considered as BILAG (Appendix 4) renal category A. If indication for HSCT
is nephritis, a renal biopsy must be obtained and document either class III or
IV glomerulonephritis.

2. For visceral organ involvement other than nephritis, participants must be BILAG
cardiovascular/respiratory category A, vasculitis category A, or neurologic
category A and must fail at least 3 months of oral or IV cyclophosphamide and be
corticosteroid dependent. Steroid dependence being defined as at least 3 months
of steroid therapy and inability to wean corticosteroid to less than 20 mg/day
of prednisone or equivalent.

3. For cytopenias that are immune mediated, participants must be BILAG hematologic
category A. Participants must have an inability to maintain platelets > 15,000,
an inability to prevent active bleeding without transfusion, an inability to
maintain hemoglobin > 7.0, or an inability to prevent cardiovascular disease
without transfusion. In addition, participants must fail corticosteroids (either
oral prednisone > 0.5 mg/kg/day for more than 6 months or pulse
methylprednisolone for at least one cycle of three days), be refractory to IVIG,
and at least one of the following: azathioprine at 2 mg/kg/day for at least 3
months, mycophenolate mofetil 2 grams daily for more than 3 months,
cyclophosphamide intravenously or orally for at least 3 months, or cyclosporine
at least 3 mg/kg/day for at least 3 months, danazol for at least 3 months, or
splenectomy.

Recipient Exclusion Criteria:

- HIV positive.

- Ongoing malignancy except localized basal cell or squamous skin cancer. Other
malignancies for which the participant is judged to be cured by local surgical
therapy, such as head and neck cancer, or stage I or II breast cancer will be
considered on an individual basis by the investigators doing the final screening for
participant qualification.

- Positive pregnancy test, inability or unwillingness to pursue effective means of
birth control, failure to willingly accept or comprehend irreversible sterility as a
side effect of therapy.

- Psychiatric illness or mental deficiency making compliance with treatment or informed
consent impossible.

- DLCO < 45% of predicted unless attributed solely to active lupus.

- Resting LVEF < 40% unless due to active lupus.

- Known hypersensitivity to E. Coli derived proteins.

- Transaminases greater than 2 times normal unless due to active lupus.

- Any illness that in the opinion of the investigator would jeopardize the ability of
the patient to tolerate this treatment.

Donor Inclusion Criteria

- Donor must be a HLA identical sibling or HLA matched cord blood donor.

- If donor is HLA matched sibling, donor must be > 18 years of age and less than
50years old.

- If multiple HLA matched donors are available, preference will be given to samesex,
same CMV status, and nulliparous donor, or in the case of cord blood higher nucleated
cell count.

- If donor is HLA matched cord blood, cord blood stem cells will be obtained from the
New York Blood Center Cord Blood Registry (Tel 212-570-3230) which is an
internationally recognized registry or, if a match is not available, from Stemcyte
(626-821-9860) which is a commercial registry that specializes in minority donors or
from National Marrow Donor Program (NMDP). One unit of HLA matched cord blood unit
will be infused on day zero.

Donor Exclusion Criteria

- Physiologic age > 50 years old or <18 years old.

- HIV positive.

- Active ischemic heart disease or heart failure.

- Acute or chronic active hepatitis.

- Uncontrolled diabetes mellitus or any other illness that in the opinion of the
investigators would jeopardize the ability of the donor to tolerate stem cell
collection.

- Prior history of malignancy except localized basal cell or squamous skin cancer.
Other malignancies for which the patient is judged to be cured by local surgical
therapy, such as (but not limited to) head and neck cancer, or stage I or II breast
cancer will be considered on an individual basis.

- Positive pregnancy test.

- Positive ANA or anti-ds DNA.

- Psychiatric illness or mental deficiency making compliance with treatment or informed
consent impossible.

- Major hematological abnormalities such as platelet count less than 150,000/ul, ANC
less than 1000/ul.

- If donor is sibling must collect a minimum of 2. 106CD34+ cells/kg to proceed to
Transplant.

- If donor is cord blood unit(s) then a minimum number of nucleated cells available
must be more than 2 x 107 /kg. To achieve this number of nucleated cells, two units
of HLA matched cord blood may be utilized. (Wagner JE Blood. 2005 Feb
1;105(3):1343-7)