Allogeneic Hematopoietic Cell Transplantation for Severe Systemic Sclerosis

PRIMARY OBJECTIVES:

I. To determine the safety and potential efficacy of reduced intensity conditioning with
fludarabine/cyclophosphamide/low-dose total body irradiation (TBI) and allogeneic
hematopoietic cell transplantation (HCT) for the stabilization or regression of disease
manifestations of severe systemic sclerosis (SSc).

SECONDARY OBJECTIVES:

I. To determine whether stable allogeneic donor engraftment can be safely established with
reduced intensity conditioning followed by matched sibling or unrelated donor bone marrow
transplantation in patients with severe SSc.

OUTLINE:

Patients receive fludarabine phosphate intravenously (IV) on days -6, -5, -4, -3 and -2 and
Cyclophosphamide IV on days -6, -5, and undergo 2 Gray TBI on day -1. Patients receive human
leukocyte antigen (HLA)-matched donor bone marrow transplantation on day 0. Patients then
receive cyclophosphamide IV on days +3 and +4, and beginning day +5 they start tacrolimus
orally (PO) and enteric coated mycophenolic acid.

After completion of initial study treatment, patients are followed up at 6 months and then
annually for 5 years.

Inclusion Criteria:

- Patients eligible for the study must have a human leukocyte antigen (HLA)-identical
sibling or HLA-matched unrelated bone marrow donor available and willing to donate.

- Patients with severe SSc as defined by the American College of Rheumatology and at
high-risk for a fatal outcome based on the following prognostic factors in groups 1-5:

- Group 1: Patients must have 1) both a and b below; and 2) at least one of c, d or e:

- a. diffuse cutaneous scleroderma with skin score of greater than or equal to 16
(modified Rodnan scale [mRSS]).

- b. duration of systemic sclerosis less than or equal to 7 years from the onset of
first non-Raynaud's symptom.

- c. presence of interstitial lung disease (either forced vital capacity [FVC] or
corrected diffusing capacity of the lung for carbon monoxide [DLCOcorr] less than
70 % of predicted) and evidence of alveolitis (abnormal bronchoalveolar lavage
(BAL) or high resolution chest computed tomography [CT] scan) after treatment
with intravenous cyclophosphamide greater than or equal 2 grams given over at
least a 3 month period; for patients not able to adequately complete pulmonary
function tests (PFT), there must be evidence of progressive disease on chest CT.

- d. left heart failure with left ventricular ejection fraction (LVEF) < 50% (that
has responded to treatment targeted to scleroderma); 2nd or 3rd atrioventricular
(AV) block with other evidence of cardiomyopathy related to SSc; myocardial
disease not secondary to SSc must be excluded by a cardiologist.

- e. history of SSc-related renal disease that is not active at the time of
screening; history of scleroderma hypertensive renal crisis is included in this
criterion.

- Group 2: Progressive pulmonary disease as defined by a decrease in the FVC or DLCOcorr
by 15 percent or greater compared to a prior FVC or DLCOcorr in the previous twelve
month period; in addition, patients may have either less skin involvement than group 1
(mRSS less than 16) and the FVC or DLCOcorr is less than 70% or both FVC and DLCOcorr
greater than or equal to 70% if they have diffuse cutaneous disease (mRSS greater than
16) at screening for the study; patients must also have evidence of alveolitis as
defined by abnormal chest CT or BAL; for patients not able to adequately complete PFT,
there must be evidence of progressive disease on chest CT.

- Group 3: Have progressive active SSc after prior autologous transplant based on the
presence of progressive pulmonary disease; this will be defined by a decrease in the
FVC or DLCO adjusted since prior autologous transplant of 15 percent or greater of the
pre-transplant percent predicted value, in addition to evidence of alveolitis as
defined by chest CT changes or BAL. If patients had prior autologous HCT on the
"Scleroderma: Cyclophosphamide Or Transplantation" (SCOT) clinical trial, they must
have failed based on the defined study endpoints and be approved by the protocol
principal investigator (PI).

- Group 4: Patients who meet group 1 inclusion criteria but may have FVC or
DLCO-adjusted less than 70% plus have had an adverse event on cyclophosphamide
preventing its further use (specifically hemorrhagic cystitis, leukopenia with white
blood cell [WBC]< 2000 or absolute neutrophil count [ANC] < 1000 or platelet count <
100,000).

- Group 5: Diffuse scleroderma with disease duration less than or equal to 2 years since
development of first sign of skin thickening plus modified Rodnan skin score greater
than or equal to 25 plus erythrocyte sedimentation rate (ESR) > 25 mm/1st hour and/or
hemoglobin (Hb) < 11 g/dL, not explained by causes other than active scleroderma.

- Unless patients have a DLCO-adjusted less than 45%, patients in all groups must have
failed either oral or intravenous cyclophosphamide regimen defined as: IV
cyclophosphamide administration for at least > 3 months between first and last
cyclophosphamide dose at a total cumulative IV dose of at least 2 grams, oral
cyclophosphamide administration for > 4 months regardless of dose, or combination of
oral and IV cyclophosphamide for at least > 6 months independent of dose.

- DONOR: HLA genotypically identical sibling or unrelated donor; unrelated donors are
required to be matched by standard molecular methods at the intermediate resolution
level at HLA-A, B, C and DRB1 and the allele level at DQB1.

- DONOR: Donors must meet the selection criteria as defined by the Foundation for the
Accreditation of Cell Therapy (FACT) and will be screened per the American Association
of Blood Banks (AABB) guidelines

- DONOR: Bone marrow is the preferred cell source

Exclusion Criteria:

- Fertile men or women unwilling to use contraceptive techniques during and for 12
months following transplant

- Evidence of ongoing active infection

- Pregnancy

- Patients with a creatinine clearance < 60 ml/min/1.73 m^2 body surface area

- Uncontrolled clinically significant arrhythmias

- Clinical evidence of significant congestive heart failure (CHF) (New York Heart
Association [NYHA] Class III or IV)

- LVEF < 45% by echocardiogram

- Severe pulmonary dysfunction with a hemoglobin corrected DLCO < 30% or FVC < 40% of
predicted or O2 saturation < 92% at rest without supplemental oxygen

- Significant uncontrolled pulmonary hypertension defined as: Pulmonary artery peak
systolic pressure > 55 mmHg by echocardiogram, or pulmonary artery peak systolic
pressure 45-55 mmHg by echocardiogram and mean pulmonary artery pressure by right
heart catheterization exceeding 25 mmHg at rest (or 30 mmHg with exercise); or
NYHA/World Health Organization (WHO), Class III or IV

- Active hepatitis or liver biopsy evidence of cirrhosis or periportal fibrosis; liver
function tests: total bilirubin > 2 x the upper limit of normal and/or serum glutamic
pyruvate transaminase (SGPT) and SGPT > 4 x the upper limit of normal

- Patients with poorly controlled hypertension

- Patients whose life expectancy is severely limited by illness other than autoimmune
disease

- Patients with poorly controlled bleeding from gastric antral vascular ectasia (GAVE)
or other gastrointestinal (GI) sites

- Untreated psychiatric illness, drug/alcohol abuse

- Inability to give voluntary informed consent or guardian's informed consent

- Demonstrated lack of compliance with prior medical care

- Malignancy within the 2 years prior to treatment, excluding adequately treated
squamous cell skin cancer, basal cell carcinoma, and carcinoma in situ; treatment must
have been completed (with the exception of hormonal therapy for breast cancer) with
cure/remission status verified for at least 2 years at time of treatment

- Human immunodeficiency virus (HIV) seropositivity

- DONOR: Identical twin

- DONOR: Current pregnancy

- DONOR: HIV seropositivity

- DONOR: Deemed medically unable to undergo bone marrow harvesting

- DONOR: Current serious systemic illness including uncontrolled infections

- DONOR: Failure to meet institutional criteria for donation as described in the
Standard Practice Guidelines