Cardiac Safe Transplants for Systemic Sclerosis

The autologous hematopoietic stem cell transplant used in this research study is an
investigational procedure that uses cyclophosphamide and fludarabine (chemotherapy), rabbit
anti-thymocyte globulin (rATG) (a protein that kills the immune cells that are thought to be
causing your disease), and rituximab (a biologic drug that targets B cells of your immune
system). After use of these treatments, the patient will receive their own previously
collected blood stem cells (autologous stem cell transplant). The ability of these
experimental treatments to stop relapses and progression (worsening) of your systemic
sclerosis will be assessed.

Inclusion Criteria:

1. Age 18 - 65 years old at the time of pre-transplant evaluation

2. An established diagnosis of systemic sclerosis

3. Diffuse cutaneous systemic sclerosis with involvement proximal to the elbow or knee
and a modified Rodnan Skin Score of ≥ 14 (see Appendix A)

AND

Any one of the following:

1. DLCO < 80% of predicted or decrease in lung function (DLCO, DLCO/VA or FVC) of 10% or
more over 12 months.

2. Pulmonary fibrosis or alveolitis on CT scan or chest x-ray (ground glass appearance of
alveolitis).

3. Abnormal EKG (non-specific ST-T wave abnormalities, low QRS voltage, or ventricular
hypertrophy), or pericardial effusion or pericardial enhancement without constriction
on MRI

4. Gastrointestinal tract involvement confirmed on radiological study. Radiologic
findings of scleroderma are small bowel radiographs showing thickened folds with
dilated loops, segmentation, and flocculation +/- diverticula, or pseudodiverticula. A
hide-bound appearance may be present (e.g. dilated and crowded circular folds). GI
involvement may also be confirmed by D-xylose malabsorption, patulous esophagus on
high-resolution computed tomography (HRCT), or esophageal manometry.

OR

Limited cutaneous systemic sclerosis (SSc) (modified Rodnan Skin Score <14) with lung
involvement defined as active alveolitis on bronchoalveolar lavage (BAL), ground-glass
opacity on CT scan, a DLCO < 80% predicted, or decrease in lung function (DLCO/VA, DLCO,
FVC) of 10% or more in last 12 months.

Other Inclusion Criteria for "CAST" Conditioning Regimen (presence of any of the
following):

1. Septal flattening or D-sign on MRI (without deep breathing)

2. PASP >40 mm Hg or >45 mm Hg with fluid challenge*

3. mPAP >25 mm Hg or >30 mm Hg with fluid challenge*

4. Non-ischemia diffuse ventricular hypokinesis or non-ischemia wall hypokinesis

- Fluid challenge is 1000 ml normal saline over 10 minutes. Fluid challenge will
not be done if right atrial pressure is >13 mm Hg at rest or pulmonary capillary
wedge pressure is >20 mm Hg at rest.

Exclusion Criteria:

1. Active ischemic heart disease or untreated coronary artery disease

2. Untreated life-threatening cardiac arrhythmia on EKG or 24-hour holter

3. Pericardial effusion > 1 cm on cardiac MRI unless successful pericardiocentesis has
been performed

4. LVEF <35%

5. End-stage lung disease characterized by TLC<45% of predicted value, or DLCO hemoglobin
corrected < 30 % predicted.

6. Serum creatinine > 1.4 mg/dl

7. Creatinine clearance <80 by 24-hour urine

8. History of breast implants that have not been removed (unless they cannot be
surgically removed due to risks of surgery)

9. Liver cirrhosis, transaminases >2x of normal limits, or bilirubin > 2.0 unless due to
Gilbert's disease

10. Uncontrolled diabetes mellitus or any other illness that in the opinion of the
investigators would jeopardize the ability of the patient to tolerate aggressive
treatment

11. Prior history of malignancy

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

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

14. Major hematological abnormalities such as platelet count < 100,000/ul or absolute
neutrophil count (ANC) < 1000/ul

15. HIV positive

16. Hepatitis B or C positive

17. PASP >50 mmHg without fluid challenge

18. mPAP >34 mmHg without fluid challenge

19. Coronary artery disease not reversed by cardiology and interventional radiology