Autologous Stem Cell Systemic Sclerosis Immune Suppression Trial
Autologous Stem Cell Systemic Sclerosis Immune Suppression Trial
ASSIST I was the first randomized trial in patients with scleroderma to not just slow disease
 progression but rather actually reverse it. It is the first treatment to have ever
 demonstrated reversal of lung disease in scleroderma with improvement in FVC, total lung
 capacity (TLC), high-resolution computed tomography (HRCT), and QOL. We now, therefore,
 purpose to compare the ASSIST I conditioning regimen of cyclophosphamide and rATG to a less
 intense regimen of rATG/cyclophosphamide/Fludarabine. In the new regimen the cyclophosphamide
 dose is decreased to 120mg/kg (60mg/kg/day x 2) compared to 200mg/kg (50mg/kg/day) in the
 standard regimen. The lower dose of cyclophosphamide will be less cardiotoxic. This study
 will determine if the less cardiotoxic regimen will be safer than the standard regimen and as
 effective as the standard regimen.
Mobilization. For patients in both arms undergoing hematopoietic stem cell transplantation
 (HSCT), peripheral blood stem cells (PBSC) will be mobilized with cyclophosphamide (2 g/m2)
 followed by 5-10 mcg/kg subcutaneous filgrastrim daily from day 5 until completion of
 apheresis. Mobilized hematopoietic stem cells (HSC) will be collected by apheresis on day 10
 and cryopreserved without selection or manipulation. There will be an interval of at least 17
 days between mobilization of PBSC and start of conditioning regimen.
Inclusion Criteria:

 1. Age 17- 60 years old at the time of pretransplant evaluation

 2. An established diagnosis of scleroderma

 3. Diffuse cutaneous scleroderma with involvement proximal to the elbow or knee and a
 Rodnan score (see Appendix V) of > 14 AND

 Scleroderma with 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 (CXR) (ground glass
 appearance of alveolitis).

 3. Abnormal EKG [non-specific ST-segment and T-wave (ST-T) (pattern in
 electrocardiogram) wave abnormalities, low QRS (a pattern seen in an
 electrocardiogram that indicates the pulses in a heart beat and their duration)
 voltage, or ventricular hypertrophy], or pericardial effusion or pericardial
 enhancement 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 due to valvulae packing i.e. dilated
 and crowded circular folds may be present. GI involvement may also be confirmed
 by D-xylose malabsorption, patulous esophagus on HRCT, or esophageal manometry.

 OR

 4. As published in New England Journal of Medicine (NEJM), 2006, 345:25 2655-2709.
 Limited or diffuse Systemic Sclerosis with (SSCL) with lung involvement defined as
 active alveolitis on Bronchoalveolar Lavage (BAL) or ground-glass opacity on CT, a
 DLCO < 80% predicted or decrease in lung function (DLCO/VA, DLCO, FVC) of 10% or more
 in last 12 months.

 Exclusion Criteria:

 1. Significant end organ damage such as:

 1. Left Ventricular Function (LVEF) < 40% on echocardiogram.

 2. Untreated life-threatening arrhythmia.

 3. Active ischemic heart disease or heart failure.

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

 5. Pulmonary arterial hypertension defined on right heart catheterization as:

 1. a resting Mean Pulmonary Artery Pressure (mPAP) > 25 mmHg;

 2. a mPAP > 30 mmHg following a 500-1000 ml normal saline bolus;

 3. pulmonary vascular resistance (PVR) > 240 dynes*s/cm5 (> 3 Wood units) ; or

 4. a decrease in cardiac output with fluid challenge (500 - 1000 cc Normal
 Saline (NS) in 10 minutes) If fluid challenge cannot be done because right
 atrial (RA) pressure > 12mm Hg or pulmonary capillary wedge pressure (PCWP)
 > 15 m Hg at rest or must be stopped due to safety concerns, patient is
 excluded as candidate.

 6. Serum creatinine > 1.4 mg/dl.

 7. Liver cirrhosis, transaminases > 3x of normal limits or bilirubin > 2.0 unless
 due to Gilbert's disease.

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

 9. Occult or clinical constrictive pericarditis

 10. On echocardiogram tricuspid annular peak systolic excursion (TAPSE) ≤ 1.8 cm or,
 grade II or worse Right Ventricular (RV) or Left Ventricular (LV) diastolic
 dysfunction

 11. On cardiac MRI, a diastolic septal bounce or diastolic septal flattering
 (D-sign), or diffuse myocardial gadolinium enhancement, or diffuse hypokinesis
 (patchy late gadolinium myocardial enhancement are not exclusion criteria)

 12. Ventricular tachycardia (sustained or non-sustained, multifocal or unifocal) on
 EKG or 24 hour Holter

 2. HIV positive.

 3. 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.

 4. Prior history of malignancy

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

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

 7. Inability to give informed consent.

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

 9. Hepatitis B or C positive