Autologous Stem Cell Systemic Sclerosis Immune Suppression Trial (DISclRituxan)

• Change in skin score (Rodnan) from baseline at 6 months [ Time Frame: base line, 6 months ] [ Designated as safety issue: No ]
  Failure of skin score (if > 14 on enrollment) to improve or increase in skin score by a 25% above lowest post treatment value and must be documented on 2 occasion 6 months apart
• Change in FVC from baseline at 6 months [ Time Frame: base line, 6 moths ] [ Designated as safety issue: No ]
  Deterioration in FVC by 10% below enrollment level or 10% below best post treatment value, due to systemic sclerosis, and documented on 2 occasion 6 months apart
• Renal failure [ Time Frame: 12 months ] [ Designated as safety issue: No ]
  Renal failure due to systemic sclerosis and defined as chronic dialysis for more than 12 months
• Gastrointestinal failure [ Time Frame: 12 months ] [ Designated as safety issue: No ]
  Gastrointestinal failure due to systemic sclerosis and defined as initiation of TPN for more than 12 months

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, TLC, HRCT, and QOL. The investigators now, therefore, purpose to compare the ASSIST I conditioning regimen of cyclophosphamide and rATG to the same regimen (rATG, cyclophosphamide) with rituximab (termed rituximab sandwich regimen). B cells have important role in the pathogenesis of scleroderma. Several small open label studies have shown that B cell depletion with monoclonal antibody to CD20 Rituximab has been effective in depletion of circulating B cells and depletion of dermal B cell along with significant improvement in skin scores. These studies however did not show significant improvement in intersticial lung disease and the response were not durable. This fact is not surprising given that B cells are only a part of what seems to be a very complex jigsaw of immune effectors cells and cytokines in the pathogenesis of scleroderma. It is likely that combining rituximab with cyclophosphamide would improve the response rate and duration for scleroderma patients. Rituximab was well tolerated in these studies and the investigators do not suspect addition of rituximab to cyclophosphamide would add to the toxicity of the treatment. The investigators propose that a conditioning regimen incorporating B cell depletion using CD20 monoclonal antibody rituximab with high dose cytoxan and rabbit ATG will improve response rate and duration in patients receiving autologous hematopoietic stem cell transplant compared to a conditioning regimen of high dose cytoxan and rabbit ATG regimen with hematopoietic stem cell support alone.

Mobilization. For patients in both arms undergoing hematopoietic stem cell transplantation, 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.

Control arm.

The control arm will have the same conditioning regimen used in ASSIST study. The conditioning regimen will be 200 mg/kg of intravenous cyclophosphamide given in 4 equal fractions on days -5 through -2 with intravenous mesna. Rabbit anti-thymocyte globulin (rATG) (Thymoglobulin®) will be dosed at 0.5 mg/kg on day-5 and then 1.5 mg/kg from day-4 thru day -1. Methylprednisolone 1000 mg will be used infused intravenously before each dose of rATG. PBSC will be infused intravenously on day 0. Filgrastrim 5-10 mcg/kg will be started on day + 5 and continued until neutrophil engraftment.

Rituximab sandwich arm

The conditioning regimen will consist of two doses of rituximab 500 mg IV (flat dose) given on day -6 and day +1. Methylprednisolone 250 mg intravenously will be given as premedication to each dose of rituximab. 200 mg/kg of intravenous cyclophosphamide will be given in 4 equal fractions on days -5 through -2 with intravenous mesna. Rabbit anti-thymocyte globulin (rATG) (Thymoglobulin®) will be dosed at 0.5 mg/kg on day-5 and then 1.5 mg/kg from day-4 thru day -1. Methylprednisolone 1000 mg will be used infused intravenously before each dose of rATG. PBSC will be infused intravenously on day 0. Filgrastrim 5-10 mcg/kg will be started on day + 5 and continued until neutrophil engraftment.

• Procedure: Rituximab sandwich regiment followed by SCT
  The conditioning regimen will consist of two doses of rituximab 500 mg IV (flat dose) given on day -6 and day +1. Methylprednisolone 250 mg intravenously will be given as premedication to each dose of rituximab. 200 mg/kg of intravenous cyclophosphamide will be given in 4 equal fractions on days -5 through -2 with intravenous mesna. Rabbit anti-thymocyte globulin (rATG) (Thymoglobulin®) will be dosed at 0.5 mg/kg on day-5 and then 1.5 mg/kg from day-4 thru day -1. Methylprednisolone 1000 mg will be used infused intravenously before each dose of rATG. PBSC will be infused intravenously on day 0. Filgrastrim 5-10 mcg/kg will be started on day + 5 and continued until neutrophil engraftment.
  Other Name: stem cell injection
• Procedure: cyclophosphamide regiment followed by SCT
  The control arm will have the same conditioning regimen used in ASSIST study. The conditioning regimen will be 200 mg/kg of intravenous cyclophosphamide given in 4 equal fractions on days -5 through -2 with intravenous mesna. Rabbit anti-thymocyte globulin (rATG) (Thymoglobulin®) will be dosed at 0.5 mg/kg on day-5 and then 1.5 mg/kg from day-4 thru day -1. Methylprednisolone 1000 mg will be used infused intravenously before each dose of rATG. PBSC will be infused intravenously on day 0. Filgrastrim 5-10 mcg/kg will be started on day + 5 and continued until neutrophil engraftment.
  Other Name: stem cell injection

• Active Comparator: cyclophosphamide regimet followed by SCT
  The control arm will have the same conditioning regimen used in ASSIST study. The conditioning regimen will be 200 mg/kg of intravenous cyclophosphamide given in 4 equal fractions on days -5 through -2 with intravenous mesna. Rabbit anti-thymocyte globulin (rATG) (Thymoglobulin®) will be dosed at 0.5 mg/kg on day-5 and then 1.5 mg/kg from day-4 thru day -1. Methylprednisolone 1000 mg will be used infused intravenously before each dose of rATG. PBSC will be infused intravenously on day 0. Filgrastrim 5-10 mcg/kg will be started on day + 5 and continued until neutrophil engraftment.
  Intervention: Procedure: cyclophosphamide regiment followed by SCT
• Experimental: Rituximab sandwich arm followed by SCT
  The conditioning regimen will consist of two doses of rituximab 500 mg IV (flat dose) given on day -6 and day +1. Methylprednisolone 250 mg intravenously will be given as premedication to each dose of rituximab. 200 mg/kg of intravenous cyclophosphamide will be given in 4 equal fractions on days -5 through -2 with intravenous mesna. Rabbit anti-thymocyte globulin (rATG) (Thymoglobulin®) will be dosed at 0.5 mg/kg on day-5 and then 1.5 mg/kg from day-4 thru day -1. Methylprednisolone 1000 mg will be used infused intravenously before each dose of rATG. PBSC will be infused intravenously on day 0. Filgrastrim5-10 mcg/kg will be started on day + 5 and continued until neutrophil engraftment.
  Intervention: Procedure: Rituximab sandwich regiment followed by SCT

Inclusion Criteria:

1. Age < 60 years old at the time of pretransplant evaluation
2. An established diagnosis of scleroderma (125)
3. Diffuse cutaneous scleroderma with involvement proximal to the elbow or knee and a Rodnan score (see Appendix V) of > 14 (126)

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 CXR (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 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 +/- diverticulae, or pseudodiverticulae. 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, or esophageal manometry.

OR

4. As published in NEJM, 2006, 345:25 2655-2709. Limited or diffuse SSL with lung involvement defined as active alveolitis on 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.

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Exclusion Criteria:

1. Poor performance status (ECOG >2) at the time of entry.

2. Significant end organ damage such as:

   1. 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 corrected < 40 .
   5. Pulmonary hypertension (systolic pulmonary arterial pressure > 40 mmHg or mean PAP > 25 mmHG measurement by pulmonary arterial catheter).
   6. Serum creatinine > 2.0 mg/dl.
   7. Liver cirrhosis, transaminases > 3x of normal limits or bilirubin > 2.0 unless due to Gilberts disease.
   8. Pericardial effusion> 1 cm on HRCT unless successful pericardiocentesis
   9. Occult or clinical constrictive pericarditis
   10. Tricuspid annular peak systolic excursion (TAPSE) ≤ 1.8 cm
3. HIV positive.
4. 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.
5. 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.
6. 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.
7. Psychiatric illness or mental deficiency making compliance with treatment or informed consent impossible.
8. Inability to give informed consent.
9. Major hematological abnormalities such as platelet count < 100,000/ul or ANC < 1000/ul.

10. Patients with duration of disease > 4 years.

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