Cyclophosphamide and rATG With Hematopoietic Stem Cell Support in Systemic Scleroderma
Condition: SYSTEMIC SCLERODERMA
MeSH terms: Scleroderma, Systemic; Scleroderma, Diffuse; Scleroderma, Localized
Intervention: standard of care; stem cell transplantation
Intervention description: standard of care medication will be given; The following is intervention: stem cell transplantation after conditioning regimen
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 19.0
Sex: All
Maximum age: 60 Years
Healthy volunteers: No

Summary:

      Scleroderma is a systemic disorder categorized as an immunologically mediated disease that
      causes collagen deposition of skin and visceral organs. The molecular pathogenesis of
      scleroderma has been elusive, although vasculopathy and immune mediated mechanisms are
      thought to be important. Once extensive cutaneous or visceral disease occurs, prognosis is
      significantly shorter than the general population. Although various treatments have been
      tried, none of them seems to have changed the natural history of scleroderma. Standard dose
      immunosuppressive treatment has been disappointing. Recently, cyclophosphamide at 1-2
      mg/kg/day orally or 800-1400 mg intravenous (IV) monthly for 6-9 months has proven effective
      in treatment of scleroderma alveolitis (1). Recent phase I studies of immunoablation with
      autologous peripheral blood stem cell transplantation (PBSCT) showed some promising data, but
      the exact efficacy is undetermined (2,3). We now propose, as a phase II randomized study,
      autologous unmanipulated PBSCT versus pulse cyclophosphamide in patients with systemic
      scleroderma.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Age 60 year or < 60 year old at the time of pretransplant evaluation.

          -  An established diagnosis of scleroderma.

          -  Diffuse cutaneous scleroderma with involvement proximal to the elbow or knee and a
             Rodnan score of > 14

        AND

        Scleroderma with any one of the following:

          -  Diffusing capacity of the lung for carbon monoxide (DLCO) < 80% of predicted or
             decrease in lung function [DLCO, diffusing capacity divided by the alveolar volume
             (DLCO/VA) or forced vital capacity (FVC) ] of 10% or more over 12 months.

          -  Active alveolitis on bronchoalveolar lavage.

          -  Pulmonary fibrosis or alveolitis on computed tomography (CT) scan or chest x-ray (CXR)
             (ground glass appearance of alveolitis).

          -  Renal disease that is not explained by a bacterial infection or other renal disorders.
             (Subjects must have two or more of the following: proteinuria - greater than trace on
             dipstick, hematuria - urine blood on dipstick or sediment, hypertension that requires
             treatment with anti-hypertensive medications or untreated but with a diastolic blood
             pressure (BP) > 95 mm/hg.)

          -  Abnormal electrocardiogram (EKG) (non-specific ST-T wave abnormalities, low QRS
             voltage, or ventricular hypertrophy), or pericardial effusion or pericardial
             enhancement on magnetic resonance imaging (MRI)

          -  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. Gastrointestinal (GI) involvement may also be confirmed by
             D-xylose malabsorption, patulous esophagus, or esophageal manometry.

        OR

        As published in NEJM, 2006, 345:25 2655-2709. Limited or diffuse SSL 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:

          -  Poor performance status Eastern Cooperative Oncology Group (ECOG 2) at the time of
             entry.

          -  Significant end organ damage such as:

               1. Left Ventricular Ejection Fraction (LVEF) < 40% or deterioration of LVEF during
                  exercise test on Multiple Gated Acquisition (MUGA) or echocardiogram.

               2. Untreated life-threatening arrhythmia.

               3. Active ischemic heart disease or heart failure.

               4. End-stage lung disease characterized by total lung capacity (TLC) <45% of
                  predicted value.

               5. Pulmonary hypertension (systolic pulmonary arterial pressure > 40 mmHg or mean
                  pulmonary arterial pressure (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> 200ml unless successful pericardiocentesis

               9. Tricuspid annular peak systolic excursion (TAPSE) ≤ 1.9 cm

              10. MRI of heart showing D sign (intraventricular flattering)

          -  Human immunodeficiency virus (HIV) positive.

          -  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.

          -  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, inability or unable 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.

          -  Inability to give informed consent.

          -  Major hematological abnormalities such as platelet count < 100,000/ul or absolute
             neutrophil count (ANC) < 1000/ul.

          -  Patients with duration of disease > 5 years.

          -  Exclude if > than 6 prior monthly IV cyclophosphamide treatments.