Campath-1h Phase I/II Pilot Trial as Immunoablative Therapy for Refractory Systemic Sclerosis

4.2 Inclusion/Exclusion criteria 4.2.1 Inclusion criteria

• 8 to 21 years of age, inclusive
• Diffuse, cutaneous dcSSc as defined by the ACR criteria with evidence of active inflammatory disease.
• Plus at least 1 of the following:
• dcSSc-related pulmonary disease with forced vital capacity (FVC) or hemoglobin-adjusted DLCO < 70% and evidence of alveolitis by high-resolution CT scan or bronchoalveolar lavage

OR

• History of SSc-related renal crisis or disease, not active at the time of screening

OR

• Moderate to severe upper and/or lower gastrointestinal involvement AND
• Unacceptable toxicity or steroid dependence > 0.3 mg/kg/d
• Failure to respond to, or unacceptable toxicity of MTX > 1mg/kg in combination with cyclosporine or azathioprine or cyclophosphamide or Rituximab 375 mg/m2 x 4 doses or Imatinib 800 mg/d or tocilizumab 8 mg/kg for at least 3 doses.
• Disease recurrence after tapering medication above (in #4)

4.2.2 Exclusion Criteria

• Pulmonary, cardiac, hepatic, or renal impairment that would limit therapy and compromise survival includes, but is not restricted to, any of the following:
• Severe pulmonary dysfunction: hemoglobin-corrected DLCO < 45%, DLCO <4 mL/mmHg/min/L or pO2 < 70 mm Hg or pCO2, ≥ 45 mm Hg without supplemental O2 sat 92% at rest without supplemental O2
• Significant pulmonary hypertension
• Uncontrolled clinically significant arrhythmias
• NYHA heart failure class IV
• LVEF < 50% by echo or prior insertion of a pacemaker or cardioverter-defibrillator
• End-stage renal disease (GFR<50 ml/min/1.73 m2 or creatinine . 2 mg/dl; estimated CrCl < 40 mL/min or active, untreated dcSSc renal crisis at time of enrollment
• Active hepatitis (ALT, AST, or bilirubin > 2x ULN)
• Active gastric antral vascular ectasia (GAVE, "watermelon stomach")
• 2 mg/kg/day prednisone or equivalent within 30 days of treatment
• Unwilling or unable to discontinue DMARDs for treatment of dcSSc
• Co-morbid illnesses with an estimated median life expectancy < 5 Years
• Active uncontrolled infection
• Positive serology for hepatitis B or C, HIV
• ANC < 1500 cells/µL, platelets < 120,000 cells/µL, Hct < 27% or Hgb < 9.0 g/dL
• Malignancy within the previous 2 years, excluding treated skin cancer
• Myelodysplasia
• Uncontrolled hypertension
• History of hypersensitivity to murine or E. coli proteins
• Pregnancy or unwilling to use contraceptive methods for at least 15 months
• Steroid dependence: > 2mg/kg/day, prednisone or equivalent within 30 days prior to treatment
• History of substance abuse within the last 5 years
• History or presence of 2nd autoimmune disease requiring immunosuppressive therapy that has a substantial risk of recurrence
• Demonstrated lack of compliance with prior medical care
• Lack of rehabilitation potential

4.3 SSc patients, who fulfill the inclusion criteria, will then be assessed for residual thymic function since our previous study of pediatric dcSSc patients demonstrated that the dcSSc patients had decreased thymic function as compared to age matched controls as measured by the proportion of naïve CD4+ T lymphocytes (CD4+, CD31+), recent thymic emigrants (RTE). (5) Patients with less than 40% RTE will be excluded because of concerns about their ability to reconstitute their immune system after immune ablation.

4.4 dcSSc patients, who fulfill the screening criteria, will be consented for entry into the clinical trial.