Autologous Stem Cell Transplantation for Progressive Systemic Sclerosis

Study Overview
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Brief Summary
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Autologous stem cell therapy has been shown to be effective in patients with systemic sclerosis. Nevertheless treatment is associated with treatment related mortality and patients die during follow up despite successful transplantation. Intention of this trial is to improve overall survival by modifying the existing protocol used for the ASTIS trial. To reduce treatment toxicity we reduce the dose of Cyclophosphamide (CYC) for mobilisation to 2x1g. Especially in patients with cardiac manifestations we also modify the conditioning regimen by adding thiotepa and reducing CYC; as CYC has known cardiotoxic side effects.

Official Title
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Highdose Chemotherapy and Transplantation of 34+ Selected Stem Cell for Progressive Systemic Sclerosis - Modification According to Manifestation

Conditions
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Scleroderma, Cardiac Involvement, Autologous Stem Cell Transplantation

Intervention / Treatment
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* Drug: Autologous stemcell transplantation with CD (cluster of differentiation) 34 selected stem cells


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of progressive systemic sclerosis <7 years Progressive course despite cyclophosphamide pretreatment Cyclophosphamide i.v.: at least 3 x with 500-1000 mg/m² every 3-4 weeks or Cyclophosphamide p.o. with at least 100mg/day for at least 2 months or Contraindication to treatment with cyclophosphamide Progress defined as at least one of the following criteria: Increase in the mRSS Worsening of the lung function Increase in fibrosis/alveolitis in thorax CT Worsening kidney function through manifestation of systemic sclerosis Limited or diffuse cutaneous progressive form of Ssc with organ manifestation in the lungs/heart or kidneys Exclusion Criteria: Age <18 years Pregnancy or inadequate contraception Severe heart failure with ejection fraction (EF) < 30% in echo Pulmonary arterial hypertension with systolic pulmonary arterial pressure (PAPsys) >50mm Hg Kidney insufficiency: creatinine clearance <30 ml/min Reduced lung function Inspiratory vital capacity (IVC) < 50% of normal Carbon monoxide (CO)-Diffusion capacity SB < 40% Previously damaged bone marrow Leukopenia < 2,000/µl Thrombopenia < 100,000/µl Previous myelotoxic treatment: Cyclophosphamide > 50g cumulative (relative) Infection (Hepatitis B/C, HIV, Salmonella carrier, syphilis, relative: history of tuberculosis) Severe concomitant psychiatric illness (depression, psychosis) Substance dependence Continued nicotine abuse Continued alcohol abuse Continued drug abuse Consent not given Poor compliance

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Conditioning with CYC/ antithymocyte globulin (ATG)<br>Each patient receives stem cell transplantation open label with cluster of differentiation (CD)34 selected stem cells mobilisation and conditioning depending on manifestation If cardiac manifestation: Conditioning with CYC 2 x 50mg + thiotepa 2x5mg + ATG If no cardiac manifestation: Conditioning with 4 x 50mg CYC + ATG | Drug: Autologous stemcell transplantation with CD (cluster of differentiation) 34 selected stem cells<br>* If no active alveolitis: mobilisation with 2x1g Cyclophosphamide If active alveolitis: mobilisation with 2x1.5g Cyclophosphamid If cardiac manifestation: Conditioning with CYC 2 x 50mg + thiotepa 2x5mg + ATG If no cardiac manifestation: Conditioning with 4 x 50mg CYC + ATG<br>|
| Experimental: Conditioning with CYC/Thiotepa/ATG<br>In patients with cardiac manifestations as defined in the protocol the conditioning for stem cell transplantation is changed to Cyclophosphamide (CYC), thiotepa and ATG | Drug: Autologous stemcell transplantation with CD (cluster of differentiation) 34 selected stem cells<br>* If no active alveolitis: mobilisation with 2x1g Cyclophosphamide If active alveolitis: mobilisation with 2x1.5g Cyclophosphamid If cardiac manifestation: Conditioning with CYC 2 x 50mg + thiotepa 2x5mg + ATG If no cardiac manifestation: Conditioning with 4 x 50mg CYC + ATG<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Efficay - Overall survival | Number of patients that are alive after 3 years | 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety - Treatment related mortality | Treatment related mortality: number of patients who die during the first 100 days after transplantation | 100 days | 
| Time to engraftment | Time in days from day 0 to platelet count > 20.000 and granulocytes >500/µl | 2 months | 
| Progression free survival | Time after transplantation without symptoms of disease activity | 3 years | 
| Efficacy - Lung function test and Skin | Number of patients that achieve either improvement of >25% in mRSS or > 10% in FVC or DLCO | 3 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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scleroderma, autologous stem cell transplantation, thiotepa, cluster of differentiation (CD) 34 selection