Cardiac Safe Transplants for Systemic Sclerosis

Study Overview
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Brief Summary
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This study is designed to treat systemic sclerosis (scleroderma) patients with an autologous stem cell transplant using a regimen of immune suppressant drugs and chemotherapy that is less toxic to your heart.

Detailed Description
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The autologous hematopoietic stem cell transplant used in this research study is an investigational procedure that uses cyclophosphamide and fludarabine (chemotherapy), rabbit anti-thymocyte globulin (rATG) (a protein that kills the immune cells that are thought to be causing your disease), and rituximab (a biologic drug that targets B cells of your immune system). After use of these treatments, the patient will receive their own previously collected blood stem cells (autologous stem cell transplant). The ability of these experimental treatments to stop relapses and progression (worsening) of your systemic sclerosis will be assessed.

Official Title
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Autologous Hematopoietic Stem Cell Transplant for Patients With Systemic Sclerosis and Cardiac Dysfunction

Conditions
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Systemic Sclerosis, Scleroderma

Intervention / Treatment
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* Drug: Rituximab
* Drug: Fludarabine
* Drug: Cyclophosphamide
* Drug: Mesna
* Drug: rATG
* Drug: Methylprednisolone
* Drug: G-CSF
* Biological: IVIg
* Biological: Autologous Stem Cells


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age 18 - 65 years old at the time of pre-transplant evaluation An established diagnosis of systemic sclerosis Diffuse cutaneous systemic sclerosis with involvement proximal to the elbow or knee and a modified Rodnan Skin Score of ≥ 14 (see Appendix A) AND Any one of the following: DLCO < 80% of predicted or decrease in lung function (DLCO, DLCO/VA or FVC) of 10% or more over 12 months. Pulmonary fibrosis or alveolitis on CT scan or chest x-ray (ground glass appearance of alveolitis). Abnormal EKG (non-specific ST-T wave abnormalities, low QRS voltage, or ventricular hypertrophy), or pericardial effusion or pericardial enhancement without constriction on 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 +/- diverticula, or pseudodiverticula. A hide-bound appearance may be present (e.g. dilated and crowded circular folds). GI involvement may also be confirmed by D-xylose malabsorption, patulous esophagus on high-resolution computed tomography (HRCT), or esophageal manometry. OR Limited cutaneous systemic sclerosis (SSc) (modified Rodnan Skin Score <14) with lung involvement defined as active alveolitis on bronchoalveolar lavage (BAL), ground-glass opacity on CT scan, a DLCO < 80% predicted, or decrease in lung function (DLCO/VA, DLCO, FVC) of 10% or more in last 12 months. Other Inclusion Criteria for CAST Conditioning Regimen (presence of any of the following): Septal flattening or D-sign on MRI (without deep breathing) PASP >40 mm Hg or >45 mm Hg with fluid challenge* mPAP >25 mm Hg or >30 mm Hg with fluid challenge* Non-ischemia diffuse ventricular hypokinesis or non-ischemia wall hypokinesis Fluid challenge is 1000 ml normal saline over 10 minutes. Fluid challenge will not be done if right atrial pressure is >13 mm Hg at rest or pulmonary capillary wedge pressure is >20 mm Hg at rest. Exclusion Criteria: Active ischemic heart disease or untreated coronary artery disease Untreated life-threatening cardiac arrhythmia on EKG or 24-hour holter Pericardial effusion > 1 cm on cardiac MRI unless successful pericardiocentesis has been performed LVEF <35% End-stage lung disease characterized by TLC<45% of predicted value, or DLCO hemoglobin corrected < 30 % predicted. Creatinine clearance <40 by 24-hour urine History of breast implants that have not been removed (unless they cannot be surgically removed due to risks of surgery) Liver cirrhosis, transaminases >2x of normal limits, or bilirubin > 2.0 unless due to Gilbert's disease 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 Positive pregnancy test, inability or unable to pursue effective means of birth control, or 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 Major hematological abnormalities such as platelet count < 100,000/ul or absolute neutrophil count (ANC) < 1000/ul HIV positive Hepatitis B or C positive PASP >50 mmHg without fluid challenge mPAP >34 mmHg without fluid challenge Coronary artery disease not reversed by cardiology and interventional radiology

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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Hematopoietic Stem Cell Transplantation<br>Hematopoietic Stem Cell Therapy will be performed as follows: Autologous stem cells will be infused after conditioning with rituximab, fludarabine, cyclophosphamide, Mesna, rATG (rabbit), and methylprednisolone. Granulocyte-colony stimulating factor (G-CSF) and intravenous immunoglobulin (IVIg) will be administered post-transplant. | Drug: Rituximab<br>* Monoclonal antibody therapy used to treat certain autoimmune diseases and types of cancer<br>* Other names: Rituxan;Drug: Fludarabine<br>* A chemotherapy medication commonly used in the treatment of leukemia and lymphoma<br>* Other names: Fludara;Drug: Cyclophosphamide<br>* A medication used as chemotherapy and to suppress the immune system<br>* Other names: Cytoxan;Drug: Mesna<br>* A medication used in those taking cyclophosphamide or ifosfamide to decrease the risk of bleeding from the bladder<br>* Other names: Mesnex;Drug: rATG<br>* A rabbit polyclonal antibody to lymphocytes<br>* Other names: Anti-Thymocyte Globulin (Rabbit);Drug: Methylprednisolone<br>* A corticosteroid medication used to suppress the immune system and decrease inflammation<br>* Other names: Depo-Medrol;Drug: G-CSF<br>* A glycoprotein that stimulates the bone marrow to produce granulocytes and stem cells and release them into the bloodstream<br>* Other names: Zarxio;Biological: IVIg<br>* Pooled immunoglobulin (IgG) from thousands of plasma donors that has immunomodulatory and anti-inflammatory effects<br>* Other names: Octagam;Biological: Autologous Stem Cells<br>* Infusion of patient's own stem cells<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Skin Score by mRSS | Defined by at least a 25% improvement (decline) in skin score by modified Rodnan skin score (mRSS) if skin score is greater than 14 on enrollment. If skin score is less than 14 on enrollment, improvement is defined by at least a 5% improvement on mRSS. The modified Rodnan skin score (MRSS) is a measure for skin disease in scleroderma and is calculated by summation of skin thickness in 17 different body sites. The scale ranges from at total score of normal skin thickness (0) to severe thickness (51). | Pre Treatment and Post Treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Survival of Treatment | Survival of Hematopoietic Stem Cell Transplant during treatment and post treatment up to 1 year. | During Treatment and Post Treatment up to 1 year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Autologous Stem Cell Transplantation, Hematopoietic Stem Cell Transplant