PFF Clinical Trial Finder

Inclusion Criteria Individuals must meet all the following criteria to be eligible for this study. 1. Patient, parent, or legal guardian must have given written informed consent. For patients ≥ 16 years of age who are developmentally able, assent or affirmation will be obtained. 2. Age 16-70, inclusive, at time of consent. 3. Diagnosed with Systemic Sclerosis (SSc), according to the 2013 ACR/EULAR criteria (van den Hoogen et al., 2013). 4. All patients must meet either the following skin or ILD criteria. Disease duration is defined as time from first non-Raynaud symptom. Skin Criteria: Diffuse SSc, defined by presence of proximal skin thickening and: A. If disease duration <2 years, patients must have intermediate or high risk of 5-year mortality based on risk prediction score (Domsic et al., 2016). B. If disease duration >2 years, patients must have evidence of active disease based upon 1) worsening Modified Rodnan Skin Score (MRSS) OR 2) presence of tendon friction rubs. ILD Criteria: A. The presence of recognized fibrosis on imaging of <2 years AND either > 10% of lung involvement by CT scan or FVC% pred <70% OR B. FVC <70% with fibrosis on imaging and decline in FVC of 10% over the preceding 12-18 months. 5. Negative for human immunodeficiency virus (HIV), hepatitis B virus and hepatitis C virus, all confirmed by PCR testing. 6. Negative pregnancy test for females. 7. All females of childbearing potential and sexually active males must agree to use an FDA approved method of birth control for up to 24 months after BMT or for as long as they are taking any medication that may harm a pregnancy, an unborn child or may cause a birth defect. Exclusion Criteria Individuals who meet any of these criteria are not eligible for this study. 1. Moderate to severe cardiac involvement defined by any of the following for subjects ≥ 18 years of age: 1. New York Heart Association classification of heart failure ≥3. 2. Left ventricular ejection fraction (LVEF) ≤40% as determined by cardiac MRI. 3. Significant pulmonary hypertension defined as mean PASP ≥30 mmHg by right heart catheterization. 4. Atrial tachycardia, atrial fibrillation or atrial flutter of ≥1-minute duration, determined by either electrocardiogram (EKG) or implanted loop recorder, or on anti-arrhythmic therapy for the arrhythmias listed above. 5. Ventricular tachycardia of ≥6 beats at rate of ≥100 beats per minute, determined by either EKG or implanted loop recorder, or on an anti-arrhythmic therapy for any ventricular arrhythmia. 6. Bundle branch block, bifascicular heart block, Mobitz 2 heart block, complete heart block or infarction pattern as determined by EKG or implanted loop recorder. 7. Presence of pacemaker or implantable cardioverter defibrillator. 2. Moderate to severe cardiac involvement defined by any of the following for subjects ≤ 17 years of age: 1. New York Heart Association classification of heart failure ≥3. 2. Left ventricular ejection fraction (LVEF) ≤40% as determined by cardiac MRI. 3. Significant pulmonary hypertension defined as mean PASP >45 mmHg by echocardiogram. 4. Atrial tachycardia, atrial fibrillation or atrial flutter of ≥1-minute duration, determined by either electrocardiogram (EKG) or cardiac event monitor, or on anti-arrhythmic therapy for the arrhythmias listed above. 5. Ventricular tachycardia of ≥6 beats at rate of ≥100 beats per minute, determined by either EKG or cardiac event monitor, or on an anti-arrhythmic therapy for any ventricular arrhythmia. 6. Bundle branch block, bifasicular heart block, Mobitz 2 heart block, complete heart block or infarction pattern as determined by EKG or cardiac event monitor. 7. Presence of pacemaker or implantable cardioverter defibrillator. 3. Hemoglobin-corrected DLCO <40% or FVC <45%, determined by pulmonary function tests OR either pO2 <70 mmHg, pCO2 ≥45 without supplemental O2, or O2 sat <92% at rest without supplemental O2, determined by an arterial blood gas. 4. Estimated CrCl <40 mL/min (using Cockcroft-Gault formula based on actual body weight) and serum creatinine >2.0 mg/dL OR active, untreated SSc renal crisis at the time of consent. 5. Dependence on nutritional supplementation/hyperalimentation OR active gastric antral vascular ectasia (GAVE) as defined by a decrease in hemoglobin greater than 1 g/dL in the preceding 60 days attributed to GAVE. 6. Active hepatitis (AST, ALT or bilirubin >2 upper limit of normal) or evidence of moderate to severe periportal fibrosis by liver biopsy. 7. Active uncontrolled infection that would be a contraindication to safe use of high-dose immunosuppressive therapy or cyclophosphamide. 8. Hematologic abnormalities as defined by peripheral blood counts: 1. ANC < 1500 cell/µL. 2. Platelets < 100,000 cells/ µL. 3. Hemoglobin < 9.0 g/dL. 9. Evidence of myelodysplasia (MDS), confirmed by bone marrow aspirate, if applicable. 10. Malignancy within 2 years prior to enrollment, excluding adequately treated squamous cell cancer, basal cell carcinoma or carcinoma in situ. Treatment should have been completed with cure/remission status documented for at least 2 years, with the exception of hormonal therapy for breast cancer. 11. Females who are pregnant or who are lactating. 12. Tobacco use, by subject admission, within previous 4 weeks of completed eligibility. 13. History of sensitivity to murine proteins or E. coli proteins. 14. Known history of substance abuse, determined by medical record or subject admission, within 6 months prior to completion of eligibility. 15. Past or current medical problems or findings from physical examination or laboratory testing that are not listed above, which, in the opinion of the investigator, may pose additional risks from participation in the study, may interfere with the participant's ability to comply with study requirements or that may impact the quality or interpretation of the data obtained from the study.

This is a single center, phase II trial where after a process of stem cell mobilization and conditioning, adult subjects receive a CD34-selected autologous peripheral blood stem cell rescue. By virtue of positive selection for the stem/progenitor cell marker of CD34, the graft will be at least 3-log depleted for T, B and NK lymphocytes and other immune cells such as monocytes that may be pathogenic. This is an open label study and there will be no randomization or blinding as a part of this study. The proposed regimen of high-dose immunoablative therapy will demonstrate safety that is consistent or improved with other published regimens in SSc patients, while maintaining a treatment effect. We also hypothesize that our mechanistic studies will yield biomarkers that may herald disease recurrence or progression following alterations in the recovery of immune cells in the skin and/or bronchial lavage or blood. The primary objectives of this study are to determine the safety and treatment effect of high-dose immunoablative therapy followed by transplantation of CD34+ positively selected peripheral blood stem cells (PBSC) for systemic scleroderma (SSc) patients using a regimen designed to maximize patient safety while also aiming to eradicate autoreactive clones responsible for the disease. Safety will be determined by monitoring for death of any cause, regimen-related toxicities, and severe or life-threatening infections. Treatment effect will be determined by assessing event-free survival in comparison to a SSc observational cohort control group treated with standard of care medication (mycophenolate mofetil) at 12 and 36 months post hematopoietic stem cell transplant (HSCT). Enrolled subjects will be followed for survival, secondary malignancies, and SSC activity at least yearly up to 36 months post-HSCT. The secondary objectives of this study are to:

• - To assess cutaneous disease response to high dose immunosuppressive therapy (HDIT) by comparing pre- and post-transplant measurements of the modified Rodnan skin score (mRSS).

• - To assess pulmonary disease response by longitudinally tracking FVC (pulmonary function test) and DLCO (diffusing capacity of the lung for carbon monoxide) yearly up to 36 months post-HSCT.

• - To evaluate the treatment effect on disease activity/progression, as indicated by severity measures of cardiac, pulmonary and renal organ involvement, and need for concomitant disease-modifying antirheumatic drugs (DMARD) use.

• - To evaluate quality of life by comparing pre- and post-transplant quality of life measurements.

These measurements will include the Scleroderma Health Assessment Questionnaire (SHAQ), the Medical Outcomes Study Questionnaire Short Form 36 Health Survey (SF-36) and the Scleroderma Skin Patient Reported Outcome (SSPRO) pre- and post-mobilization. The research (mechanistic) objectives are as follows:

• - Understand the effect of the combination of rituximab and alemtuzumab on lymphocyte subsets and myeloid cells in the skin of patients undergoing treatment.

• - Understand the effect of total body irradiation (TBI) and Thiotepa on subsets of lymphocytes and myeloid cells in the skin of patients undergoing treatment.

• - Understand the relationship between the response of patient skin disease to depletion and repopulation of skin leukocyte subpopulations and gene expression.

- Characterize the evolution of humoral and cellular immune markers of autoreactivity in blood and BAL (bronchoalveolar lavage)when feasible