Autologous Stem Cell Transplantation in Patients With Systemic Sclerosis (SSc)

Autologous Stem Cell Transplantation With CD34-Selected Peripheral Blood Stem Cells (PBSC) in Patients With Treatment Resistant Systemic Sclerosis (SSc)

The purpose of this study is to determine whether a 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.

Study Overview

• Status: Recruiting
• Conditions: Systemic Sclerosis; Pulmonary Hypertension; Interstitial Lung Disease; Diffuse Sclerosis Systemic
• Intervention / Treatment: Drug: Cyclophosphamide; Drug: Mesna; Drug: Rituximab; Drug: Alemtuzumab; Drug: Thiotepa; Drug: GM-CSF; Drug: Intravenous immunoglobulin; Radiation: Total Body Irradiation; Drug: Anti Thymocyte Globulin

Detailed Description

This is a single center, phase II trial where after a process of stem cell mobilization and conditioning, 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 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.

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, 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, musculoskeletal, gastrointestinal, vascular 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.

• Study Type: Interventional
• Enrollment (Estimated): 8
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Paul Szabolcs, MD; Phone Number: 412-692-6225; Email: paul.szabolcs@chp.edu
• Study Contact Backup: Name: Shawna McIntyre, RN; Phone Number: 412-692-5552; Email: mcintyresm@upmc.edu

Study Locations

• United States
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15261
      • Recruiting
      • University of Pittsburgh Medical Center
      • Contact: Robert Lafyatis, MD; Phone Number: 412-647-6700; Email: lafyatisra@upmc.edu
    • Pittsburgh, Pennsylvania, United States, 15213
      • Recruiting
      • Children's Hospital of Pittsburgh of UPMC
      • Sub-Investigator: Adam Olson, MD
      • Sub-Investigator: Kathryn Torok, MD
      • Sub-Investigator: Robyn Domsic, MD, MPH
      • Sub-Investigator: Annie Im, MD
      • Sub-Investigator: Daniel Kass, MD
      • Sub-Investigator: Geoffrey Kurland, MD
      • Sub-Investigator: Robert Lafyatis, MD
      • Sub-Investigator: Allison Morris, MD, MS
      • Sub-Investigator: Kirsten Rose-Felker, MD
      • Sub-Investigator: Franziska Rosser, MD, MPH
      • Sub-Investigator: Paulina Horvei, MD
      • Sub-Investigator: Joshua Levenson, MD
      • Principal Investigator: Paul Szabolcs, MD
      • Contact: Shawna McIntyre, RN; Phone Number: 412-692-5552; Email: mcintyresm@upmc.edu
      • Sub-Investigator: Archana Ramgopal, DO

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 8 years to 60 years (Child, Adult)
• Accepts Healthy Volunteers: No

Description

Cohort 1: Children, Adolescents and Young Adults (Cohort 1)

Inclusion:

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 ≥ 168 years of age who are developmentally able, assent or affirmation will be obtained.
2. Age 8-24, inclusive, at time of consent.
3. Diagnosed with Systemic Sclerosis (SSc) at the age of ≤19.

4. Failure to respond, specifically no improvement or progression of disease, to at least 2 disease-modifying antirheumatic drugs (DMARDS) within 12 months of consent with any of the following conditions:

   1. Progression of skin thickening over the past 6 months or Modified Rodnan skin score (mRSS) ≥ 20

   2. Progression of ILD within 18 months prior to consent. Progression to be determined by either of the following:

      • CT scan showing increased ground glass opacities or reticulations OR
      • Pulmonary function testing (PFTs) showing a decrease in FVC% or DLCO% predicted value of ≥10%.
   3. Myositis - CPK > 2x upper limit of normal or MRI consistent with myositis
   4. Childhood Myositis Assessment Score < 30
   5. Arthritis
   6. Digital tip ulcerations
5. Cardiology clearance to undergo stem cell transplantation (documented in subject's medical chart)
6. Negative for human immunodeficiency virus (HIV), hepatitis B virus and hepatitis C virus, all confirmed by PCR testing.
7. Negative pregnancy test for females. who have reached menarche.

87. 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:

Individuals who meet any of these criteria are not eligible for this study.

1. FVC <35%, determined by pulmonary function tests for those able to complete spirometry adequately (per investigator's determination)
2. O2 sat <92% at rest in room air
3. Estimated CrCl <40 mL/min,using Cockcroft-Gault formula based on actual body weight.
4. Active, untreated SSc renal crisis at the time of consent.
5. ALT > 4x upper limit of normal.
6. Active, uncontrolled infection that would be a contraindication to safe use of high-dose immunosuppressive therapy or cyclophosphamide.

7. Hematologic abnormalities as defined by any of the following peripheral blood counts:

   1. ANC < 1500 cell/µL.
   2. Platelets < 100,000 cells/ µL.
   3. Hemoglobin < 9.0 g/dL.
8. 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.
9. Past or current medical problems or findings from medical history, 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.

Cohort 2 for Adults

Inclusion:

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 1618-705560, inclusive, at time of consent. Patients up to age 24, diagnosed with SSc at age ≤ 19, will be included in Cohort 1 and evaluated according to the Pediatric and Young Adult criteria listed in sections 3.1.1 and 3.1.2.
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 is of <2 years, patients must have a calculated mortality risk prediction score which places them in the intermediate or high- risk category (Domsic et al., 2016). Refer to Appendix 5 for calculation criteria.

   B. If disease duration is of >2 years, patients must have evidence of active cutaneous disease based upon 1) a worsening Modified Rodnan Skin Score (MRSS) in the preceding three months or 2) the presence of palpable 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 <80% or B. Fibrosis on imaging of any duration with a decline in FVC% pred 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:

   1. New York Heart Association classification of heart failure ≥3.
   2. Left ventricular ejection fraction (LVEF) <50% as determined by cardiac MRI.
   3. Significant pulmonary hypertension, for subjects ≥ 18 years of age, defined as mean PASP ≥30 mmHg determined by right heart catheterization, or for subjects ≤ 17 years of age, defined as mean PASP >45 mmHg, determined by echocardiogram.
   4. Atrial tachycardia, atrial fibrillation or atrial flutter of ≥1-minute duration, determined by electrocardiogram (EKG) or, cardiac event monitor and/or implanted loop recorder (if applicable), 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 EKG or, cardiac event monitor and/or implanted loop recorder (if applicable), or on an anti-arrhythmic therapy for any ventricular arrhythmia.
   6. Left bundle branch block, bifascicular heart block, Mobitz 2 heart block, complete heart block or infarction pattern as determined by EKG or, cardiac event monitor and/or implanted loop recorder
   7. Presence of pacemaker or implantable cardioverter defibrillator.

2. Moderate to severe pulmonary involvement defined by any of the following:

   1. Hemoglobin-corrected DLCO <45%, determined by pulmonary function tests.
   2. FVC <45%, determined by pulmonary function tests.
   3. pO2 <70 mmHg, determined by an arterial blood gas (not applicable for subjects ≤17 years of age).
   4. pCO2 ≥45 without supplemental O2 determined by an arterial blood gas (not applicable for subjects ≤17 years of age).
   5. O2 sat <92% at rest without supplemental O2, determined by an arterial blood gas (not applicable for subjects ≤17 years of age).
   6. Six-minute walk (6MW) results <400 feet.

3. Steroid therapy defined by either of the following:

   1. Subjects who received > 10 mg/day prednisone or equivalent within 30 days prior to start of conditioning regimen on Day -21.
   2. Subjects who have been treated for concurrent illnesses (eg, asthma) with the equivalent of prednisone 1 mg/kg/day or its equivalent for > 5 days on > 2 occasions during the previous 12 months (prior to conditioning) or > 1 occasion in the prior 6 months (prior to conditioning).
4. Estimated CrCl <40 mL/min,using Cockcroft-Gault formula based on actual body weight.
5. Serum creatinine >2.0 mg/dL.
6. Active, untreated SSc renal crisis at the time of consent.
7. Dependence on nutritional supplementation/hyperalimentation.
8. Active gastric antral vascular ectasia (GAVE), defined by a decrease in hemoglobin greater than 1 g/dL in the preceding 60 days, attributed to GAVE.

9. Active hepatitis defined by any of the following:

   1. AST > 2x upper limit of normal.
   2. ALT > 2x upper limit of normal.
   3. Bilirubin >2x upper limit of normal.
10. Evidence of moderate to severe periportal fibrosis, determined by liver biopsy, if applicable.
11. Active, uncontrolled infection that would be a contraindication to safe use of high-dose immunosuppressive therapy or cyclophosphamide.

12. Hematologic abnormalities as defined by any of the following peripheral blood counts:

    1. ANC < 1500 cell/µL.
    2. Platelets < 100,000 cells/ µL.
    3. Hemoglobin < 9.0 g/dL.
13. Evidence of myelodysplasia (MDS), confirmed by bone marrow aspirate, if applicable.
14. 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.
15. Females who are pregnant or who are lactating.
16. Tobacco use, by subject admission, within previous 4 weeks of time of consent.
17. History of sensitivity to murine proteins or E. coli proteins.
18. Known history of substance abuse, determined by medical record or subject admission, within 6 months of time of consent.
19. Patient with systemic reaction to anti-thymocyte globulin or any other equine gamma globulin preparation
20. 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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Autologous Stem Cell Transplantation; CD34-selected autologous stem cell being performed on CliniMACS depletion device. Conditioning regimen will not start sooner than 3 weeks, and ideally no more than 90 days, after cyclophosphamide dose in the mobilization regimen.

Drug: Cyclophosphamide; Stem Cell Mobilization; Drug: Mesna; Stem Cell Mobilization; Drug: Rituximab; Transplantation Conditioning; Other Names: Rituxan; Drug: Alemtuzumab; Transplantation Conditioning; Other Names: Campath-1H; Drug: Thiotepa; Transplantation Conditioning; Drug: GM-CSF; Transplantation Conditioning; Other Names: Neupogen, Filgrastim; Drug: Intravenous immunoglobulin; Transplantation Conditioning; Radiation: Total Body Irradiation; Transplantation Conditioning; Drug: Anti Thymocyte Globulin; Transplantation Conditioning; Other Names: Thymoglobulin

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
High Dose Immunoablative therapy-Safety	Safety will be determined by monitoring for death of any cause, regimen-related toxicities, and severe or life-threatening infections.	Up to 36 months post HSCT
Death	How many, if any, patients die	Post Transplant through study completion, an average of 36 months
Respiratory Failure	defined by one of the following 3 criteria without explanation for causation other than disease progression: 1. decline in DLCO of ≥30% or FVC≥20% as measured by actual difference in percent predicted units; 2. Resting arterial p02 < 60 mmHg or pCO2 > 50 mmHg supplemental oxygen;3. Resting pulse oximetry of 88% or lower measured by forehead probe.	Post Transplant through study completion, an average of 36 months
Renal Failure	Defined by chronic dialysis for >6 months or renal transplantation	Post Transplant through study completion, an average of 36 months
The occurrence of cardiomyopathy	confirmed by clinical congestive heart failure (New York Heart Association) or LVEF (left ventricular ejection fraction) <30% on echocardiogram	Post Transplant through study completion, an average of 36 months
Treatment-related mortality (TRM)	defined as death occurring at any time after stem cell mobilization and definitely or probably resulting from treatment given in the study. TRM will be determined yearly with a focus on the first 2 years.	Mobilization through study completion, an average of 36 months
High Dose Immunoablative therapy-Treatment Effect	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).	up to 36 months post HSCT (hematopoietic stem cell transplantation)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
An increase of mRSS (modified Rodnan skin score ) by ≥5 points for skin score	To assess cutaneous response the modified Rodnan skin score (mRSS) will be used.	Disease response will be defined as subject improvement. This will be assessed for both skin and interstitial lung disease at 12 and 24 months post-HSCT.
Increase by ≥25% if the baseline mRSS > 20.	To assess cutaneous response the modified Rodnan skin score (mRSS) will be used.	Disease response will be defined as subject improvement. This will be assessed for both skin and interstitial lung disease at 12 and 24 months post-HSCT.
Worsening of > 10% of FVC (pulmonary function testing)	to evaluate interstitial lung disease an increase of ≥15% in DLCO or ≥10% of FVC (actual change in % predicted units from baseline) sustained for ≥3 months on 2 determinations.	1 year post transplant through study completion, an average of 36 months
Decrease in DLCO sustained for 3 months or longer on pulmonary function tests (PFT)	to evaluate interstitial lung disease an increase of ≥15% in DLCO or ≥10% of FVC (actual change in % predicted units from baseline) sustained for ≥3 months on 2 determinations.	1 year post transplant through study completion, an average of 36 months
Worsening of cardiac involvement	With use of Imaging, EKG, Echocardiogram, Cardiac MRI, right heart cauterization, implanted loop recorder and 2 week cardiac event monitor. Defined as new or worsening arrhythmias that require medical treatment of 3 months or longer, or require ablative therapy, pacemaker or defibrillator insertion or defined as a decline in ejection fraction of ≥10 EF units, determined by echocardiogram.	Post Transplant through study completion, an average of 36 months
Development of scleroderma renal crisis (hypertensive or non-hypertensive)	Hypertensive renal crisis can be defined as a rise in SBP ≥ 30 points or DBP ≥ 20 points from baseline and one of the following: 1) Increase in baseline serum creatinine of ≥ 50%, 2) thrombocytopenia < 100,000 plts/mm3 or 3. hemolysis by blood smear or increased reticulocyte count.	Post Transplant through study completion, an average of 36 months

Collaborators and Investigators

• Sponsor: Paul Szabolcs
• Investigators: Principal Investigator: Paul Szabolcs, MD, University of Pittsburgh

Study record dates

Study Major Dates

• Study Start (Actual): July 31, 2018
• Primary Completion (Estimated): August 1, 2026
• Study Completion (Estimated): August 1, 2026

Study Registration Dates

• First Submitted: August 7, 2018
• First Submitted That Met QC Criteria: August 9, 2018
• First Posted (Actual): August 14, 2018

Study Record Updates

• Last Update Posted (Estimated): October 15, 2025
• Last Update Submitted That Met QC Criteria: October 13, 2025
• Last Verified: October 1, 2025

More Information

Terms related to this study

• Keywords: Pulmonary Hypertension; Stem Cell Transplantation; Autologous; Systemic Sclerosis; Scleroderma; Interstitial Lung Disease; ILD (Interstitial Lung Disease); BMT ( bone marrow transplantation)
• Additional Relevant MeSH Terms: Vascular Diseases; Cardiovascular Diseases; Connective Tissue Diseases; Respiratory Tract Diseases; Lung Diseases; Skin Diseases; Hypertension; Skin and Connective Tissue Diseases; Lung Diseases, Interstitial; Scleroderma, Systemic; Scleroderma, Diffuse; Hypertension, Pulmonary; Peptides; Amino Acids, Peptides, and Proteins; Proteins; Sulfur Compounds; Organic Chemicals; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Investigative Techniques; Therapeutics; Hydrocarbons, Acyclic; Hydrocarbons; Biological Factors; Carbohydrates; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Serum Globulins; Globulins; Alkanes; Alkanesulfonates; Alkanesulfonic Acids; Sulfonic Acids; Sulfur Acids; Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Phosphoramides; Organophosphorus Compounds; Intercellular Signaling Peptides and Proteins; Immunoglobulin Isotypes; Glycoproteins; Glycoconjugates; Immunoglobulin G; Radiotherapy; Antibodies, Monoclonal, Murine-Derived; Biological Products; Complex Mixtures; Triethylenephosphoramide; Aziridines; Azirines; Colony-Stimulating Factors; Hematopoietic Cell Growth Factors; Cytokines; Granulocyte Colony-Stimulating Factor; Sulfhydryl Compounds; Immune Sera; Rituximab; Alemtuzumab; Cyclophosphamide; Mesna; Immunoglobulins, Intravenous; Thiotepa; Antilymphocyte Serum; Whole-Body Irradiation; Filgrastim; Granulocyte-Macrophage Colony-Stimulating Factor; thymoglobulin
• Other Study ID Numbers: STUDY19050297

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No