Long-Term Outcomes of Cardiac-Safe Hematopoietic Stem Cell Transplantation (HSCT) for Systemic Sclerosis (SSc) Patients with Impaired Cardiac Function

Abstract

Introduction

SSc is a devastating autoimmune disease that affects multiple organ systems with high risk of mortality. Three trials (ASSIST, ASTIS, SCOT) established that high-dose conditioning and autologous HSCT can significantly reduce disease severity and improve overall survival for SSc patients (pts). However, due to the cardiotoxic effects of high-dose cyclophosphamide (CY) used in the conditioning regimen, current guidelines recommend excluding pts with SSc cardiac involvement from high-intensity conditioning HSCT. The Cardiac-Safe Transplantation for SSc Trial (CAST) conducted at Northwestern Memorial Hospital was a sequential, non-randomized study that evaluated reduced intensity conditioning for SSc pts with impaired cardiac function. Between 2015-2019, 42 pts received reduced-intensity autologous HSCT conditioning (Fludarabine 120 mg/m² +ATG 6 mg/kg + CY 60 mg/kg ± Rituximab, 500 or 1000 mg, ± IVIG). Initial results with 1-year follow-up were favorable; however, the long-term outcomes of CAST trial pts were unknown.

Objective

To determine the long-term outcomes of reduced intensity autologous HSCT in SSc pts with cardiac involvement.

Methods

To determine long-term outcomes after reduced intensity conditioning, CAST pts were consented by telephone to the current IRB-approved study and were administered a questionnaire regarding SSc disease status, medication usage, and organ function. Relapse was defined as reinitiating disease modifying anti-rheumatic drugs (DMARDs). If pts contact was not possible, survival status was determined through public records search. Overall survival (OS) and relapse-free survival (RFS) estimates were determined by Kaplan Meier method, and Cox regression was used to determine if pre-transplant parameters were associated with OS or RFS.

Results

The median age of pts was 49 years (20-65), and 62% were female. 2 of 42 (5%) pts were lost to follow-up prior to 5 years post-transplant. The 5-year OS was 75% (95% CI: 63-90%, Fig 1). The 5-year RFS was 61.3% (95% CI: 48-78%, Fig 2). Post-transplant, 1 (3%) pts developed malignancy (breast cancer), and 6 pts (14%) developed new autoimmune disease. Age and sex were not associated with outcome. Table 1 shows the pre-transplant parameters that were associated with increased mortality post-HSCT. Only the presence of SCL-70 antibodies was significantly associated with increased relapse (Hazard Ratio 2.8, 95% CI: 1.1-7.0, p-value = .03, Fig 3).

Conclusion

These data suggest that a reduced intensity conditioning regimen autologous HSCT is a potentially effective treatment option for certain SSc pts with cardiac involvement.