High-dose chemotherapy and transplantation of autologous CD34+ selected stem cells for progressive systemic sclerosis adjusted to cardiac and lung manifestation: An open-label, non-inferiority phase 2 trial

• Adjusted high-dose chemotherapy with reduced cyclophosphamide and added thiotepa is feasible in patients with systemic sclerosis with cardiac involvement and a high SCOpE score • These results support the potential of the adapted regimen as a viable alternative to conventional treatments and warrant further validation in larger, multi-centre trials. Objectives: Autologous hematopoietic stem cell transplantation (aHSCT) for systemic sclerosis (SSc) is an effective treatment strategy but carries a high treatment-related mortality (TRM). Consequently, patients with severe organ dysfunction have been excluded from previous randomized trials such as ASTIS. This study aimed to evaluate the feasibility and non-inferiority of a disease-manifestation–adapted chemotherapy protocol designed to mitigate toxicity to also treat patients who would have been ASTIS-ineligible. Methods: In this prospective, open-label, monocentric, phase II non-inferiority trial at the University Hospital Tübingen, Germany, patients with progressive SSc (disease duration ≤6 years) were stratified by lung and cardiac involvement. Mobilization included 1500mg/m² cyclophosphamide (CYC) for patients with inflammatory interstitial lung disease (iILD) versus 1000mg/m² otherwise, both reduced compared to the ASTIS protocol. Conditioning comprised rabbit anti-thymocyte globulin (4×10 mg/kg); patients without cardiac involvement additionally received CYC 4×50 mg/kg. In those with cardiac involvement, CYC was reduced by 50% and thiotepa (2×5 mg/kg) was added. Results: Between 09/2012 and 07/2022, 35 patients were treated (no iILD/cardiac involvement: n=14; iILD only: n=3; cardiac only: n=12; both: n=6). Three-year overall survival (OS) was 77%, meeting non-inferiority compared to EBMT registry data (80%). TRM within 100 days was 11% (n=4) in the whole group. Conclusions: This adapted regimen showed comparable 3y-OS in patients with advanced organ involvement who would have been excluded from prior trials. While feasibility is demonstrated, aHSCT in this high-risk population remains associated with substantial risk, and efficacy cannot be definitively established. Further studies are warranted.