Hematopoietic Cell Transplantation for Systemic Sclerosis-A Review

Abstract

Systemic sclerosis (SSc) is an autoimmune, multi-organ, connective tissue disease associated with significant morbidity and mortality. Conventional immunosuppressive therapies demonstrate limited efficacy. Autologous hematopoietic stem cell transplantation (HCT) is more efficacious but carries associated risks, including treatment-related mortality. Here, we review HCT as a treatment for SSc, its efficacy and toxicity in comparison to conventional therapies, and the proposed mechanisms of action. Furthermore, we discuss the importance of and recent developments in patient selection. Finally, we highlight the knowledge gaps and future work required to further improve patient outcomes.

Keywords: ILD; hematopoietic stem cell transplant; sclerosis; systemic sclerosis.

Figure 1

Schematic of hematopoietic stem cell transplantation ((A), allogeneic, (B), autologous). Step No. 1 is stem cell mobilization (from marrow to blood) and collection by apheresis. Step No. 2 is chemotherapy, usually with anti-lymphocyte antibodies (e.g., antithymocyte globulin) and sometimes with total body irradiation. Step No. 3 is the infusion of the stem cells, usually fresh stem cells in the allogeneic setting and usually thawed, previously cryopreserved stem cells in the autologous setting. Step No. 4 (not shown here) is post-transplant supportive care (e.g., transfusions for low cell counts, antibiotics for infections).

Figure 2

Change in modified Rodnan skin score [mRSS], where larger scores indicate worse skin tightness) over 60 months from randomization in 26 patients treated with autologous hematopoietic cell transplantation (auto-HCT: blue line) vs. 23 patients treated with conventional therapy (12 months of IV cyclophosphamide: red line) [67]. The skin tightness improved faster and to a greater degree after HCT compared to the conventional therapy. Reproduced with permission from Springer Nature, Bone Marrow Transplantation; published by Springer Nature, 2021.

Figure 3

Longitudinal trends over 66 months from randomization for Forced Vital Capacity (FVC: left) and diffusing lung capacity for carbon monoxide (DLCO: right) in patients undergoing autologous hematopoietic cell transplantation (autoHCT: blue line) vs. conventional therapy (12 monthly infusions of cyclophosphamide: red line) [68]. AutoHCT patients had slightly improved FVC at 54 and 66 months compared to baseline, whereas the FVC worsened in the conventionally treated patients. Similar trends were observed for DLCO. Reproduced with permission from Wiley Global Publishing, Arthritis Care and Research, published by Wiley Publishing Global, 2021.

Figure 4

Longitudinal trend over 66 months from randomization for quality of life, as measured by the Health Assessment Questionnaire Disability Index (HAQ-DI) for patients undergoing autologous hematopoietic cell transplantation (autoHCT: blue line) vs. conventional therapy (12 monthly infusions of cyclophosphamide: red line) [68]. The HAQ-DI improved (became lower) in the autoHCT patients, whereas it worsened in the conventionally treated patients. Reproduced with permission from Wiley Global Publishing, Arthritis Care and Research, published by Wiley Publishing Global, 2021.

Figure 5

Survival data from the SCOT trial comparing autologous hematopoietic cell transplantation (autoHCT: red line) to conventional therapy (12 monthly doses of IV cyclophosphamide: blue line) [23]. The graphs show the overall survival and the event (organ failure)-free survival in the intention-to-treat analysis (including all participants who had undergone randomization: top) and per-protocol analysis (including only participants who received HCT or completed ≥9 doses of cyclophosphamide: bottom). The vertical dashed line denotes the 54-month time point. Both overall survival and event-free survival were significantly higher in autoHCT patients in the per-protocol analysis and trended to be higher in the intention-to-treat analysis. Reproduced with permission from Massachusetts Medical Society, The New Engl. J. Med., published by Massachusetts Medical Society, 2018.