Autologous Hematopoietic Cell Transplantation: Way of the Future in Severe Systemic Sclerosis?

By Soumya Chatterjee, MD, MS, FRCP, and Navneet Majhail, MD, MS

Systemic sclerosis (systemic scleroderma, SSc) is an autoimmune disease of unclear etiology characterized by progressive fibrosis of skin and various internal organs (mainly the lungs, heart, gastrointestinal tract and kidneys), a widespread occlusive microvasculopathy and presence of certain autoantibodies. Despite significant medical advancements in the last century, so far no therapy has proven consistently effective in altering the natural history of this devastating disease. The available immunosuppressive, antifibrotic and vasoactive therapies offer modest benefit at best. Moreover, they are fraught with side effects that are often unacceptable for the marginal degree of stabilization or improvement that they may provide.

In the last decade, autologous hematopoietic cell transplantation (AHCT) has gained progressive acceptance as a form of salvage therapy for severe autoimmune diseases. The mechanisms underlying the benefit of AHCT in autoimmune diseases are still not fully elucidated. Increasing evidence supports that it helps in re-establishment of immunological tolerance in addition to its nonspecific immunosuppressive effect.

In the absence of potentially effective, disease-modifying therapy that can prevent SSc from progressing or reverse damage to the internal organs, high-dose chemotherapy in conjunction with AHCT has been investigated in several observational and clinical studies. Based on these studies, the European League Against Rheumatism (EULAR) issued evidence-based practice guidelines for the treatment of SSc that recommend AHCT for the treatment of selected patients with rapidly progressive disease at risk of irreversible organ failure.

The evidence at hand

Several observational and uncontrolled phase 1/2 trials have suggested the efficacy of AHCT in patients with severe scleroderma. A retrospective study compared the outcomes of 18 AHCT recipients with rapidly progressive, diffuse scleroderma to a demographically and clinically matched group of 36 patients receiving conventional therapies. Compared with the AHCT group, the control patients had significantly lower overall survival (HR 6.94, P < 0.002), including the subset who had received cyclophosphamide-based regimens (HR 5.98, P < 0.006). AHCT recipients had a significantly higher likelihood of improving skin tightness and preserving lung function.

Three randomized controlled trials have compared AHCT and standard of care (cyclophosphamide-based therapy) for severe scleroderma:

(1) American Scleroderma Stem cell versus Immune Suppression Trial (ASSIST),

(2) Autologous Stem Cell Transplantation International Scleroderma (ASTIS) trial, and

(3) Scleroderma: Cyclophosphamide Or Transplantation (SCOT) trial.

The patient characteristics and eligibility criteria were similar among the three trials. All three trials validated a benefit in the AHCT arm regarding their primary endpoints (clinical improvement in ASSIST, event-free survival in ASTIS and change in global rank composite score in SCOT). Also, patients receiving AHCT had better overall survival and a lower rate of disease progression. Treatment-related mortality in the AHCT arm was 0 percent at 12 months in ASSIST, 10.1 percent in ASTIS and a much more favorable 3 percent at 54 months in SCOT. It was 0 percent in the cyclophosphamide arms in all three studies. Recurrent disease in the AHCT arm was seen in 0 patients in ASSIST (8/9 patients in the cyclophosphamide arm), 22.4 percent in ASTIS (43.8 percent in the cyclophosphamide arm) and 9 percent in SCOT (44 percent in the cyclophosphamide arm).

A systematic review and meta-analysis included three randomized trials and one comparative observational study. Patients in the control arm received monthly cyclophosphamide in all three trials and so also did the majority of patients in the observational study. Compared to controls, patients receiving AHCT had lower all-cause mortality (RR 0.50; P = 0.0007), and improved skin scores, forced vital capacity, total lung capacity and quality of life. In sensitivity analyses that only included data from the randomized trials, the improvement in overall mortality was maintained (RR 0.61, P = 0.02).

The evidence we need

Although it would be too optimistic to call AHCT curative for SSc, it has thus far shown the most promise as a potential disease-modifying therapy. Currently, studies are ongoing to evaluate the effectiveness of continuing immunosuppressive therapy (with mycophenolate mofetil) to help maintain disease remission achieved through AHCT and prevent future relapse. It is clear that patient selection is critical in determining successful outcomes for AHCT.

It cannot be overstressed that for the best results, AHCT should only be performed in centers with sufficient experience and expertise in providing multidisciplinary care for both scleroderma and AHCT. Careful follow-up to evaluate long-term outcomes is essential. Currently, consideration of AHCT has been limited to patients with SSc of four to five years’ duration, with mild-to-moderate but progressive internal organ involvement, who have failed to improve (or have worsened) on conventional immunosuppressive therapy. In the future, we need recommendations about whether AHCT should be offered as an up-front treatment option or as salvage therapy.

The cost-effectiveness of AHCT also must be established for third-party payers. Appropriate decision tools are needed to better understand and address the trade-off between the short-term, treatment-related morbidity and mortality and the long-term benefits of AHCT. Further ongoing research to help refine the treatment protocol involving AHCT is essential to help provide the highest possible benefit with the lowest possible risk in this critically ill patient population.

Dr. Chatterjee directs the Scleroderma Program in the Department of Rheumatic and Immunologic Diseases. Dr. Majhail directs the Blood and Marrow Transplant Program at Cleveland Clinic Cancer Center.