1. Scleroderma patients treated with myeloablative autologous stem-cell transplantation experienced significantly higher rates of disease-free survival at 52 months post-treatment compared to those treated with cyclophosphamide.
2. Treatment-related mortality occurred in some patients treated with stem-cell transplantation.
Evidence Rating: 1 (Excellent)
Study Rundown: Scleroderma is an autoimmune disorder often resulting in fatal pulmonary complications, along with sclerosis of other internal organs. Cyclophosphamide treatment has been shown to improve lung function compared to placebo, though improvements are generally not maintained long-term. Prior studies assessing autologous hematopoietic stem-cell transplantation indicated improved pulmonary function, but uncertainty surrounding long-term results and safety data has not led to widespread use of this treatment in clinical practice. The SCOT trial (Scleroderma: Cyclophosphamide or Transplantation) aimed to assess myeloablative autologous stem-cell transplant compared to cyclophosphamide treatment. The primary outcome at 54 months post-treatment was patient disease status in the two treatment groups, with superior results observed in the transplantation group. Notably, improved event-free survival was observed in transplantation patients compared to those treated with cyclophosphamide. Fewer patients in the transplantation group started DMARDs (disease-modifying antirheumatic drugs) at 54 months compared to cyclophosphamide treated patients. Treatment-related mortality was observed in transplantation treated patients and absent in those treated with cyclophosphamide.
This study provides evidence that myeloablative autologous stem-cell transplantation can be a superior treatment to cyclophosphamide with improved outcomes over a long period of follow-up. Strengths of the study include assessing stem-cell transplantation with myeloablation compared to prior non-myeloablative studies and extended follow-up, while a significant limitation is enrolled patients had intermediate disease severity making generalizability to patients with mild or severe presentations difficult.
In-Depth [randomized controlled trial]: This multicenter, phase 2 trial conducted between 2005 and 2011 randomized patients into myeloablative autologous hematopoietic stem-cell transplant (n = 36) and cyclophosphamide (n = 39) treatment groups. Eligible adult patients had scleroderma with pulmonary or renal involvement diagnosed less than 5 years prior. Exclusion criteria included markedly reduced pulmonary, cardiac, or renal function testing or prior cyclophosphamide treatment for 6 months or more. Patients in the transplantation group had hematopoietic stem-cells (CD34+) harvested, received myeloablation consisting of total-body irradiation and cyclophosphamide, and subsequently received autologous stem-cell transplantation. Patients in the cyclophosphamide group received 12 monthly infusions with mesna prophylaxis. Patients were evaluated monthly for 1 year and then quarterly until year 5 for multiple markers of disease activity and severity.
In the intention-to-treat population, the primary endpoint at 54 months of a global rank composite score (assessing multiple simultaneous scleroderma disease manifestations) favored transplantation in 67% out of 1404 (36×39) patient comparisons (p = 0.01). In the per-protocol population 70% of 1404 comparisons favored transplantation (p = 0.004) at 54 months. A total of 21 deaths occurred over 72 months of follow-up, with 7 in the transplantation group (2 treatment-related) and 14 in the cyclophosphamide group. Serious adverse events were experienced in 51% and 74% of cyclophosphamide and transplantation treated patients, respectively, though the rates of serious adverse events per person-year were not different between the transplantation and cyclophosphamide treatment groups (0.38 and 0.52, respectively; p = 0.08).
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