Scleroderma with internal organ involvement is a severe, life-threatening form of the disease with limited therapeutic options. Treatment with disease-modifying antirheumatic drugs (DMARDs) and biologics has not been shown to provide durable benefit in patients with severe scleroderma, and cyclophosphamide has only shown short-term benefit.
Results from a recent study demonstrated that myeloablative autologous stem-cell transplantation (ASCT) improved outcomes in patients with severe scleroderma, providing longer-term benefit and superior event-free survival (EFS) and overall survival (OS) compared with 12 months of cyclophosphamide (Sullivan KM, et al. N Engl J Med. 2018;378:35-47).
“The current randomized trial compares 12 monthly infusions of cyclophosphamide with high-dose chemotherapy plus whole-body irradiation designed to wipe out [myeloablate] the defective, self-reactive immune system and replace it with patients’ own stem cells treated to remove self-reacting lymphocytes. This was the first study to test whether myeloablative ASCT could re-establish a normal functioning immune system in patients with scleroderma,” said the study’s lead investigator, Keith M. Sullivan, MD, Professor of Medicine at Duke University Medical Center, Durham, NC, in an interview with Value-Based Care in Rheumatology.
“Two previous studies of non-myeloablative stem-cell transplant showed superiority to conventional cyclophosphamide, but clinical practice did not change in the United States due in part to concerns about patient safety and durability of response,” he explained.
From July 2005 through September 2011, the investigators randomized 75 of 205 screened patients to either high-dose chemotherapy plus total body irradiation followed by autologous CD34+ selected ASCT mobilized with granulocyte colony-stimulating factor or 12 months of conventional cyclophosphamide with mesna prophylaxis. Patients enrolled in the trial had scleroderma with pulmonary or renal involvement for ≥5 years, and were evaluated monthly through year 1 and then quarterly through year 5.
The primary end point of the trial was a global rank composite score at 54 months. This tool accounts for multiple disease manifestations simultaneously without measuring disease activity or severity. The score reflects how a patient compares with other patients on the basis of a hierarchy of ordered outcomes that include death, EFS, forced vital capacity of the lungs, disability score on the Health Assessment Questionnaire Disability Index, and modified Rodnan skin score.
At 54 months, in an intent-to-treat analysis, global rank composite scores showed that transplantation was superior to cyclophosphamide: 67% of 1404 pairwise comparisons favored ASCT and 33% favored cyclophosphamide in terms of features of scleroderma that included death, organ failure, quality of life, and skin hardening.
In the per-protocol population (patients who underwent ASCT or received ≥9 doses of cyclophosphamide), the EFS rate at 54 months was 79% for ASCT versus 50% for cyclophosphamide.
At 72 months, Kaplan-Meier estimates of EFS (74% vs 47%, respectively) and OS (86% vs 51%, respectively) favored transplantation over cyclophosphamide.
In addition, at 54 months, the use of DMARDs was much lower in the posttransplant group compared with the cyclophosphamide group (9% vs 44%).
“Evidence that patients with scleroderma could have significant improvement and remain free of DMARDs supports myeloablative transplantation as a treatment for this serious disease,” Dr Sullivan and colleagues noted.
The incidence of treatment-related mortality and morbidity was higher for ASCT patients but lower than that reported for trials of nonmyeloablative ASCT in this population, the investigators reported. Treatment-related mortality was 3% at 54 months and 6% at 72 months in the transplantation group versus 0% in the cyclophosphamide group.
Over a 72-month period, the percentage of patients who had serious adverse events was lower in the cyclophosphamide group compared with the ASCT group (51% vs 74%, respectively). In the ASCT cohort, 96% of serious adverse events were reported in the first 26 months compared with 71% of serious adverse events in the cyclophosphamide cohort. One hundred percent of the ASCT group versus 84% of the cyclophosphamide group had an adverse event of grade 3 or higher.
“At 54 months after randomization, myeloablative CD34+ selected ASCT resulted in significantly better clinical outcomes than 12 months of cyclophosphamide. Although there was greater hematopoietic toxicity and an unquantified risk of second cancers from exposure to total-body irradiation, toxic effects should be weighed against the beneficial results of treatment and the seriousness of the underlying disease. Patients with scleroderma and internal organ involvement should be referred by their primary care physicians for consultation at stem-cell transplant centers to weigh the pros and cons of transplant. This approach represents a new standard for effective care of this devastating condition,” Dr Sullivan concluded.