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Myeloablative autologous stem cell transplantation was significantly more effective than 12 months of cyclophosphamide among patients with severe scleroderma, an open-label multicenter study found.
On global rank composite scores that compared each individual patient with all other patients, 67% of 1,404 pairwise comparisons favored transplantation at 54 months, while only 33% favored cyclophosphamide (P=0.01), according to Keith Sullivan, MD, of Duke University Medical Center in Durham, N.C., and colleagues.
Similarly, at 48 months, 68% of comparisons favored transplantation compared with 32% favoring cyclophosphamide (P=0.008), the researchers reported in the Jan. 4 New England Journal of Medicine.
Treatment options are limited in scleroderma with internal organ involvement, and mortality has not declined over 4 decades, particularly among patients with pulmonary disease.
Previous studies of autologous hematopoietic stem cell transplantation and nonmyeloablative transplantation showed some benefits for scleroderma, but the results have not altered practice in the U.S., because of concerns about safety and how durable response would be.
To evaluate a different form of transplantation, Sullivan and colleagues performed myeloablation with total-body irradiation, and then reconstitution with a CD34+ autograft, versus monthly infusions of cyclophosphamide, 750 mg/m2, with follow-up of 4.5 years.
The study enrolled 75 patients from 26 centers during the years 2005 to 2011, and was sponsored by the National Institute of Allergy and Infectious Diseases.
Participants had scleroderma of 5 years or less duration and pulmonary or renal disease.
The primary endpoint of global rank composite score compares participants' status on a hierarchy of outcomes, with rankings from highest to lowest for death, event-free survival, forced vital capacity, scores on the Health Assessment Questionnaire Disability Index, and Rodnan skin score. It does not reflect disease severity or activity.
A total of 27 patients in the transplantation group and 19 in the cyclophosphamide group completed the trial.
At baseline, mean Rodnan skin score was 30, mean diffusing capacity of the lung for carbon monoxide was 53% of predicted, and 97% had lung involvement.
Results on prespecified secondary outcomes support the results of the composite score, with event-free survival (no respiratory, renal, or cardiac failure) rates of 79% versus 50% at month 54 in the transplantation and cyclophosphamide groups, respectively. Respiratory failure was seen in five patients in the transplantation group and in 13 of the cyclophosphamide group, cardiac failure was observed in one cyclophosphamide patient, and renal failure developed in one transplantation patient.
At 72 months, event-free survival rates were 74% and 47% in the transplantation and cyclophosphamide groups (P=0.03), respectively, while overall survival rates were 86% and 51% (P=0.02).
By month 54, only 9% of patients in the transplantation group had relapsed and started taking disease modifying anti-rheumatic drugs (DMARDs) compared with 44% of those given cyclophosphamide (P=0.001). "Evidence that patients with scleroderma could have significant improvement and remain free of DMARDs supports transplantation as a treatment for this serious disease," the investigators stated.
No cases of congestive heart failure or pulmonary arterial hypertension were seen in the transplantation group, whereas these events were seen in 12% and 15%, respectively, of the cyclophosphamide group (P=0.04 and P=0.02).
Serious adverse events occurred at a rate of 0.38 per person-year in the transplantation group and 0.52 per person-year in the cyclophosphamide group (P=0.08). Infections also were similar in the two groups, although the rate of grade 3 infections was higher with transplantation. Varicella zoster was seen in 12 patients following transplantation and in one given cyclophosphamide (P<0.001).
Among the seven patients in the transplantation group who died, two had treatment-related myelodysplastic syndrome and two had previously had respiratory, renal, or cardiac failure. Among the 14 in the cyclophosphamide group who died, seven had a previous organ failure, but no deaths were considered treatment-related.
Four malignancies were observed, three in the transplantation group.
The overall mortality rate in the study was 3% at 54 months and 6% at 72 months, with no deaths occurring during the first year, while in an earlier trial known as ASTIS of nonmyeloablative transplantation, treatment-related mortality was 10.7% in the first year.
The difference in mortality from the earlier trial may relate to baseline factors, such as the exclusion in the current study of patients with heart involvement or pulmonary arterial hypertension, but also may relate to the use of high-dose cyclophosphamide, "which may be too toxic for some patients with severe scleroderma, particularly in the presence of heart disease," the investigators noted.
"Although there was greater hematopoietic toxicity and and unquantified risk of second cancers from exposure to total-body irradiation, toxic effects should be weighed against the beneficial effects of treatment and the seriousness of the underlying disease," they concluded.
A limitation of the study was the lack of blinding, which is not possible in a transplantation trial.