BERLIN – Hematopoietic stem cell transplantation appears to be a breakthrough in the treatment of poor-prognosis early diffuse cutaneous systemic sclerosis.
This complex, multistage therapy produced significantly better long-term survival than conventional pulsed-dose cyclophosphamide, despite the 10% treatment-related mortality in the first 100 days, according to the first report from the ASTIS (Autologous Stem Cell Transplantation International Scleroderma) trial.
Dr. Jacob M. van Laar
Preliminary analysis indicates smoking canceled out the benefits of hematopoietic stem cell transplantation (HSCT) in ASTIS. If this finding is confirmed, it will create a "very tricky" ethical question: namely, should smokers with severe scleroderma be excluded from this therapy, said Dr. Jacob M. van Laar, who presented the ASTIS results at the European College of Rheumatology.
ASTIS was a 27-center European, randomized trial involving 156 patients with poor-prognosis early diffuse cutaneous scleroderma. Given that the condition’s mortality rivals that of lymphoma, the ASTIS investigators decided to study a therapy developed by oncologists for lymphoma: high-dose cyclophosphamide plus growth colony–stimulating factor, followed by collection of the patient’s CD34+ hematopoietic stem cells, another round of high-dose cyclophosphamide plus T-cell ablative therapy to ‘condition’ the immune system, then reintroduction of the CD34+ cells in order to fashion a new healthy immune system.
It’s an arduous procedure that takes place over the course of several months. The study hypothesis was that although some scleroderma patients would die early because of transplant-related complications, the net result in those who survived the procedure would be improved long-term outcomes, compared with conventional, lower-risk therapy. And that’s exactly what was seen, according to Dr. van Laar, who is professor of clinical rheumatology at Newcastle (U.K.) University.
The primary study end point was event-free survival; that is, survival without persistent organ failure involving the lungs, heart, or kidneys. During an average follow-up of 7 years, an event occurred in 19 patients in the HSCT group, compared with 27 who were randomized to standard therapy with 12 monthly intravenous pulses of cyclophosphamide at 750 mg/m2.
There were 16 deaths in the HSCT arm, compared with 26 in the control group. Half of the deaths in the transplant arm were treatment related, five resulted from disease progression, and one each from sepsis, stroke, and major organ failure.
In sharp contrast, major causes of death in the control group included disease progression in 15 cases, four fatal malignancies, and three deaths from major organ failure.
The HSCT group had a 2.5-fold greater risk of mortality than did controls during the first 4 months of the study. But by 1 year, the HSCT group had a 61% lower risk of death than patients on standard therapy and, since then, they have had a 78% lower mortality extending through 8 years of follow up.
Dr. van Laar emphasized that this was a sick group of scleroderma patients. They had an average disease duration of roughly 1.5 years at enrollment, an average age of 44 years, a modified Rodnan skin score of 25, major organ involvement in a high proportion of cases, and poor physical functioning as reflected in a mean Health Assessment Questionnaire Disease Index (HAQ-DI) score of 1.3.
Many (52%) of participants were past or current smokers. In those patients, there was no significant difference in long-term event-free survival among those who received HSCT as compared with conventional therapy. But among nonsmokers, HSCT was associated with nearly a 90% long-term event-free survival rate, compared with a 60% rate if they received conventional cyclophosphamide therapy.
Asked if he thought one of the lessons of ASTIS is that smokers should not have access to HSCT, the rheumatologist replied that it’s too early to say. He and his coinvestigators haven’t yet broken down the results in terms of past vs. current smokers, number of pack-years, and other potentially relevant factors. It will be instructive as well to see if the ongoing National Institutes of Health-sponsored SCOT (Scleroderma: Cyclophosphamide Or Transplantation) trial being conducted in 226 U.S. poor-prognosis scleroderma patients confirms that smoking has a deleterious effect on long-term outcomes, Dr. van Laar added.
Dr. Xavier Mariette, Congress scientific program chairman and professor of rheumatology at Hôpital Bicêtre in Paris, took issue with the ASTIS investigators’ description of their treatment regimen as HSCT.
"It’s very important to realize it’s not the autologous stem cell transplantation that is curative, it is the high-dose cyclophosphamide that is the most important element in the combination treatment," he asserted.
Dr. van Laar disagreed. He cited evidence that high-dose cyclophosphamide alone doesn’t bring sustained long-term benefits, and other data to suggest that stem cell transplantation may mediate immune effects.