How to decide: Stem cell transplant vs. non-transplant therapy in scleroderma

Complex scleroderma patients appear to get the same benefit from modern conventional treatments as they do from autologous stem cell transplantation (ASCT)—as far as four-year event-free survival goes.“It is very exciting that within the last 10 to 15 years there have become significantly more treatment options for severe systemic sclerosis, both ASCT and medications. And this is a disease where prior to this, treatments options were very limited,” said Dr. Kate Gregory, a rheumatologist and academic associate at Monash University in Melbourne.She coauthored a study in Arthritis & Rheumatology which examined event-free survival over four years of patients with systemic sclerosis (dcSSc) who qualified for autologous stem cell transplant (ASCT) but were managed without it. The study analyzed data from previously published randomized controlled trials (RCTs) and compared outcomes to a more recent cohort which included newer medications.There are two main types of scleroderma, dcSSc and limited cutaneous systemic sclerosis, Dr. Gregory told the Medical Post. They are defined by the extent of the skin involvement. The limited form involves just the skin on just the face as well as skin distal to the elbows and knees, while the diffuse form includes skin involvement elsewhere.“Both subtypes can have life threatening organ involvement. However, the diffuse subtype has more frequent and severe heart, lung and kidney involvement, and a higher mortality than patients with the limited subtype,” she said. Treatment via ASCT is most common in patients with the diffuse form, but there are no universal criteria for determining who should be offered the approach.“In general, patients have to have high levels of skin involvement and in most cases also had significant major organ involvement, either lung, cardiac or renal disease,” Dr. Gregory said.She noted that in studies of ASCT, patients are often excluded if their disease is too severe, and if they have poor lung, cardiac or renal function. These patients have higher mortality risk.“It is tricky to decide who to select for stem cell transplant. Patients need to have severe enough disease to benefit, but if their disease is too severe they are excluded as the risks are too high and then they unfortunately do quite poorly,” she said. But the question is whether patients still benefit as much from ASCT in comparison to treatments that have appeared over the past two decades.The researchers designed a study to determine the event-free survival rates of dcSSc patients who would have met the crtiteria for ASCT used in past studies, but who continued with conventional treatment instead. The original randomised control trials from which criteria were taken included ASTIS (Autologous Stem Cell Transplantation International Scleroderma-1), which was published in 2014; and SCOT (Scleroderma: Cyclophosphamide Or Transplantation-2) from 2018. Both ASTIS and SCOT showed that ASCT was superior to an immunosuppressive regimen over the long term.A control regimen for both of these older studies was the immunosuppresant cyclophosphamide, which was more commonly used then. Outcomes from those studies were then compared to that of patients who were enrolled more recently in the Australian Scleroderma Cohort Study (ASCS).Overall, a total of 492 patients with dcSSc were identified from the ASCS cohort. Patients' ages ranged from 16 to 69 years. As well, data for patients who met the exclusion criteria in the ASTIS and SCOT studies were analyzed.Of the dcSSc patients in the ASCS cohort, 56 met the inclusion criteria for ASCT from the ASTIS study, and 30 met inclusion criteria from SCOT. The two trials had slightly differing criteria defining which patients would qualify for ASCT. Some patients were excluded from the analyses because they either ended up getting ASCT or there weren’t enough data.This left a total of 59 (12.0%) of ASCS patients who would’ve met inclusion criteria for ASCT in either the ASTIS or SCOT trials. The authors noted that although the numbers were small, there was some ethnic variation in meeting eligibility criteria. Non-white patients more frequently met exclusion criteria, suggesting they had more aggressive or advanced disease at presentation.Results showed that event-free survival at four years in the ASCS patients in the ASTIS cohort was 83.3%, and 81.2% for those who met the SCOT criteria.“Event-free survival at four years in ASCS patients who met ASTIS and SCOT inclusion but also exclusion criteria was 46.7% and 45.7% respectively”, the study said.The more modern ASCS patients who met inclusion criteria for either ASTIS or SCOT, but managed without stem cell transplantation had similar event-free survival (EFS) at four years than patients who got stem cell transplantation.ASCT does come with risks and “there was a 10% treatment related mortality in the original ASTIS trial,” Dr. Gregory said. However, transplant units have gotten better at doing transplants for systemic sclerosis patients.“The findings of this study are actually quite different to other similar retrospective studies that have looked at un-transplanted patients who met criteria for transplant. Un-transplanted patients in the Australian cohort that I studied actually had much better outcomes than I expected. It may be that standard of care is improving,” Dr. Gregory said. However, there are limitations and bias in retrospective studies and more work needs to be done, she added. Longer studies would help. Some evidence suggests “transplanted patients do better than un-transplanted patients when you look at more long-term outcomes. This makes sense as transplant is the only therapy that has been actually shown to have improved event-free survival compared to baseline and it is potentially a ‘cure’ for systemic sclerosis with some patients managing to be medication free after transplant,” she said. In the meantime, other treatments have appeared.For one, the drug mycophenolate was found to be as effective as cyclophosphamide at treating systemic sclerosis associated lung disease (ILD) and has less toxicity. It is now first line treatment for patients with lung involvement."This is important as the control arm of those original ASCT randomized controlled trials was cyclophosphamide, not mycophenolate,” Dr. Gregory said.Other treatments that have become part of systemic sclerosis management in the past 10 years include combination therapy for pulmonary arterial hypertension (PAH); rituximab for skin sclerosis, and tocilizumab for systemic sclerosis associated ILD.“There is also a relatively new antifibrotic therapy called nintedanib which was shown to slow progression of lung disease,” she said.

How to decide: Stem cell transplant vs. non-transplant therapy in scleroderma

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