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Patients who underwent autologous stem cell transplantation (ASCT) for diffuse cutaneous systemic sclerosis (dcSSc), also known as scleroderma, did no better than others receiving conventional treatment, researchers found.

In an analysis of systemic sclerosis patients enrolled in an Australian cohort study, those who would have been eligible for ASCT in either of two clinical trials but were treated with now-standard drugs such as methotrexate or mycophenolate mofetil had almost identical event-free survival rates over 4 years of follow-up as those who did undergo ASCT in those trials, according to Kate Gregory, MBChB, of Monash University in Melbourne, Australia, and colleagues.

Patients who had ASCT in the two trials -- Autologous Stem Cell Transplantation International Scleroderma (ASTIS) and Scleroderma: Cyclophosphamide or Transplantation -- had 4-year event-free survival of 81% and 79%, respectively. But among patients in the treated conventionally who could have joined those trials, 4-year event-free survival stood at 83% and 81%, respectively, the researchers reported in .

Findings were similar for all-cause mortality, Gregory and colleagues noted. Overall survival rates over 4 years topped 90% among cohort members who could have joined one or the other trial.

Both ASTIS and SCOT had found that stem cell transplantation was clearly superior to an immunosuppressive regimen over the long term, and pointed toward the possibility that ASCT would become the therapy of choice for scleroderma. But those studies were conducted years ago -- beginning in 2001 and 2005 -- and the control regimen was based on cyclophosphamide, the standard of care at that time. Gregory and colleagues wanted to know how the trials' results would stand up when compared with outcomes for patients treated more recently. They examined data from the Australian cohort, which enrolled patients from 2007 to 2022.

With cohort members' event-free survival similar to that seen with transplantation in ASTIS and SCOT, those rates were, of course, also superior to those assigned to cyclophosphamide in those trials. Gregory and colleagues suggested that, while the cohort members might have differed in unmeasured ways from the trial participants, their study's findings "may also reflect improved standard of care for dcSSc over time."

Indeed, most cohort members meeting enrollment criteria for the two trials had treatments other than cyclophosphamide. They primarily involved methotrexate and/or mycophenolate, with smatterings having used rituximab (Rituxan) or tocilizumab (Actemra). Amazingly, considering the generally good outcomes, some 30% had not used any kind of disease-modifying drug. (Gregory's group did not examine whether these patients were the ones most commonly developing adverse events during follow-up.)

Eligibility criteria for ASTIS included diagnosis of dcSSc, age 18-65, modified Rodnan skin score of at least 15, and cardiac, renal, or pulmonary involvement. SCOT participants could be somewhat older (up to 69) and needed certain degrees of pulmonary or renal involvement, but no heart involvement was necessary; Rodnan score of at least 16 was required.

For the new study, Gregory's group picked cohort patients meeting those criteria from the total of 492 with dcSSc diagnoses: 56 who could, in theory, have joined ASTIS and 30 meeting SCOT criteria. These groups largely overlapped, with only seven who could not have been included in both.

Cohort members who would have met those trials' exclusion criteria were also identified. These generally reflected more severe organ involvement (e.g., forced vital capacity less than 45%) as well as significant previous cyclophosphamide treatment. Eleven cohort patients met ASTIS's exclusion criteria and 11 met SCOT's.

Cardiac, renal, and pulmonary failure, along with death from any cause, were counted as events during follow-up. Each trial had its own specific definitions of these outcomes, which differed slightly. Gregory and colleagues followed a middle path in defining them for the cohort members. Counting of events began at the time each cohort member first met the trials' criteria.

The cohort members who would have been excluded from ASTIS and/or SCOT -- generally, those with the severest disease at baseline -- fared poorly, with event-free survival rates below 50%. Moreover, death accounted for most of the events in these patients.

Gregory and colleagues could not ensure that cohort members were exactly similar to those allowed into the original trials. Differences included older age, poorer lung function, and less prior cyclophosphamide use in the cohort versus one or both of the earlier trials. Naturally, cohort members who met the trials' exclusion criteria were generally sicker than those enrolled in those trials. Overall this meant that comparisons between the cohort's and the trials' outcomes "must be interpreted with caution," Gregory and colleagues acknowledged.

And the researchers weren't arguing that ASCT no longer deserves a role in scleroderma. "[J]ust as new, more efficacious, therapies for SSc have led to improvements in 'standard therapy' over the last decade, careful patient selection for ASCT and use of less toxic regimens may also result in greater transplant efficacy and lower rates of [treatment-related mortality]," they wrote. "Protocols utilizing lower doses of cyclophosphamide [for conditioning] may achieve good outcomes in high-risk groups with lower cardiac toxicity and may broaden access to transplantation in groups who have previously been excluded."

Besides the likelihood of unmeasured differences between cohort members chosen for analysis and the actual trial participants, Gregory and colleagues noted that only a small proportion of the cohort would have been eligible for ASTIS or SCOT. Also, the cohort itself may not be fully representative of the overall dcSSc population, as members were recruited primarily during outpatient visits and therefore wouldn't include many with very severe disease.

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