The analysis of gene profile in blood samples may help identify scleroderma patients who could benefit most from stem cell transplant, a research study suggests.
The study findings were discussed at the recent 2018 ACR/ARHP Annual Meeting, in the presentation “Machine Learning Classification of Peripheral Blood Gene Expression Identifies a Subset of Patients with Systemic Sclerosis Most Likely to Show Clinical Improvement in Response to Hematopoietic Stem Cell Transplant.”
Previous results from the Phase 2/3 SCOT trial (NCT00114530) showed that stem cell transplant has a greater potential to improve the outcome of patients with scleroderma than standard therapy with high-dose monthly Cytoxan (cyclophosphamide), including better functional ability and disease control, and prolonged survival.
Evaluation of patients’ outcomes upon 11 years of receiving the treatment revealed that the estimated overall survival was 80% for transplant patients, and 52% for those treated with Cytoxan. In addition, 92% of transplant patients were able to stop using disease-modifying anti-rheumatic drugs (DMARDs), whereas such clinical improvement was only achieved by 61% of patients in the Cytoxan group, demonstrating more disease control in transplant survivors.
Now, a team of researchers led by Michael Whitfield, PhD, Scleroderma Research Foundation-funded researcher and professor at Geisel School of Medicine at Dartmouth, made an additional analysis of data collected during the SCOT trial.
They evaluated the levels of genes in blood samples collected from SCOT trial participants before and 48 to 54 months after receiving treatment with Cytoxan (12 patients) or stem cell transplant (14 patients).
Researchers found that transplanted patients’ genes had changed considerably more, with a total of 4,788 genes with changed levels compared to only 21 genes in the Cytoxan group approximately four years after the treatment. The genes that increased in transplant patients were linked to protein production, whereas reduced genes were mainly associated with cell proliferation and immune response.
Using a computer-based analysis method developed by the team, researchers were able to divide the patients into three groups according to their initial genetic profile: normal-like, inflammatory, or fibroproliferative profiles.
The analysis revealed that those who had a profile enriched in inflammatory-associated genes tended to have improved survival upon stem cell transplant compared with Cytoxan treatment.
Importantly, patients who had a fibroproliferative-enriched profile, and often respond more poorly to immunosuppressive therapy, were found to be the most likely to benefit from stem cell transplants.
In contrast, patients who did not show any particular gene profile enrichment (normal-like profile) were found to have a similar survival outcome irrespective of the received treatment.
“The results are striking, because one group of patients [normal-like profile] showed little difference in event-free survival between treatment arms, whereas another group, the fibroproliferative subset, showed the most significant improvement in event-free survival in the stem-cell transplant arm,” Jennifer Franks, author of the study and a doctoral student at Dartmouth, said in a press release.
Whitfield added: “Our next steps are to continue to try to understand the molecular differences between these patients so we can better determine why some improve and some do not, and ultimately identify therapies most likely to benefit each set of patients, which we hope will make a major impact on the quality of life of these patients.”
The team plans to further explore the potential of the newly developed computer-based analysis method. They expect to transform it into a diagnostic tool that can be used by physicians to help with making decisions about treatment, identifying patients most likely to benefit from less-aggressive therapies, and improving their outcomes.
“This is an important result and potentially a significant step for scleroderma research,” Deann Wright, who is a scleroderma patient family member and board member of the Scleroderma Research Foundation, said in a separate press release. “If this classifying tool can be validated and developed for clinical use, then it can help guide patients and their clinicians who are considering a stem cell transplant. This would be a big step toward personalized medicine for scleroderma patients.”