Hard-to-treat Patients With Sclerosis Respond to Stem Cell Transplantation
CHICAGO — Patients with sclerosis assigned to a fibroproliferative subset, who are typically unresponsive to immunosuppressive drugs such as abatacept or mycophenolate mofetil, benefited from hematopoietic stem cell transplantation, according to Michael Whitfield, PhD, of the Geisel School of Medicine at Dartmouth.
“Because of its heterogeneity, there are some patients with systemic sclerosis that will improve on a drug, and other patients that will not,” Whitfield said, addressing attendees at the ACR/ARHP 2018 Annual Meeting. “When I came into this field 15 years ago, one of the things we did was find if we could break down the heterogeneity in scleroderma, and we measured all genes in the genome in these patients, either in in-target tissues or in peripheral blood and found that they have a couple of different fingerprints, allowing you to group them into distinct expression subsets — inflammatory, fibroproliferative and normal-likened.”
Noting that there are different fundamental pathways that are driving the disease in patients with systemic sclerosis, Whitfield said he and his colleagues predicted that they would likewise respond differently to therapy.
To identify which patients with scleroderma were most and least likely to benefit from stem cell transplant, the researchers studied 67 participants from the previously reported Scleroderma: Cyclophosphamide or Transplantation (SCOT) trial. That trial had compared myeloablative CD34+ selected autologous hematopoietic stem cell transplantation to cyclophosphamide infusions in patients with diffuse systemic sclerosis. Published this year, it found that transplantation was the superior treatment.
In their new study, Whitfield and colleagues used machine learning to evaluate gene expression data from the peripheral blood of the 67 participants — 36 treated with cyclophosphamide and 31 who had received stem cell transplant — at baseline and at 48 or 54 months. Through their algorithm, the researchers divided the participants into the distinct gene subsets — inflammatory, fibroproliferative and normal-likened — based on their expression prior to treatment. They then examined whether certain subsets were predictive of treatment success, measured as event-free survival.
According to Whitfield, in the normal-likened subgroup, patients in both treatment cohorts demonstrated a lack of active immune response. However, in the fibroproliferative subset, patients that received stem cell transplant demonstrated significant improvement in event-free survival compared with patients who received cyclophosphamide.
“The important thing about this is that the fibroproliferative patients are the ones who have not seen improvements in small investigator-initiated studies on inflammatory modulators, like mycophenolate mofetil, which is where we have the most data,” Whitfield said. “These fibroproliferative patients tend not to improve on mycophenolate mofetil, despite it being the standard of care, and they are more likely to have lung disease, so we think these patients are very hard to treat. Here we have a therapy that really does well for those patients, and I think for those most severe patients, stem cell transplant is going to be a possible game-changer, whereas, for normal-likened patients, it may not be the way to go.” – by Jason Laday
Disclosure: Whitfield reports no relevant financial disclosures.
Whitfield M. Abstract 1876. Presented at ACR/ARHP Annual Meeting, Oct. 20-24, 2018; Chicago.