Stem cell transplant offers long-term hope for severe scleroderma patients

An intensive stem cell transplant regimen achieved better event-free survival and overall survival compared to cyclophosphamide drug treatment for patients with severe scleroderma, shows a study published in the New England Journal of Medicine.

“Scleroderma with internal organ disease is a morbid and mortal autoimmune disorder. In the past 40 years, despite drug treatments, there has been no change in the progressive mortality,” said Keith Sullivan, M.D., professor of medicine and cellular therapy at Duke University Medical Center, and corresponding author of the Jan. 4 study.  

Dr. Sullivan

In a previous review on stem cell transplantation for scleroderma, Dr. Sullivan and colleagues reported on analysis suggesting the standardized mortality ratio, which is the ratio of deaths compared to expected deaths in the general population, for systemic sclerosis, or scleroderma, was 3.5, with little noticeable change in four decades. Another study cited found a standardized mortality ratio of 3.8, which is a 280 percent higher mortality rate than in the general population.

“This present study is important because it offers hope for these individuals. We demonstrate for the first time in a controlled trial that myeloablative stem cell transplant can improve and reverse the disease, improve survival and other features of scleroderma and those benefits are durable,” he said.

Dermatologists see the external part of scleroderma, which is hardening of the skin throughout the body. For patients with only skin involvement, which is about two-thirds of the approximately 300,000 people in the U.S. who have scleroderma, stem cell transplant is not a consideration because while morbid, scleroderma limited to the skin is not a highly mortal disease. But the approximately 100,000 individuals with scleroderma who have organ involvement, should be referred to a transplant center to discuss their options.

While the numbers may vary, there about 6,000 new scleroderma patients each year with internal organ involvement in the U.S. Most patients are women (four in one) and between 25 to 50 years old.

THE STUDY

Dr. Sullivan and colleagues developed the myeloablative autologous (self) hematopoietic stem cell transplant regimen, including high-dose chemotherapy and whole-body radiation.

“Prior studies have suggested that this type of transplant could reset the immune system after high doses of chemotherapy and whole body radiation to wipe out the blood and immune-forming systems. Afterwards we reinfuse with T-cell depleted autologous -stem cells. We’re  wiping the slate clean and putting back CD34 selected stem cells to re-establish a normal immune system that is not self-destructive,” he said.

Researchers randomly assigned 75 individuals with severe scleroderma, defined as 97 percent lung involvement and a mean Rodnan Skin Score (dermal thickening) of 30. Of these, 36 received the transplant; 39 received 12 monthly intravenous infusions of cyclophosphamide, an anti-rheumatic disease modifying antirheumatic drug (DMARD) given for scleroderma with lung involvement.

“Previous studies showed that compared to placebo, cyclophosphamide given for scleroderma lung disease improved outcome at 12 months. There are many other DMARD approaches, including other immunosuppressive drugs or biologic agents. While they control symptoms briefly, in the long-term, benefits are not durable,” he said.

The present SCOT (Scleroderma: Cyclophosphamide or Transplantation) study was conducted at 26 universities in the U.S. and Canada and followed patients for up to 72 months.

In the randomized, intent-to-treat, population, at 54 months transplant recipients had superior primary endpoint outcome using a global rank composite score of scleroderma-specific features including overall survival, organ function, quality of life and skin hardening. In treated participants, organ-failure free survival at 54 months was 79 percent post-transplant versus 50 percent with cyclophosphamide.

At 72 months, event-free survival was 74 percent in transplant recipients and 47 percent in cyclophosphamide recipients. Overall survival at 72 months was 86 percent in the transplant group versus 51 percent in the drug therapy group.

While 9 percent of transplant patients started disease modifying antirheumatic drugs at 54 months versus 44 percent of those on cyclophosphamide.

Patients who benefited from the transplant not only lived longer, but had better measures of quality of life and improved skin thickness.

DOWNSIDES TO AGGRESSIVE TREATMENT

But there were downsides with the aggressive treatment. Mortality related to treatment was 3 percent at 54 months and 6 percent at 72 months for transplants, compared to zero percent in the cyclophosphamide group. Transplant patients were also more likely to suffer serious side effects in the short-term with treatment. Among those side effects: low blood counts and grade 3 or higher infections.

IMPLICATIONS

This isn’t the first controlled study to look at stem cell transplant as a treatment for scleroderma. Researchers have used less intensive treatment without irradiation, and have shown improved survival compared to cyclophosphamide but the disease often returned and the safety profile was a big concern.

The improved results in this present study make referring severe scleroderma patients for transplant consultations a new standard of practice, according to Dr. Sullivan.

The work, he says, is exciting for additional reasons. Laboratory studies are exploring the mechanisms whereby stem cell transplants improve severe scleroderma.

Colleagues in the SCOT trial will be presenting new data from this National Institutes of Health-funded research at the World Scleroderma Conference in February.

“Data will be presented showing that, in the SCOT study, transplantation normalizes molecular signatures of scleroderma at 24 months compared to baseline, while cyclophosphamide recipients had no genomic improvement,” Dr. Sullivan says.

The use of this regimen to reset the immune system so that it doesn’t self-destruct could apply to other severe autoimmune diseases, he says.

REFERENCE

Sullivan KM, Goldmuntz EA, Keyes-Elstein L, et al. “Myeloablative Autologous Stem-Cell Transplantation for Severe Scleroderma,” New England Journal of Medicine. Jan 4, 2018. DOI: 10.1056/NEJMoa1703327

Sullivan KM, Shah A, Sarantopoulos S, Furst DE. “Review: Hematopoietic Stem Cell Transplantation for Scleroderma: Effective Immunomodulatory Therapy for Patients with Pulmonary Involvement,” Arthritis and Rheumatology. October 2016. DOI: 10.1002/art.39748. Review.