Stem Cell Transplant Improves Severe Scleroderma Survival

Marcia Frellick

January 04, 2018

Among patients with a life-threatening form of scleroderma, myeloablative autologous hematopoietic stem cell transplant improved survival to 86% compared with 51% for cyclophosphamide, a study found.

Findings of the Scleroderma: Cyclophosphamide or Transplantation (SCOT) trial, conducted over 10 years at 26 universities in the United States and Canada, were published online January 4 in the New England Journal of Medicine.

"In these severe cases, conventional drug therapies are not very effective long-term, so new approaches are a priority, lead author, Keith Sullivan, MD, James B. Wyngaarden Professor of Medicine and Cellular Therapy at Duke University Medical Center in Durham, North Carolina, said in a news release.

Earlier work showed promise for stem cell transplants in treating diffuse systemic sclerosis, but the trials used a less intensive treatment that did not completely destroy the bone marrow. In the previous studies, survival rate improved but the disease often returned, so the standard of care in the United States has remained immunosuppressive drugs.

The study included 75 patients aged 18 to 69 years who had diffuse systemic sclerosis with lung or kidney involvement. Dr Sullivan and colleagues randomly assigned patients to receive transplantation (n = 36), a combination designed to destroy the patients' defective autoreactive immune system and replace it with their own treated blood stem cells, or 12 monthly intravenous injections of cyclophosphamide (n = 39).

Significantly Improved Survival  

Researchers in this open-label, phase 2 trial found significant benefit with transplant. Overall survival at 72 months was 86% compared with 51% after cyclophosphamide (P = .02.) At 72 months, Kaplan-Meier estimates of event-free survival were 74% with transplant vs 47% with drugs (P = .03).

The primary endpoint at 54 months was a composite score of outcomes, including survival without respiratory, renal, or cardiac failure; organ function; the score on the Disability Index of the Health Assessment Questionnaire; and the modified Rodnan skin score. Results showed 67% of 1404 pairwise comparisons favored transplant compared with 33% favoring cyclophosphamide.

In addition, by the endpoint, fewer transplant recipients started disease-modifying antirheumatic drugs (9% vs 44% of the drug group; P = .001).

However, treatment-related mortality in the transplant group was 3% at 54 months and 6% at 72 months, compared with 0% in the cyclophosphamide group.

The transplant group also had more short-term side effects, such as low blood counts and infections. The authors note that 96% of serious adverse events happened in the first 26 months after transplantation. Varicella zoster infection developed in 12 of 33 transplant recipients (36%), they report.

Long-term follow-up will be needed to determine the additional risk for cancer from the irradiation. The researchers continue to follow many of the SCOT participants.

"Although there was greater hematopoietic toxicity and an unquantified risk of second cancers from exposure to total-body irradiation, toxic effects should be weighed against the beneficial results of treatment and the seriousness of the underlying disease," the authors write.

Anthony S. Fauci, MD, director of the National Institute of Allergy and Infectious Diseases (NIAID), which sponsored the study, welcomed the results.

"We need effective therapies for scleroderma and other severe autoimmune diseases, which can be not only debilitating to the patient but also difficult to treat," he said in a news release. "These results add to the growing evidence that stem cell transplants should be considered as a potential treatment option for people with poor-prognosis scleroderma."  

SCOT study data are available through the NIAID-sponsored ImmPort database.

The work was funded by the NIAID and the National Institutes of Health. Dr Sullivan reports personal fees from Kiadis Pharmaceutical and Roche Genentech outside the submitted work. A coauthor reports a patent related to chimeric antigen receptors having mutations in the fc spacer region and methods for their use, with royalties paid to Mustang Bio; a patent related to costimulatory chimeric antigen receptor T cells targeting IL13Ra2, with royalties paid to Mustang Bio; and a patent related to administration of cellular immunotherapy for treatment of cancers in the central nervous system, with royalties paid to Mustang Bio. Coauthors also report grants and personal fees from AbbVie, Actelion, AstraZeneca, Aviara Pharmaceuticals, Bayer, BMS, Boehringer, Bristol-Myers Squibb, Cardinal Health, Celgene, ChemomAb, Corbus, Covis, Cytori, DOD, Eicos, Eiger Biopharma, EMD Serono, Genentech/Roche, Gilead, GSK, Immune Tolerance Network, Ingelheim, Ironwood, Medac, Medtelligence,  OctaPharma Pfizer, Reata, Sanofi-Aventis, SARL, the Scleroderma Research Foundation, Seattle Genetics and UCB Pharma, United Therapeutics, and University of Michigan. A coauthor reports involvement in an ongoing clinical trial of hematopoietic stem cell transplant for systemic sclerosis, the STAT trial.

N Engl J Med. Published online January 4, 2018. Abstract

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