June 12, 2008 — High-dose cyclophosphamide (HiCy) reduces disease activity and disability in people with severe aggressive multiple sclerosis (MS) who have not undergone bone marrow transplantation.
In a 2-year open-label trial of 9 patients with aggressive relapsing remitting MS (RRMS), investigators at Johns Hopkins University in Baltimore, Maryland, found that administering a 1-time immunoablative regimen of 50 mg per kilogram of intravenous cyclophosphamide over 4 consecutive days resulted in a statistically significant reduction in disability that was durable at an average follow-up of 23 months, with no adjunctive immunomodulatory therapies.
"We did not expect this [reduction in disability]. We found that disability levels at the beginning of the study were much greater than at the end of the study. Patients had a return of function that, for some, translated into significant improvements, such as returning to work, dispensing with walkers or canes, and regaining bladder control," Douglas A. Kerr, MD, PhD, told Medscape Neurology & Neurosurgery.
Furthermore, the treatment appeared safe and well tolerated, with no deaths or unexpected serious adverse events.
The study was published online June 9 in the Archives of Neurology.
Starting From Scratch
Cyclophosphamide, a chemotherapeutic agent, has been used for about half a century, primarily to treat cancer. When it was used to treat MS in the 1980s, its efficacy as a single-pulse therapy was, at best, modest and did not justify its routine use, said Dr. Kerr.
Currently, cyclophosphamide is often used as a component of a chemotherapeutic cocktail given as adjunctive therapy preceding bone marrow transplantation for the treatment of RRMS.
The HiCy 1-time regimen used in the current study has been shown to be safe and effective in other autoimmune diseases, including lupus erythematosus, autoimmune aplastic anemia, and myasthenia gravis.
The regimen, which was developed about 15 years ago by Robert Brodsky, MD, and Richard Jones, MD, hematologists at Johns Hopkins, works by eliminating the "misbehaving" immune system while preserving hematopoietic stem cells, allowing the immune system to "recreate itself from scratch." Based on promising results and these other autoimmune conditions, the investigators decided to test it in MS.
Worst of the Worst
Nine patients — 6 men and 3 women — with RRMS were selected for the study. The mean age of the participants was 29 years. Eight subjects had failed conventional therapy and 1 was treatment naive. All had ongoing active inflammatory disease and a high risk for continued progression and loss of function.
"These patients were the worst of the worst in terms of the severity of their disease," said Dr. Kerr.
The primary end point was safety and tolerability of the treatment. Secondary outcome measures included a change in gadolinium-enhancing lesions on magnetic resonance imaging and a change in disability measures on the Expanded Disability Status Scale (EDSS) and the Multiple Sclerosis Functional Composite (MSFC).
At a mean follow-up of 23 months, investigators found an average reduction of 39.4% in disability and an average improvement in MSFC scores of 87%. In addition, the average number of brain lesions decreased, from 6.5 at study outset to 1.2 at follow-up.
Of the 9 study subjects, 5 had no disease activity at follow-up. The other 4, said Dr. Kerr, "did well, but not perfectly, and had some evidence of disease activity, usually demonstrated by a brain lesion and not a clinical attack. Still, it wasn't perfect."
Nevertheless, he said, overall patients experienced a dramatic improvement with this 1-time high-dose therapy that appears to reverse MS-related disability and is unlike any previous MS treatment.
Currently, he said, MS drugs that are available, or even those that are on the horizon, are designed solely to hold the disease at bay and limit disease progression. However, once patients stop taking the medication, the disease continues to advance.
"This treatment is based on a completely different model — a 1-time therapy with a long-term benefit," said Dr. Kerr.
Less Toxicity, Lower Cost
HiCy also offers several advantages over bone marrow transplantation, which has been associated with a 5% to 7% mortality rate and toxicity to a number of organs, including the brain. To date, he said, there has been no mortality or organ toxicity associated with HiCy therapy in the more than 250 patients who have received the treatment for other types of autoimmune disease.
Furthermore, the cost of bone marrow transplantation runs about $300,000 in the first year alone; HiCy therapy costs approximately $25,000 to $30,000.
Although the mechanism is not entirely clear, Dr. Kerr said it was interesting to note that patients with a return of function tended to have a shorter disease duration (less than 10 years) and more active inflammatory disease.
This finding is important, he said, and suggests that inflammation itself plays a role in MS disability and that "once you get rid of that inflammatory cascade within the nervous system, patients start to improve."
Dr. Kerr said his team is currently working on improving the HiCy regimen, possibly by adding drugs that will help "reeducate" the immune system. In addition, he said, the investigators are also planning a multicenter phase 3 trial that will have broader inclusion criteria, enrolling patients with less severe, less aggressive disease.
The study was supported by General Clinical Research Center of the Johns Hopkins School of Medicine, the National Multiple Sclerosis Society, Mr. Alvin Myerberg, and the Johns Hopkins Project RESTORE.
Arch Neuro. Published online before print June 9, 2008.
Caroline Cassels is a Senior Journalist for Medscape Neurology & Neurosurgery. A medical and health journalist for 20 years, Caroline has written extensively for both physician and consumer audiences. She helped launch and was the editor of Health Digest, an award-winning Canadian consumer health publication. She was also national editor of the Heart & Stroke Foundation of Canada's Web site before joining Medscape Neurology & Neurosurgery in 2005. She is the recipient of the 2008 American Academy of Neurology Journalism Fellowship Award. She can be contacted at CCassels@medscape.net.
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