Last week the respected British medical journal The Lancet published a Canadian study that landed with a bang: it revealed that a small, select segment of people diagnosed with multiple sclerosis (MS) experienced remarkable results after undergoing autologous hematopoietic stem cell transplant (aHSCT). In the 13-year study, Ottawa-based doctors Harold Atkins, a haematologist, and Mark Freedman, a neurologist, treated 24 patients. They administered a drug that caused the stem cells in their bone marrow to move into their bloodstream, then extracted these stem cells, and processed them in a lab to purify them. Patients were given a chemotherapy drug that wiped out their immune system, then the immune system was rebuilt, with the purified stem cells re-injected into their bloodstream. This group was tracked between four and 13 years: eight saw a return of function taken away by the disease, such as vision, balance or ability to walk, and eight saw disease progression halted; seven people experienced worsening disease progression. One person died after liver failure.
Both the MS Society of Canada, which funded the research, and the Ottawa Hospital, where the research took place, spoke in terms of a “breakthrough.” Medical professionals used the words “miracle” and “cure” to describe the results of the phase II study. “Everyone is hesitating to use the ‘c word,’ but these patients are cured,” Michael Rudnicki, director of the Regenerative Medicine Program and the Sprott Centre for Stem Cell Research at the Ottawa Health Research Institute, who was not involved in the research, told Vox.
It’s not surprising then that headlines suggested a cure for MS itself was at hand: “An aggressive Canadian treatment offers stunning results for MS patients,” claimed the Toronto Star. “This isn’t hype: Canadian doctors just reversed severe MS using stem cells,” Vox proclaimed. “New treatment can ‘halt’ multiple sclerosis, says study,” reported the BBC. Many news reports led with the heart-warming story of the study’s most successful participant: 41-year-old Jennifer Molson, diagnosed with MS in 1996 at age 21; when Molson underwent the procedure in 2002, she was living in assisted care. In another nice twist, she now works at the Ottawa Hospital, where she was treated. Not only can she walk independently, but she can also ski and kayak. She’d marry, and dance at her wedding. There are lasting effects of the year of horrible sickness, of course; Molson cannot bear children and is on constant watch against infection. But those lingering effects and the risks, which included a 10 percent chance of of death, were worth it, Molson told the Star: “I have been given a second chance at life.”
Anyone familiar with MS, an unpredictable mysterious degenerative condition that can rob people of their ability to touch, to see, to walk, to move, will be inspired by Molson’s tale of recovery and that of several of the study’s participants. They will also understand why the patients in the study were willing to take such a risk to forestall degeneration. But to see this as an MS “cure” is mistaken; if anything, the study’s results provide a glimpse of how heterogeneous the population living with an MS diagnosis can be. Only a small subset fit the study’s criteria: those with an early, active, highly inflammatory, relapsing-remitting form of the disease who do not respond to drug therapies. Study participants ranged in age from 21 to 50; all had been diagnosed within the previous 10 years; all were ranked between 3 and 6 on an MS disability scale ranging between 0 and 10 (6 is someone who needs a walking aid to walk 100 metres). Atkins estimated five percent of the MS population could potentially benefit. That is a not inconsiderable number given that 2.3 million people are estimated to be living with MS worldwide, more than 100,000 of them in Canada where the MS Society has declared the condition “Canada’s disease.” And it is undeniably a breakthrough, but there’s a danger in forgetting it’s not a potential cure for 95 per cent of people living with MS. Hematopoietic stem cell transplantation (HSCT), which has shown considerable success treating paediatric cancer, is not a new treatment for MS; Richard Burt of Northwestern University pioneered its use in the mid-’90s; over the past two decades, thousands of cases have been treated. Results from Burt’s 2015 study, published in the Journal of the American Medical Association, were promising—though not as dramatic. The Ottawa study is the most aggressive and high-risk in carpet bombing (rather than suppressing) immune cells; it was also more selective in harvesting immature stem cells. Other studies are in the works. An innovative FDA-approved stem cell treatment trial that does not rely on chemotherapy is under way at the Tisch MS Research Centre in New York City. Phase I results, presented at the American Academy of Neurology meeting in April, are promising: it was found to be safe and well-tolerated with no serious adverse events reported. An aHSCT study of 20 people underway at Sheffield University in the U.K. uses lower intensity, and thus less dangerous chemotherapy to target the immune system that triggered a flurry of similarly jubilant headlines earlier this year: the BBC reported “patients who were paralysed have been able to walk again.”
Such uplifting stories are staples of medical news; media coverage of the Ottawa study highlighted the most dramatic recovery; we didn’t learn the name of the person who died, per clinical trial protocols which protect anonymity. As promising as the Ottawa study is, it’s far from definitive, as Freedman himself notes in The Lancet press release: “The sample size of 24 patients is very small, and no control group was used for comparison with the treatment group. Larger clinical trials will be important to confirm these results.” Nor has aHSCT been tested in a randomized, double-blinded, placebo-controlled trial— the “gold standard” in medical research. “A blinded trial would not be feasible in this case,” Freedman and Aitkins told Maclean’s in an email, “because the effects of the chemotherapy (e.g. hair loss, nausea, infections) would be very obvious and the participants (and researchers) would easily know which group they were in.” The research community has talked about randomized, controlled (but not blinded) trials but questions remain, Freedman and Atkins say: “For example, it is unclear if patients who would be eligible for this trial would consent to be part of it, knowing that if they were assigned to the control arm, they would not have access to this procedure.” There are still kinks to be worked out: A quarter of participants developed infections and all but one had a toxic response to the treatment; one landed in intensive care.
Risks associated with procedure remain high, Jan Dörr, of NeuroCure Clinical Research Center, Charité-Universitätsmedizin, Berlin, writes in The Lancet. “These results are impressive and seem to outbalance any other available treatment for multiple sclerosis,” he says, adding it’s the first trial to “show complete suppression of any inflammatory disease activity in every patient for a long period…However, aHSCT has a poor safety profile, especially with regards to treatment-related mortality.” Dörr doubts the study will change MS treatment in the short term, “mainly because the mortality rate will still be considered unacceptably high.” Stem cell specialist Paolo Muraro called for caution in interview posted on the U.K. MS Society website: “High-intensity chemotherapy, as used in this study, is associated with higher toxicity. Additionally, the benefit of purifying the stem cells is currently unclear, and needs more investigation.”
Other questions remain. Studies show chemotherapy itself affects neurological function and stem cells affect brain atrophy. Freedman was the co-author of a study published last month that indicated MS patients showed accelerated whole-brain atrophy after treatment “likely associated with treatment-related toxicity and degeneration of “committed” tissues.” It also noted “atrophy eventually slowed to that expected from normal aging, suggesting that stopping inflammatory activity in MS can reduce secondary degeneration and atrophy.” Freedman was also a co-author of a 2007 study that found aHSTC didn’t work: “it fails to halt the demyelination and inflammation of MS,” it concluded. Two factors made it difficult to interpret that study’s results, he tells Maclean’s: “The study examined five patients who received different forms of chemotherapy and autologous stem cell therapy (one was from our trial at the Ottawa Hospital, but the others were from different trials that used different procedures). Also, all of the patients died fairly soon after the therapy due to treatment-related complications.”
Stem cell specialist Rudnicki remains optimistic about the aggressive Ottawa protocol which is now being performed at the Ottawa Hospital on those that fit the criteria: “I think this is going to be the new standard of care for progressive MS,” he told Vox. Muraro is more circumspect: “[The Ottawa study] confirms previous thinking that aHSCT is not suitable for people with progressive forms of MS who have accumulated long-standing disability no longer related to ongoing inflammatory damage. For these people, the risks of treatment outweigh any potential benefit.”
Fifteen people have received treatment, covered by OHIP, at the Ottawa Hospital; their progress is being tracked for study. Freedman and Atkins contend the benefits outweigh the risks: “The evidence from this study clearly shows that our treatment can produce a long lasting remission in a select patient population…who have already failed other therapies,” they write. “While further research is aimed at refining the technique to minimize toxicity, we feel that the treatment should be made available for similar poor prognostic patients as long as it is offered by centres with comparable transplantation expertise.”
The new Ottawa study puts a lens on MS, a complex condition that remains little understood. Some media coverage would lead one to believe that wiping out and replacing the immune system addresses the root cause of MS, when what it does, according to researchers themselves, is reduce inflammation. The cause, or even causes, of MS remain a mystery. The dominant theory that MS is an autoimmune condition caused by the body attacking its own immune system, repeated like gospel, remains unproven. Other news coverage suggests that those ineligible for the treatment are well-served by other therapies. “Latest MS ‘miracle treatment’ overshadows the real news: Multiple sclerosis was once considered a hopeless disease. Today, drug treatments are highly effective,” the CBC reported. The accompanying story states “one of the major reasons why today’s bone marrow transplant story is not relevant to 95 per cent of MS patients is that they won’t need it.” Yet people diagnosed with the most debilitating form of MS who do not experience relapses and are not eligible for the Ottawa stem cell treatment, more than 10 per cent of the MS population, have no MS drug therapies available to them. Exactly how effective MS “disease modifying-drugs” are for a condition characterized by unpredictable relapses and remissions is unclear. A spate of studies indicate that a major class of these drugs do not stop disability; all come with serious side effects, which can include cancer and death. Frustration with MS drugs, in fact, is driving stem cell research, as Burt’s January 2015 study states: “No current therapy for relapsing-remitting multiple sclerosis results in significant reversal of disability.”
The promise of stem cell therapy has given rise to understandable optimism but also hope ripe for exploitation. A British doctor lost his licence in 2010 after offering MS patients a treatment that turned out to use bovine stem cells. Last month, the International Society for Stem Cell Research issued new guidelines instructing scientists to be circumspect when talking about their research. It’s a useful instruction when discussing potential MS “cures.” The news that five percent of the MS population could potentially see disease reversal as the result of a new therapy is good news, and a most welcome development. To call it an MS “cure” is to forget the remaining 95 percent.