Some patients in a small trial who got stem cell transplants after chemo saw their quality of life and disability improve.
By the time Amanda Loy turned 28, her multiple sclerosis had progressed to the point that she could no longer work full time. Her hands and legs felt numb all the time, her bladder always felt full, and she had to rely on a cane to walk for more than 10 minutes. After she gave birth to a son a year later, in 2008, the symptoms worsened. It was around then that she decided to travel from her home in Anchorage, Alaska, to Chicago to inquire about a new treatment she’d heard about at a Seattle hospital.
Nearly a dozen years on, Loy is now back to working full time as a teacher in the radiology program at the University of Alaska. She runs half-marathons and plays soccer with her son, who is 10. She no longer takes MS medications. Her only lingering symptom is some mild nerve pain from time to time.
“It sounds so dramatic, but [the treatment] gave me my life back,” she said.
The treatment is an experimental chemotherapy and hematopoietic stem cell transplant. Loy got it as part of the first randomized trial comparing the outcomes of patients with what’s called “relapsing remitting” MS who received the treatment to patients who took standard MS medications.
The results of the trial appeared on January 15 in the journal JAMA: Among the 55 patients in the control group who took medication, 34 saw their disease worsen. But for the 55 (including Loy) who received the chemo and stem cell transplant, only three got worse. The rest saw their quality of life and disability improve.
The small trial appears to provide more evidence that chemo and a stem cell transplant can help some people with MS. “I do think it’s going to change the natural history of MS,” said Northwestern University stem cell researcher Richard Burt, the study’s lead author and Loy’s doctor. “When you use it in the right group of patients with MS, you get these really gratifying results.”
But some researchers are also questioning the integrity of the study’s findings. That’s because Burt was the subject of a 2016 warning letter from the Food and Drug Administration, which oversees clinical trials. The 10-page, partially redacted letter details violations of federal regulatory standards and ethical norms governing research on humans. According to Burt, it’s focused on the JAMA MS trial, as well as two other trials.
“Some of the alleged issues could have affected the results [of the JAMA trial], but it is hard to know whether they were nipped in the bud or not,” Harvard health law professor Glenn Cohen told Vox. The issues uncovered by the health regulator were later resolved, according to another FDA closing letter. But, as Simon Fraser University health law professor Tania Bubela told me, “This level of sloppiness reflects poorly on the clinical trial site and the oversight of the research ethics board in particular.”
The particulars of this trial aside, a few things about stem cell transplants for MS are clear: The turnarounds the patients in the study experienced have been seen in other studies. At the same time, transplants are a high-risk therapy, and doctors still don’t know which patients with MS will most benefit and how the treatment compares to newest — and most effective — MS drugs on the market.
Doctors running the trial did not expect such dramatic improvements in the patients treated with stem cell therapy
MS affects about 2.3 million people around the world, particularly women in more temperate climates like Canada and the northern US.
Instead of protecting the body from foreign invaders, in patients with MS, the immune system turns on its host, in particular damaging the myelin, a protective coating around the nerve fibers in the brain and spinal cord.
Eventually, these attacks can severely damage and destroy the nerves and myelin, interrupting the communication between the brain and body and leading to symptoms like numbness, trouble walking, and even blindness.
But not all patients’ symptoms manifest in the same way. People with “relapsing remitting” MS — or 85 percent of people with the disease — experience it in fits and starts: their symptoms show up for a few days or weeks, followed by weeks, months, or even years of remission.
For most patients with this version of the disease, those periods of remission get smaller over time and eventually disappear, moving them into another phase of the disease known as “secondary progressive MS.”
Loy and the other patients in the trial had relapsing-remitting MS. Loy had tried medication, but it didn’t help.
Burt told her the best she could hope for from the stem cell transplant was that her symptoms wouldn’t worsen. “I didn’t really expect all of these improvements. I went into it thinking, ‘If I at least don’t get worse from this point, that’ll be okay,’” she said. “So all the improvements have been totally unexpected but a nice surprise, that’s for sure.”
How stem cells rebuilt Loy’s immune system
The road to Loy’s stem cell transplant wasn’t straightforward. She found out about the approach a couple of years after her diagnosis, and contacted a hospital in Seattle to inquire about another similar study in 2010. “They weren’t taking new patients, but they told me there’s this guy in Chicago I might look into,” she said.
That guy was Burt, at Northwestern. So she went to meet him in 2010 and found out she qualified for his study. Instead of a treatment at first, she was randomly assigned to the control group.
Within two years, though, her MS symptoms worsened. Burt asked her to come back to Chicago to assess her disability, and determined she could transfer over to the treatment group. In 2012, she traveled to Chicago for a transplant.
The treatment involved four major steps: Doctors first put Loy through a short course of chemotherapy to stimulate the production of hematopoietic stem cells, which are the cells responsible for regenerating the immune system. They then hooked her up to a machine that cycled through her blood to collect the stem cells, which were frozen. Another higher dose of chemo wiped out Loy’s immune system.
“I had a hard time with the chemo,” Loy recalls. “It made me really, really sick and pretty miserable-feeling — nausea, vomiting.”
Then her stem cells were thawed and transplanted back into her body, just like a blood transfusion. Loy was so tired from the chemo that she napped through the transfusion.
But then something amazing happened: Right after getting the transplant, Loy noticed her MS-related bladder symptoms had gone away. And with a year, all her other symptoms — fatigue, heat intolerance, numbness, nerve pain — improved or dissolved.
The only side effect from the treatment, she said, was temporary menopause during the chemo — but that also went away quickly and had no effect on her fertility. Common side effects in the other patients in the transplant group of the trial were infections (such as chest colds and urinary tract infections) and electrolyte disorders. No one died as a result of the transplant.
Not every MS patient will be eligible for this treatment
The study that gave Loy the chance to kick her MS into remission was an international, multi-center, blinded, randomized trial conducted at four centers: in Chicago, at the Sheffield Teaching Hospitals NHS Foundation Trust & University of Sheffield in England, at the University of Uppsala in Sweden, and at the University of São Paulo in Brazil. Patients were enrolled at each of these hospitals between 2005 and 2016 and followed up for at least one year to see whether their disease had progressed.
The study built on decades of basic research about MS, stem cells, and the immune system, including years of experience using the treatment in patients with blood and bone marrow cancers like leukemia and lymphoma. It also built on earlier research examining this approach to treating MS, such as a rigorous 2016 study out of Canada in which 70 percent of the 24 patients who received chemotherapy and stem cell bone marrow transplant saw the progression of their disease halted or reversed. Esteemed medical specialists at the time called that study a “miracle.”
“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, told me in 2016.
Recently, I circled back to a patient I’d profiled then, Jennifer Molson, who had a turnaround as miraculous as Loy’s — and she was still doing well, with no new MS symptoms. “I just walked up six stories in heels because we had a fire alarm,” she told me.
Previous studies, like the 2016 paper, had followed people with MS who got the treatment and shown similarly impressive results — but they lacked a control arm for comparison. And that’s what makes this new study different, said Harry Atkins, a stem cell transplant physician and scientist at the Ottawa Hospital in Canada who led the 2016 study.
“It’s the best evidence comparing stem cell transplants to standard therapy,” Atkins said. “This is one of the first pieces of proof that, yes, patients who have aggressive MS do better after a transplant than with the standard therapy.” (There was another randomized trial published a few years back, but it was marred with methodological problems that Burt’s paper overcame, Atkins said.)
The new study also focused on the most important outcome in MS: disease progression. “They’ve shown that in the conventionally treated arm of the study, those patients continue to deteriorate compared to the transplant patients — many of whom have stabilized or gotten better over the follow-up period.”
But the treatment isn’t for everyone, and there are important limitations to the study. Burt focused on the subset of patients with relapsing-remitting MS who had at least two flare-ups in the past year. “It’s clearly beneficial in those patients, but whether the risks and benefits balance out in patients with more conventional MS wasn’t addressed,” he said.
Another limitation is that since the study was designed, new MS drugs have come on the market. These drugs appear to be more effective than older drugs, Atkins said, and it’s possible they might compare favorably to transplants in a head-to-head study, but that hasn’t been done yet.
What’s more, in early studies of stem cell transplants for MS, 5 percent of patients died. In the past five to seven years, that mortality rate has dropped to 1 to 2 percent — particularly as the chemo regimens have become less toxic — “but it’s not zero,” said Atkins. “So that’s where this whole idea of matching the risk to the outcome or benefits we expect is important.”
So doctors don’t know whether that risk-benefit ratio makes sense in patients who have less aggressive forms of MS (meaning they have fewer relapses) or how soon after a diagnosis the treatment should be applied.
There’s also the problem of access. You can’t just go to a doctor’s office and get the treatment; while the chemo drugs used in the trial were all FDA-approved, there are few hospitals in the world with experience doing these treatments on MS patients. Patients typically need to be eligible for a clinical trial.
While’s Loy’s medical care was mostly paid for by her health insurance plan, that’s not true for all patients. And she had to pay out of pocket the estimated $10,000 to $20,000 in hotel and travel costs to Chicago — the kind of urban research hub that runs trials out of reach for many Americans.
“This study shows a broad benefit for patients,” Atkins added. “It opens up stem cell transplant to be a more widely applied treatment. But there are lots of other questions.”
The FDA warning letter
The FDA warning letter also raises many questions. University of Minnesota bioethicist Leigh Turner called it “an indictment” of the research Burt does.
The letter contains a long list of violations of the federal regulations that govern research involving humans. These include the failure to report deaths to the FDA in one study in a timely manner (Burt says this violation did not relate to the MS study but another lupus study), the failure to evaluate the side effects patients experienced and to report them to the FDA on time, and the failure to do interim analyses of study data, as promised in a study plan.
Burt said the letter focused on three clinical trials, including the new MS study and the lupus study, and that the issues uncovered by the health regulator were later resolved. He said he couldn’t go into more detail about a third study because it wasn’t yet published or peer-reviewed. He would not provide the unredacted letter to Vox, saying “it would very likely get me in trouble with the FDA.”
A spokesperson at JAMA said the journal didn’t know about the letter prior to publishing the study. And Turner wondered, if they had seen it, whether it would have changed their assessment of the study.
“The most charitable assessment of this list of violations is that Dr. Burt functioned as an alarmingly sloppy and disorganized principal investigator,” he said. “A sharper-tongued critic would ask fundamental questions about Dr. Burt’s ability to conduct research involving human research participants.”