Alicia Ault

June 10, 2016

NATIONAL HARBOR, Maryland — All but 1 of the 24 patients with relapsing-remitting multiple sclerosis (MS) participating in a Canadian study were relapse-free for as long as 13 years after receiving autologous hemopoietic stem cell transplantation (aHSCT), new data show.

The results were presented at the Consortium of Multiple Sclerosis Centers (CMSC) 2016 Annual Meeting by lead investigator Mark S. Freedman, MD, professor of medicine, University of Ottawa, Ontario, Canada. They are also published online June 9 in The Lancet.

Before transplantation, the 24 patients in the Canadian MS Bone Marrow Transplantation Study experienced 167 relapses, or 1.2 per patient per year, said Dr Freedman. After transplant, there were no relapses in the 23 surviving patients, out to 13 years of follow-up.

However, 1 patient (4%), died of hepatic necrosis and sepsis attributed to the chemotherapy regimen.

The rationale behind the stem cell transplant was to remove the diseased immune system and replace it with a fully functional system that would not redevelop MS. Even with that aim, the trialists had designed experiments to monitor signs that the disease was returning. But that has not happened.

"I was completely skeptical that we'd be able to achieve this," Dr Freedman told Medscape Medical News in an interview during the CMSC meeting.

I was completely skeptical that we'd be able to achieve this. Dr Mark S. Freedman

But the results validate the goal set by these investigators. "If you're going to the extent of doing bone marrow transplant, you want to arrest the disease," he said. "You don't want to buy people 2 or 3 years of NEDA [no evidence of disease activity] and then have to take drugs again."

Mortality Rate "Unacceptably High"

In a linked commentary accompanying the Lancet publication, Jan Dörr, MD, from the NeuroCure Clinical Research Center, Charité-Universitätsmedizin, Berlin, Germany, called the results, "impressive and seem to outbalance any other available treatment for multiple sclerosis."

This trial is the first to show complete suppression of any inflammatory disease activity in every patient for a long period, Dr Dörr writes. "However, aHSCT has a poor safety profile, especially with regards to treatment-related mortality."

The study will probably not change the treatment for MS in the short term, he cautions, "mainly because the mortality rate will still be considered unacceptably high.

"Over the longer term [and] in view of the increasing popularity of using early aggressive treatment, there may be support for considering aHSCT less as a rescue therapy and more as a general treatment option, provided the different protocols are harmonised and optimised, the tolerability and safety profile can be further improved, and prognostic markers become available to identify patients at risk of poor prognosis in whom a potentially more hazardous treatment might be justified."

Michael K. Racke, MD, professor of neurology and neuroscience at Wexner Medical Center at the Ohio State University in Columbus, also called the results impressive. "They didn't see any evidence after transplant of any patients having MRI lesions," Dr Racke told Medscape Medical News. On the other hand, one patient died, "presumably as a complication off the transplant because it's a more aggressive regimen," he said.

Still, that doesn't rule transplant out as a treatment for some patients, said Dr Racke, noting that other MS therapies come with dangerous side effects. "We've gone to an era now where as we have higher efficacy treatments, they are also associated with higher risks," he said. With stem cell transplants, the issue will be to "balance the intensity of the regimens with the associated risks."

No one is advocating stem cell transplants for newly diagnosed patients, said Dr Racke, who is also an investigator in the HALT-MS (High-dose Immunosuppression and Autologous Stem Cell Transplantation for Poor Prognosis Multiple Sclerosis) trial. Researchers "are talking about patients who have already broken through several treatments," he said, adding that "those patients are already at risk for poor prognosis."

Robert Lisak, MD, president of the CMSC, also sounded a note of caution. For now, it appears that researchers cannot predict which patients will benefit from a transplant, Dr Lisak told Medscape Medical News. "The other thing is it's not clear the stem cells are doing anything," said Dr Lisak, Parker Webber Chair in Neurology at Wayne State University School of Medicine, Detroit, Michigan.

They may be having an immunomodulatory effect, but no published evidence shown that the transplants are stimulating oligodendrocytes to repopulate, Dr Lisak said.

Complete Myeloablation

The Canadian regimen was designed to completely wipe out the existing immune system, rather than just suppress it. The investigators wanted "to erase the immunological memory and knock out any of the cells that potentially could come back and harm," Dr Freedman said.

Fourteen women and 10 men were enrolled at three centers in Ottawa, Montreal, and Toronto, and the first transplant was completed in 2001. Eight patients with relapsing-remitting MS acted as controls and did not receive a transplant.

To be eligible, patients had to have a high probability of significant disease progression over 10 years, must have had multiple early relapses and/or sustained disability, a score of 3.0 to 6.0 on the Expanded Disability Status Scale (EDSS), ongoing active disease despite a year of treatment, and no significant medical comorbidities.

Patients in the study had significant disability. Eleven had an EDSS score of 6.0, and 5 had an EDSS score of 4.0. In 10 patients, one prior therapy had failed; in seven, two previous treatments; and in seven, three previous treatments.

The median age at transplant was 34 years, and the mean duration of disease was 6 years at the time of transplant.

For the procedure, stem cell mobilization was accomplished by giving patients cyclophosphamide (4.5 gm/m2) and recombinant human granulocyte colony-stimulating factor (10 μg/kg per day for 10 days). Cells were then collected via leukapheresis. Then the immune system was destroyed with a combination of busulfan (9.6 mg/kg intravenously), cyclophosphamide (200 mg/kg intravenously), rabbit antithymocyte globulin (5 mg/kg intravenously). The autologous CD34 selected cells were then infused.

The primary outcome of the study was MS activity–free survival at 3 years, as measured by relapses, new brain lesions, and sustained progression of EDSS scores. This occurred in 69.6% of patients after transplantation.

Most patients had active lesions on MRI coming in to the study, an average of 1.2 relapses per year. With 13 years of follow-up, no T2 lesion or enhancing lesion has been seen in any of the surviving 23 patients, said Dr Freedman.

Before the trial, most patients were on a rapid trajectory of increasing disability on the EDSS, he said. After transplant, some patients experienced some disease progression, but only early on. "After 2 years there was no more documented progression," said Dr Freedman. Eight (35%) of the 23 patients had a sustained improvement in their EDSS score at 7.5 years after treatment, the authors note.

"These clinical outcomes were mirrored by freedom from detectable new disease activity on 327 MRI images after haemopoietic stem-cell transplantation," the researchers write in the Lancet paper. The initial 24 MRI scans revealed 93 brain lesions, and after the treatment only one of the 327 scans showed a new lesion.

Most patients had a considerable increase in brain atrophy within 6 months of the transplant, but that was attributed to the chemotherapy, Dr Freedman said. One year later, brain atrophy began to slow, and by 5 years, "it was in the range of what we see in patients who don't have MS at all," he said.

Individuals in the study reported a significant change in their lives thanks to the transplant. At 3 years, six patients (37%) were able to reduce or stop receiving disability insurance and return to work or school, the researchers write. Five patients (31%) married or became engaged, and two had children using previously banked or donated gametes

One patient died, but the authors point out, "The overall survival of 95% in our study is similar to the 93% among 345 patients reported to the European Bone Marrow Transplant Registry and the 97% among 143 patients reported to the Consortium for International Blood and Marrow Transplantation Research."

Eight (33%) of the 24 patients had a moderate toxic effect and 14 (58%) patients had only a mild toxic effect related to transplantation, they note.

Not Ready for Prime Time?

Despite the positive results, Dr Freedman said many questions remain about the therapy. The optimal patient and best time for transplant have not been determined. It's not clear why some patients recover neurologic function but others do not, or whether the transplant regimen can be used for other MS disease states beside relapsing-remitting.

Many want to know whether the same results be achieved with less risk and toxicity, said Dr Freedman. He thinks that's possible. Since the original cohort was studied, he and his colleagues have performed transplants for "another 20 or so patients with better success even," he told Medscape Medical News. "We've really cleaned up the protocol and made it more safe."

Even with his success, he said that patients should be wary of stem cell claims, especially from things they find on the Internet. "I think everybody is very excited about the stem cell world. It has so much to offer," he said. "The problem is promoting this well before it's ripe and ready."

Dr Lisak said that, among neurologists, enthusiasm has in some cases gotten out of hand, but that others were perhaps not giving enough credence to the possibilities.

"You have two views," he told Medscape Medical News. "Overly skeptical that it has any future vs thinking that it has been proven to work, and neither is true."

The study was funded by the MS Society of Canada and Multiple Sclerosis Scientific Research Foundation. Dr Freedman has disclosed no relevant financial relationships. Dr Racke disclosed that he received consulting fees from Abbvie, EMD Serono, Genentech, Novartis, Roche, and Teva Pharmaceuticals and research support from the National Multiple Sclerosis Society. Dr Lisak has disclosed no relevant financial relationships.

Consortium of Multiple Sclerosis Centers (CMSC) 2016 Annual Meeting: Presented June 2, 2016.

Lancet. Published online June 9, 2016. Abstract Commentary

For more Medscape Neurology news, join us on Facebook and Twitter.


Comments on Medscape are moderated and should be professional in tone and on topic. You must declare any conflicts of interest related to your comments and responses. Please see our Commenting Guide for further information. We reserve the right to remove posts at our sole discretion.