Deborah Brauser

February 28, 2017

ORLANDO — Along with decreasing inflammatory activity in patients with severe multiple sclerosis (MS), immunoablation and autologous hematopoietic stem-cell transplantation (aHSCT) may reduce MS-related fatigue, new research suggests.

Further analysis from the 24-person Canadian aHSCT study showed improvements at each postprocedure checkpoint, including a nearly 30% reduction in fatigue scores and no progression in overall disability at 3 years.

However, one patient died of transplant-related complications and two patients dropped out at 18 months, highlighting that "this treatment requires utmost discretion," note the investigators.

"The difference between this particular transplant in comparison to some of the others coming out of Europe or the States is that we used quite a rigorous immunoablation regime," lead author, Gauruv Bose, MD, neurology resident at the University of Ottawa, Ontario, Canada, told Medscape Medical News.

"It's a serious procedure and should only be used in patients with very severe disease," he said. "We're finding that people are doing very well with this procedure but there is a high risk associated with it."

Dr Gauruv Bose

He added that they aren't saying the procedure should be done in order to reduce fatigue but that this appears to be an added bonus with the attempt to decrease disease progression.

Dr Bose presented the findings here at Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) 2017.

Fatigue One of the Worst MS Symptoms?

Earlier results from the Canadian aHSCT study, which were published in The Lancet last year, "demonstrated a complete halt of all detectable central nervous system inflammatory activity and stabilization or improvement in most patients" after the procedure, write the researchers.

For the current analysis, they wanted to assess treatment effect on heavy fatigue, a common occurrence in MS. In fact, fatigue is reported by up to 92% of patients with MS, "with over half of them saying it's one of their worst symptoms, in addition to motor disability," said Dr Bose.

"Fatigue is something that isn't as well measured, so we wanted to see if this type of transplant, which has such astounding impact on patient inflammation and lesions on MRI, has any role in patient fatigue as well," he added.

The single-arm Canadian aHSCT study included 24 patients aged 18 to 50 years (mean age, 33 years; 58% women) who were enrolled at three hospitals from 2000 to 2009. Of these, 50% had relapsing-remitting MS (RRMS).

At baseline they all had ongoing disease activity, even though they were using medication; they had scores of 3 to 6 on the Expanded Disability Status Scale (EDSS; mean score, 5.5).

"Autologous stem cell grants were mobilized with cyclophosphamide and filgrastim and further manipulated by immunomagnetic separation to purify CD34+ cells and purge any contaminating T-cells," report the investigators.

An intense conditioning period included 4 to 5 days of high-dose busulfan and another 3 days of cyclophosphamide, followed by antithymocyte globulin "and a standard post-transplant regimen of IVIG [intravenous immunoglobulin], antibiotics, anti-viral, and anti-fungal agents."

Significant Improvements

At baseline and at 6, 12, 18, 24, 30, and 36 months, the 40-question global Fatigue Impact Scale (FIS) was administered, along with the EDSS. FIS scores range from 0 to 160, with higher scores signifying more fatigue.

The mean global FIS score was 68.7 at baseline and decreased to 48.0 at 36 months (29.2% improvement; P < .04). Interestingly, 17% of the patients (all women) had overall FIS scores of 0 at the end of the follow-ups.

In addition, each subcategory of FIS improved significantly over time, including cognition (change, 26.8%), physical dimension (change, 33.0%), and social dimension (change, 17.9%).

Although this finding was not statistically significant, women had greater improvement after a-HSCT than men in overall (mean change, 37% vs 19%, respectively), cognitive (42% vs 6%) and social (28% vs 4%) scores; those with secondary progressive MS had greater improvements in all FIS dimensions than did those with RRMS.

The mean EDSS score was 5.0 at baseline and remained 4.73 at the 3-year time point, showing no significant progression.

The one death was from hepatoxicity and occurred at 2 months. The two discontinuations due to chronic cerebrospinal venous insufficiency occurred at 14 and 23 months.

Dr Bose reported that more analyses of Canadian aHSCT study are being done, including those on quality of life and MS functional scores during follow-up and possibly a cost analysis. In addition, the patients have been rolled into an extension period for another 3 years.

"Useful Observation"

When asked for comment, ACTRIMS President-Elect Jeffrey A. Cohen, MD, Cleveland Clinic Neurological Institute–Mellen Center, Ohio, told Medscape Medical News that "there's been an increasing interest" in aHSCT as a treatment for aggressive MS that hasn't responded to other therapies.

"This group previously reported very potent efficacy. There were some significant safety concerns but mostly they were front-loaded and decreased over time," he said.

Dr Jeffrey A. Cohen

"People are not going to pursue transplant to treat fatigue in MS, but this is a useful observation and underscores the potential efficacy," added Dr Cohen. "And it might give us some insights into the mechanisms that cause fatigue in MS."

He noted that one theory has been that fatigue is caused by ongoing, overactive inflammation. "So suppression of that could lead to less fatigue."

Or it could be caused by the increased work of carrying out activities of daily living. "So a functional benefit of the transplant, improving disability, may be what decreases fatigue," he speculated.

"I think it's an interesting observation and adds to the emerging picture about the potential utility for the approach," Dr Cohen concluded.

The Canadian aHSCT study was funded by the Multiple Sclerosis Scientific Research Foundation. Dr Bose has disclosed no relevant financial relationships.

Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) 2017. Abstract P029. Presented February 23, 2017.

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