Stem Cell Transplant Slows Progression in MS

January 16, 2019

In the first randomized trial in relapsing remitting multiple sclerosis (RRMS) comparing stem cell transplant with disease-modifying therapy, there was a dramatic reduction in disease progression for patients who underwent transplant.

The study enrolled 110 patients and had a mean follow-up of 2.8 years. Disease progression occurred in three patients who received stem cell transplant vs 34 patients who received drug therapy.

"There have been several series reports of MS patients treated with stem cell transplant — we have previously reported on 150 patients, the HALT phase 2 study reported on 30 patients, and Canadian and Swedish groups have also published," lead author Richard K. Burt, MD, Division of Immunotherapy, Northwestern University Feinberg School of Medicine, Chicago, Illinois, told Medscape Medical News.

"They all show similar results with a marked improvement in disease after stem cell transplant, but this is the first randomized data, and if anything, I would say this data is slightly better than the previous nonrandomized data," he said.

The study was published online January 15 in JAMA.

For the study, 110 patients with RRMS who had experienced at least two relapses while receiving disease-modifying therapy in the prior year and whose Expanded Disability Status Scale (EDSS) scores were from 2.0 to 6.0 were enrolled at four US, European, and South American centers. The patients were randomly assigned to receive either hematopoietic stem cell transplant or disease-modifying drug therapy of higher efficacy or of a different class than that taken during the previous year.

For the transplant, the immune system was first ablated with intravenous cyclophosphamide and antithymocyte globulin. Burt described the regime as "gentler" than others historically used for stem cell transplant.

"This is a relatively low-intensity regimen," he said. "It is not comparable to that used for cancer treatment. We do not destroy the bone marrow; we are just resetting the immune system. The treatment is directed to killing off the immune system for a short time, then we collect and reinfuse the stem cells — like a supportive blood product infusion."

The primary endpoint was time to disease progression, defined as an increase in EDSS score of 1.0 point or more after at least 1 year.

The median time to progression could not be calculated in the transplant group because of too few events; it was 24 months in the group that underwent drug treatment (hazard ratio [HR], 0.07; 95% confidence interval [CI], 0.02 - 0.24; P < .001).

During the first year, mean EDSS scores decreased (improved) from 3.38 to 2.36 in the transplant group and increased (worsened) from 3.31 to 3.98 in the group that underwent drug treatment (between-group mean difference, −1.7; P < .001).

Table. Proportion of Patients With Disease Progression Up to 5 Years

Timepoint Stem Cell Transplant (%) Drug Therapy (%)
1 year 1.92 24.5
2 years 1.92 54.5
3 years 5.19 62.5
4 years 9.71 71.2
5 years 9.71 75.3

Relapse rates showed a similar pattern, with 15% of the transplant group having had a relapse at 5 years compared with 85% of those treated with drug therapy. Stem cell transplant was also associated with improved MRI lesion load.

There were no deaths, and no patients who received stem cell transplant experienced nonhematopoietic grade 4 toxicities, such as myocardial infarction, sepsis, or other disabling or potentially life-threatening events.

Changing the Natural History

Asked whether he considered stem cell transplant a cure for MS, Burt said: "I don't use that word because we don't have sufficient long-term data to say that. If we can show no evidence of disease activity at 15 to 20 years, then we may be able to able to talk about the possibility of a cure, but it is far too premature for that at present. But from our results, I think we can certainly say that it changes the natural history of the disease."

He estimated that stem cell transplant may be suitable for about 15% of patients with RRMS — those patients whose disease follows an aggressive course with frequent relapses despite receiving disease-modifying treatment.

He does not recommend stem cell transplant for patients with newly diagnosed MS, even if they are having frequent relapses. "I would always try drug therapy first. But if they fail on a couple of drugs early on, then they could well be a candidate for stem cell transplant."

At the other end of the spectrum, he also does not recommend stem cell transplant for patients whose disease has reached the progressive stage. "It's too late then. The damage has already been done," he said. "There would be limited benefit."

Burt noted that although many neurologists are cautious about referring patients for such stem cell transplant, patients are keen to be considered for the procedure.

"Neurologists tend to think in terms of years of life lived, but patients tend to focus more on quality of life," Burt said. "Yes, there is a risk associated with this procedure, but many are willing to take a risk to get better quality of life, and we showed a much greater improvement in quality of life with stem cell transplant in this study."

Mean quality-of-life scores on the Short Form 36 increased from 50.5 at baseline to 70.3 at 1 year in the transplant group, whereas in the group that received drug treatment, the mean score decreased from 49.5 at baseline to 46.1 at 1 year, giving a between group difference of 23.

Burt pointed out that another advantage of stem cell transplant is that it is much cheaper than lifetime drug therapy. "There is a large up-front cost, but after that, most patients need no more therapy, so long-term costs will be less."

But he cautioned: "This is a powerful therapy, and we have to be cautious how we use it. We have to select patients carefully."

He said he would also not recommend the procedure for patients who had comorbidities, because for these patients, the up-front risk would be higher. "And while we did not specify age, younger patients tended to show greater benefits."

He also stressed it was important for patients to undergo treatment at a recognized center experienced in the practice. "There are several centers now doing this for MS in the US, Canada, and Europe, and as more data like this is published, more centers will come on board."

In an accompanying editorial, Harold Atkins, MD, University of Ottawa, Canada, says the study shows that hematopoietic stem cell transplant "is a more effective treatment for patients with highly active relapsing MS than conventional DMT [disease-modifying therapy] and can be performed with tolerable toxicities."

However, he emphasizes the need for caution in patient selection and safety procedures. He points out that although the safety results were good in this trial, deaths have been reported using the same procedure for patients with other autoimmune diseases.

"Hematopoietic stem cell transplantation is a resource-intensive treatment and requires specialized medical and nursing expertise and dedicated hospital infrastructure to minimize its risks," Atkins states.

"An increase in the number of patients with MS undergoing HSCT [hematopoietic stem cell transplantation], based on the findings in this study, might be met with limitations in current transplant resources," he notes. In addition, he writes that specific training programs and resource development plans will need to be designed for the broader adoption of the procedure for MS.

Atkins points out some limitations of the study, including the fact that it did not compare stem cell transplant with the most effective disease-modifying therapy now available. The study did not allow treatment with alemtuzumab (multiple brands), and oral cladribine and ocrelizumab (Ocrevus, Genentech) were not commercially available during the study period.

But he concludes, "Even with the limitations of the trial, the results support a role for HSCT delivered at centers that are experienced in the clinical care of patients with highly active MS."

The study was funded with support from the Danhakl family, the Cumming Foundation, the McNamara Purcell Foundation, Morgan Stanley, and the National Institute for Health Research Sheffield Clinical Research Facility. There was no industry or pharmaceutical support. Dr Burt has disclosed no relevant financial relationships. Financial disclosures for Dr Burt's coauthors are listed in the original article. Dr Atkins has disclosed no relevant financial relationships.

JAMA. Published online January 15, 2019. Abstract, Editorial

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