Literature Review

DMTs, stem cell transplants both reduce disease progression in MS

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Although effective, DMTs and HSCT entail risks

The study by Brown et al. provides evidence that DMTs slow the appearance of persistent disabilities in patients with multiple sclerosis (MS), Harold Atkins, MD, wrote in an accompanying editorial (JAMA. 2019 Jan 15;321[2]:153-4). Although disease-modifying therapies (DMTs) may suppress clinical signs of disease activity for long periods in some patients, these therapies slow MS rather than halt it. DMTs require long-term administration and may cause intolerable side effects that impair patients’ quality of life. These therapies also may result in complications such as severe depression or progressive multifocal leukoencephalopathy.

“The study by Burt et al. ... provides a rigorous indication that HSCT [hematopoietic stem cell transplantation] can be an effective treatment for selected patients with MS,” Dr. Atkins said. Treating physicians, however, have concerns about this procedure, which is resource-intensive and “requires specialized medical and nursing expertise and dedicated hospital infrastructure to minimize its risks.” Many patients in the study had moderate to severe acute toxicity following treatment, and patient selection thus requires caution.

An important limitation of the study is that participants did not have access to alemtuzumab or ocrelizumab, which arguably are the most effective DMTs, Dr. Atkins said. The study began in 2005, when fewer DMTs were available. “The inclusion of patients who were less than optimally treated in the DMT group needs to be considered when interpreting the results of this study,” Dr. Atkins said.

Furthermore, Burt and colleagues studied patients with highly active MS, but “only a small proportion of the MS patient population exhibits this degree of activity,” he added. The results therefore may not be generalizable. Nevertheless, “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,” Dr. Atkins concluded.

Dr. Atkins is affiliated with the Ottawa Hospital Blood and Marrow Transplant Program at the University of Ottawa in Ontario. He reported no conflicts of interest.


 

FROM JAMA

Disease-modifying therapies give patients with relapsing-remitting multiple sclerosis a lower risk of developing secondary progressive disease that may only be topped in specific patients with highly active disease by the use of nonmyeloablative hematopoietic stem cell transplantation, according to findings from two studies published online Jan. 15 in JAMA.

Photo of a clipboard with the words multiple sclerosis lying next to pills, an injection needle, and stethoscope copyright Zerbor/Thinkstock

The first study found that interferon-beta, glatiramer acetate (Copaxone), fingolimod (Gilenya), natalizumab (Tysabri), and alemtuzumab (Lemtrada) are associated with a lower risk of conversion to secondary progressive MS, compared with no treatment. Initial treatment with the newer therapies provided a greater risk reduction, compared with initial treatment with interferon-beta or glatiramer acetate.

The second study, described as “the first randomized trial of HSCT [nonmyeloablative hematopoietic stem cell transplantation] in patients with relapsing-remitting MS,” suggests that HSCT prolongs the time to disease progression, compared with disease-modifying therapies (DMTs). It also suggests that HSCT can lead to clinical improvement.

DMTs reduced risk of conversion to secondary progressive MS

Few previous studies have examined the association between DMTs and the risk of conversion from relapsing-remitting MS to secondary progressive MS. Those that have analyzed this association have not used a validated definition of secondary progressive MS. J. William L. Brown, MD, of the University of Cambridge, England, and his colleagues used a validated definition of secondary progressive MS that was published in 2016 to investigate how DMTs affect the rate of conversion, compared with no treatment. The researchers also compared the risk reduction provided by fingolimod, alemtuzumab, or natalizumab with that provided by interferon-beta or glatiramer acetate.

Dr. Brown and his colleagues analyzed prospectively collected clinical data from an international observational cohort study called MSBase. Eligible participants had relapsing-remitting MS, the complete MSBase minimum data set, at least one Expanded Disability Status Scale (EDSS) score recorded within 6 months before baseline, and at least two EDSS scores recorded after baseline. Participants initiated a DMT or began clinical monitoring during 1988-2012. The population had a minimum follow-up duration of 4 years. Patients who stopped their initial therapy within 6 months and those participating in clinical trials were excluded.

The primary outcome was conversion to secondary progressive MS. Dr. Brown and his colleagues defined this outcome as an EDSS increase of 1 point for participants with a baseline EDSS score of 5.5 or less and as an increase of 0.5 points for participants with a baseline EDSS score higher than 5.5. This increase had to occur in the absence of relapses and be confirmed at a subsequent visit 3 or fewer months later. In addition, the increased EDSS score had to be 4 or more.

After excluding ineligible participants, the investigators matched 1,555 patients from 68 centers in 21 countries. Each therapy analyzed was associated with reduced risk of converting to secondary progressive MS, compared with no treatment. The hazard ratios for conversion were 0.71 for interferon-beta or glatiramer acetate, 0.37 for fingolimod, 0.61 for natalizumab, and 0.52 for alemtuzumab, compared with no treatment.

Treatment with interferon-beta or glatiramer acetate within 5 years of disease onset was associated with a reduced risk of conversion (HR, 0.77), compared with treatment later than 5 years after disease onset. Similarly, patients who escalated treatment from interferon-beta or glatiramer acetate to any of the other three DMTs within 5 years of disease onset had a significantly lower risk of conversion (HR, 0.76) than did those who escalated later. Furthermore, initial treatment with fingolimod, alemtuzumab, or natalizumab was associated with a significantly reduced risk of conversion (HR, 0.66), compared with initial treatment with interferon-beta or glatiramer acetate.

One of the study’s limitations is its observational design, which precludes the determination of causality, Dr. Brown and his colleagues said. In addition, functional score subcomponents of the EDSS were unavailable, which prevented the researchers from using the definition of secondary progressive MS with the best combination of sensitivity, specificity, and accuracy. Some analyses were limited by small numbers of patients, and the study did not evaluate the risks associated with DMTs. Nevertheless, “these findings, considered along with these therapies’ risks, may help inform decisions about DMT selection,” the authors concluded.

Financial support for this study was provided by the National Health and Medical Research Council of Australia and the University of Melbourne. Dr. Brown received a Next Generation Fellowship funded by the Grand Charity of the Freemasons and an MSBase 2017 Fellowship. Alemtuzumab studies conducted in Cambridge were supported by the National Institute for Health Research Cambridge Biomedical Research Centre and the MS Society UK.

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